Lipophilic salts of poorly soluble compounds to enable high-dose lipidic SEDDS formulations in drug discovery

Abstract

Self-emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water-soluble drugs to improve exposure in high-dose pharmacokinetic (PK) and toxicokinetic (TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophilic counterions to prepare lipophilic salts of drugs. SEDDS formulations of two lipophilic salts-atazanavir-2-naphthalene sulfonic acid (ATV-2-NSA) and atazanavir-dioctyl sulfosuccinic acid (ATV-Doc)-were characterized and their performance compared to atazanavir (ATV) free base formulated as an aqueous crystalline suspension, an organic solution, and a SEDDS suspension, using in vitro, in vivo, and in silico methods. ATV-2-NSA exhibited ∼6-fold increased solubility in a SEDDS vehicle, allowing emulsion dosing at 12mg/mL. In rat PK studies at 60mg/kg, the ATV-2-NSA SEDDS emulsion had comparable exposure to the free-base solution, but with less variability, and had better exposure at high dose than aqueous suspensions of ATV free base. Trends in dose-dependent exposure for various formulations were consistent with GastroPlus™ modeling. Results suggest use of lipophilic salts is a valuable approach for delivering poorly soluble compounds at high doses in Discovery.

API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility

“…2h had the lowest melting point in this series, highlighting the ability of the docusate to disrupt crystal packing. 17,18,47,52,53 Only the docusate salt lacked birefringence As all of the third series of cinnarizine compounds were miscible, only one IL is shown. Lrefers to linear alkyl sulfates.…”

Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure

“…A potential limitation of the utility of LBFs is low drug loading in the formulation such that the therapeutic drug dose cannot be solubilized in a volume of lipid that can be filled into one or two capsules [6]. The use of ionic liquid forms of drugs can increase drug loading in LBFs [6,[32][33][34], but whether solubilization is maintained at these higher drug loads as the formulation is dispersed and digested is not well understood. Similarly, the relationship between formulation type and composition and the fate of an API-IL during formulation digestion has not been widely explored.…”

Sistemas de entrega de fármacos autoemulsificables: una plataforma de desarrollo alternativa para la industria farmacéutica colombiana

“…El SCB se basa en estos dos factores para agrupar los principios activos en cuatro categorías principales [61], como se muestra en la figura 6. Inicialmente, los SEDDS surgieron como una alternativa ante la necesidad de superar los inconvenientes en la formulación de principios activos cuya baja solubilidad acuosa conlleva a una absorción gastrointestinal limitada por la disolución y a su vez en una biodisponibilidad baja y variable [62,63]. Generalmente, estos compuestos se encuentran categorizados como clase II o clase IV en el SCB [64,65].…”

“…Se expresa constitutivamente en una variedad de tejidos donde funciona como moduladora de la salida de una amplia variedad de sustratos a través de la membrana celular [97]. En la membrana del epitelio intestinal la P-gp es capaz de reconocer como sustrato a muchos principios activos (por ejemplo, Paclitaxel [58], Edaravona [129], Atazanavir [62], Darunavir [51], Emodina [142], etc.) lo que da como resultado su salida de regreso hacia el lumen intestinal, reduciendo significativamente su biodisponibilidad.…”

“…Mediante la modificación molecular de los principios activos se puede alterar sus propiedades fisicoquímicas con la finalidad de aumentar su lipofilicidad y ser incorporados en SEDDS para mejorar su biodisponibilidad mediante la estimulación del transporte linfático para su absorción [87]. El uso de contraiones lipofílicos (emparejamiento iónico) [62,146] y la esterificación de los principios activos (profármacos) [147,148] permiten aumentar su solubilidad en la fase oleosa de los SEDDS con el objetivo de promover su absorción sistémica. En particular, el emparejamiento iónico es una alternativa muy atractiva para la administración de péptidos orales debido al extenso metabolismo de primer paso hepático al que son sometidos al ser administrados por la vía oral [149,150].…”