Interfacial Adsorption of Polymers and Surfactants: Implications for the Properties of Disperse Systems of Pharmaceutical Interest

Duro, R.J.; Souto, C.; Gómez-Amoza, J.L.; Martínez‐Pacheco, Ramón; Concheiro, Angel

doi:10.1081/ddc-100102244

Cited by 66 publications

(41 citation statements)

References 120 publications

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“…The rate of adsorption of small molecular excipients onto drug particles has been shown to be faster than that of large molecular excipients. 19,38) Hence, it was thought that Tween 80, which has a molecular weight approximately one-tenth that of HPMC (3 cP), contributed to stabilizing particles during the milling process by its rapid adsorption onto the drug particles, which resulted in the formation of nanosuspensions. On the other hand, HPMC (3 cP) was effective for stabilizing nanoparticles during storage.…”

Section: Discussionmentioning

confidence: 99%

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro/in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds

Komasaka¹,

Fujimura

Tagawa

et al. 2014

Chem. Pharm. Bull.

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The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)-0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher C max and 4.4 and 1.6 times higher area under the concentration-time curve from 0-24 h (AUC 0-24 h ) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.Key words nanosuspension; toxicology study; wet media milling; mixer mill; rotation revolution mixer; oral absorptionThe proportion of poorly water-soluble compounds among drug candidates in the discovery stage has been increasing for the past decade.1,2) Because of the poor solubility of these compounds, sufficient oral absorption is not observed in animal studies, and the evaluation of pharmacological and toxicological profiles of drug candidates has therefore become more challenging. In particular, this problem frequently occurs in toxicology studies that require high oral absorption and is now a common problem in pharmaceutical companies.3)The application of formulation technologies such as solubilizing excipients, 4) solid dispersions, 5,6) and nanosuspensions 7,8) is an attractive strategy for improving oral absorption of poorly water-soluble compounds. However, the use of solubilizing excipients and solid dispersions for toxicology studies in the discovery stage is practically limited because of toxicities of excipients and amount of drug substances for formulation studies, respectively. On the other hand, nanosuspensions have the potential to solve these problems. Because nanosuspensions can be prepared as highly drug-loaded formulations with small quantities of excipients, adverse effects caused by excipients can be avoided. 9) In addition, n...

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Section: Discussionmentioning

confidence: 99%

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro/in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds

Komasaka¹,

Fujimura

Tagawa

et al. 2014

Chem. Pharm. Bull.

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“…19 Supporting evidence for these scenarios can be found in studies of polymer/polymer and polymer/surfactant systems. 20,21 Based on our experimental data, we can speculate that when bile salts are present in monomeric form in seeded solutions (binary-L), both bile salts are adsorbed. A different effectiveness of each bile salt at the crystal surface in terms of preventing addition of solute molecules results in the observed intermediate inhibition effect relative to the individual bile salts.…”

Section: Binary and Ternary Bile Salt Systemsmentioning

confidence: 99%

Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

Ormes

Lowinger

et al. 2017

CrystEngComm

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Bile salts are endogenous surfactants present in the human gastrointestinal tract in the form of mixed micelles that also contain phospholipids. Due to the inevitable encounter of oral drug formulations with bile salts, it is important to understand the impact of bile salts on the crystallization tendency of poorly soluble compounds that form supersaturated solutions in vivo in order to maximize oral drug absorption. Although there has been an increasing number of studies focusing on the role of individual bile salts on drug crystallization, the effects of mixed micelles and biorelevant media composition on crystallization kinetics have only been studied to a limited extent. In this study, we evaluated the ability of binary and ternary bile salt combinations to maintain supersaturated aqueous solutions of telaprevir. Crystallization kinetics were also compared in more complex media that also contained the phospholipid, lecithin. These included fasted state simulated intestinal fluid (FaSSIF) (a widely used medium for formulation testing which contains a single bile salt, sodium taurocholate), and media that contained several endogenous bile salts. Finally, the combined effects of a polymer, hydroxypropylmethyl cellulose acetate succinate, and the testing media on crystallization kinetics were evaluated to provide insights into supersaturation formulation design. Solution bile salt composition was found to significantly influence crystallization kinetics. However, the presence of the polymer increased induction times sufficiently that differences between media were minimized. This study suggests that when evaluating the crystallization kinetics of systems with a propensity to undergo supersaturation in vivo, attention should be paid to selecting biorelevant media.

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“…This consists of 2 terminal hydroxyl groups PEO (poly(ethylene oxide)) and a central PPO (poly(propylene oxide)) chain. 110 The chemical structure is schematized in Figure 2.…”

Section: Dispersion and Individualization Of Swnts In Aqueousmentioning

confidence: 99%

“…110 In SDBS, charge repulsion is the dominating factor impeding SWNTs aggregation. 58 In Pluronic F98 hydrophobic interactions 116,182,183 link sidewalls with the polymer molecules.…”

Section: Diameter Separation 321 Effect Of Bundling and Surfactanmentioning

confidence: 99%

Density Gradient Ultracentrifugation of Nanotubes: Interplay of Bundling and Surfactants Encapsulation

et al. 2010

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Density gradient ultracentrifugation (DGU) has emerged as a promising tool to prepare chirality enriched nanotube samples. Here, we assess the performance of different surfactants for DGU. Bile salts (e.g., sodium cholate (SC), sodium deoxycholate (SDC), and sodium taurodeoxycholate (TDC)) are more effective in individualizing Single Wall Carbon Nanotubes (SWNTs) compared to linear chain surfactants (e.g., sodium dodecylbenzene sulfonate (SDBS) and sodium dodecylsulfate (SDS)) and better suited for DGU. Using SC, a narrower diameter distribution (0.69-0.81 nm) is achieved through a single DGU step on CoMoCAT tubes, when compared to SDC and TDC (0.69-0.89 nm). No selectivity is obtained using SDBS, due to its ineffectiveness in debundling. We assign the reduced selectivity of dihydroxy bile salts (SDC and TDC) in comparison with trihydroxy SC to the formation of secondary micelles. This is determined by the number and position of hydroxyl (-OH) groups on the R-side of the steroid backbone. We also enrich CoMoCAT SWNTs in the 0.84-0.92 nm range using the Pluronic F98 triblock copolymer. Mixtures of bile salts (SC) and linear chain surfactants (SDS) are used to enrich metallic and semiconducting laser-ablation grown SWNTs. We demonstrate enrichment of a single chirality, (6,5), combining diameter and metallic versus semiconducting separation on CoMoCAT samples.

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Interfacial Adsorption of Polymers and Surfactants: Implications for the Properties of Disperse Systems of Pharmaceutical Interest

Cited by 66 publications

References 120 publications

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

Density Gradient Ultracentrifugation of Nanotubes: Interplay of Bundling and Surfactants Encapsulation

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