Methacrylate-Copolymer Eudragit EPO as a Solubility-Enabling Excipient for Anionic Drugs: Investigation of Drug Solubility, Intestinal Permeability, and Their Interplay

Abstract

The purpose of this work was to investigate the use of the dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) in oral solubility-enabling formulations for anionic lipophilic drugs, aiming to guide optional formulation design and maximize oral bioavailability. We have studied the solubility, the permeability, and their interplay, using the low-solubility nonsteroidal anti-inflammatory drug mefenamic acid as a model drug. Then, we studied the biorelevant solubility enhancement of mefenamic acid from EPO-based formulations throughout the gastrointestinal tract (GIT), using the pH-dilution dissolution method. EPO allowed a profound and linear solubility increase of mefenamic acid, from 10 μg/mL without EPO to 9.41 mg/mL in the presence of 7.5% EPO (∼940-fold; 37 °C); however, a concomitant decrease of the drug permeability was obtained, both in vitro and in vivo in rats, indicating a solubility−permeability trade-off. In the absence of an excipient, the unstirred water layer (UWL) adjacent to the GI membrane was found to hinder the permeability of the drug, accounting for this UWL effect and revealing that the true membrane permeability allowed good prediction of the solubility−permeability trade-off as a function of EPO level using a direct relationship between the increased solubility afforded by a given EPO level and the consequent decreased permeability. Biorelevant dissolution studies revealed that EPO levels of 0.05 and 0.1% were insufficient to dissolve mefenamic acid dose during the entire dissolution time course, whereas 0.5 and 1% EPO allowed complete solubility with no drug precipitation. In conclusion, EPO may serve as a potent solubility-enabling excipient for BCS class II/IV acidic drugs; however, it should be used carefully. It is prudent to use the minimal EPO amounts just sufficient to dissolve the drug dose throughout the GIT and not more than that. Excess amounts of EPO provide no solubility gain and cause further permeability loss, jeopardizing the overall success of the formulation. This work may help the formulator to hit the optimal solubility−permeability balance, maximizing the oral bioavailability afforded by the formulation.

Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies

“…It should be noted that some solubility-enabling formulations may simultaneously decrease the drug's permeability, and overall absorption may be unimproved. This solubilitypermeability interplay was shown for formulations based on cyclodextrins [162][163][164], surfactants [165], cosolvents [166], and hydrotropes [167,168]. In amorphous solid dispersions (ASD), on the other hand, the solubility increases (via supersaturation) with unchanged permeability, and thus, ASD may be preferred over other carrier systems, given supersaturation can be achieved and maintained for sufficient time [169].…”

Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

“…Through rational selection of polymers, additional benefits, in terms of the drug's oral bioavailability, could be achieved through the formation of the drug-rich metastable phase; however, a plateau may be reached when an excess amount was used. For example, in relation to the Eudragit ® E, the equilibrium solubilities of bezfibrate, indomethacin, piroxicam, and warfarin were increased proportionally with the increases in the polymer concentration up to 2% (w/w) until a plateau is reached [141,142]. Besides, when a strong interaction is formed between drug and polymeric excipients, such as ionic interaction, the solubility-permeability tradeoff occurs [143,144].…”

Additives for Kinetic Hydrate Inhibitor Formulations To Avoid Polymer Fouling at High Injection Temperatures: Part 1. A Review of Possible Methods

“…One example is a class of terpolymers mostly consisting of three methacrylate monomers: butyl methacrylate, 2-dimethylaminoethyl methacrylate, and methyl methacrylate (see Figure ). , The polymer by itself is soluble in water or brines at pH values of 5–6 or less. This polymer is particularly helpful at solubilization acidic drugs via ionic interactions (e.g., protonated amine moieties) and by multiple hydrophobic contacts with the polymeric side chains. , A few nonacidic hydrophobic drugs have also been solubilized using this polymer. , Therefore, by judicial choice of the correct functional groups, it should be possible to help solubilize KHIs, which are predominantly polyamides.…”

“…One example is a class of terpolymers mostly consisting of three methacrylate monomers: butyl methacrylate, 2-dimethylaminoethyl methacrylate, and methyl methacrylate (see Figure 9). 123,124 The polymer by itself is soluble in water or brines at pH values of 5−6 or less. This polymer is particularly helpful at solubilization acidic drugs via ionic interactions (e.g., protonated amine moieties) and by multiple hydrophobic contacts with the polymeric side chains.…”