Counterion optimization for hydrophobic ion pairing (HIP): Unraveling the key factors.

In the present study, various surfactants were combined with insulin (INS), bovine serum albumin (BSA) and horseradish peroxidase (HRP) via hydrophobic ion pairing to increase lipophilicity and facilitate incorporation into self-emulsifying drug delivery systems (SEDDS). Lipophilicity of model proteins was successfully increased, achieving log Dn-butanol/water values up to 3.5 (INS), 3.2 (BSA) and 1.2 (HRP). Hereby, key factors responsible for complex formation were identified. In particular, surfactants with branched alkyl chains or chain lengths greater than C12 showed favorable properties for hydrophobic ion pairs (HIP). Furthermore, flexibility of the carbon chain resulted in higher lipophilicity and suitability of polar head groups of surfactants for HIP decreased in the rank order sulfonate > sulfosuccinate > phosphate = sulfate > carbonate > phosphonic acids = sulfobetaines. Stability studies of formed HIP complexes were performed in various gastrointestinal fluids and their solubility was determined in commonly used SEDDS excipients. Formed complexes were stable in simulated gastrointestinal fluids and could be incorporated into SEDDS formulations (C1: 10% caprylocaproyl polyoxyl-8 glycerides, 20% PEG-40 hydrogenated castor oil, 20% medium-chain triglycerides, 50% n-butanol; C2: 10% caprylocaproyl polyoxyl-8 glycerides, 20% PEG-40 hydrogenated castor oil, 20% medium-chain triglycerides, 40% n-butanol, 10% 1,2-butanediol), resulting in suitable payloads of up to 11.9 mg/ml for INS, 1.0 mg/ml for BSA and 1.6 mg/ml for HRP.

Self-emulsifying drug delivery systems (SEDDS): In vivo-proof of concept for oral delivery of insulin glargine.

In spite of recent progress made in the field of peptide and protein delivery, oral administration of insulin and similar drugs remains a challenge. In this study, lipophilicity of insulin glargine (IG) was successfully increased via hydrophobic ion pairing (HIP) with sodium octadecyl sulfate to enable incorporation into self-emulsifying drug delivery systems (SEDDS). Two SEDDS formulations (F1: 20% Labrasol®ALF, 30% polysorbate 80, 10% Croduret 50, 20% oleyl alcohol, 20% Maisine® CC; F2: 30% Labrasol®ALF, 20% polysorbate 80, 30% Kolliphor® HS 15, 20% Plurol® oleique CC 497) were developed and loaded with the IG-HIP complex. Further experiments confirmed increased lipophilicity of the complex, achieving LogDSEDDS/release medium values of 2.5 (F1) and 2.4 (F2) and ensuring sufficient amounts of IG within the droplets after dilution. Toxicological assays indicated minor toxicity and no toxicity inherent to the incorporated IG-HIP complex. SEDDS formulations F1 and F2 were administered to rats via oral gavage and resulted in a bioavailability of 0.55% and 0.44%, corresponding to a 7.7-fold and 6.2-fold increased bioavailability, respectively. Thus, incorporation of complexed insulin glargine into SEDDS formulations provides a promising approach to facilitate its oral absorption.

Hydrophobic Ion Pairing of Small Molecules: How to Minimize Premature Drug Release from SEDDS and Reach the Absorption Membrane in Intact Form.

The present work aimed to form hydrophobic ion pairs (HIPs) of a small molecule remaining inside the oily droplets of SEDDS to a high extent. HIPs of ethacridine and various surfactants classified by functional groups of phosphates, sulfates, and sulfonates were formed and precipitation efficiency, log Dn-octanol/water, and solubility in different excipients were investigated. Most lipophilic HIPs were incorporated into SEDDS and evaluated regarding drug release. Docusate HIPs showed the highest increase in lipophilicity with a precipitation efficiency of 100%, a log Dn-octanol/water of 2.66 and a solubility of 132 mg/mL in n-octanol, 123 mg/mL in oleyl alcohol, and 40 mg/mL in medium chain triglycerides. Docusate HIPs were incorporated into three SEDDS of increasing lipophilicity (F1 < F2 < F3) based on medium chain triglycerides, oleyl alcohol, Kolliphor EL, and Tween 80 (F1: 1 + 5 + 2 + 2; F2: 3 + 3 + 2 + 2; F3: 5 + 1 + 4 + 0). Highest achievable payloads ranged from 74.49 mg/mL (F3) to 97.13 mg/mL (F1) and log DSEDDS/RM increased by at least 7.5 units (4.99, F1). Drug release studies via the diffusion membrane method confirmed minor release of docusate HIPs from all SEDDS (<2.7% within 4 h). In conclusion, highly lipophilic HIPs remain inside the oily phase of SEDDS and likely reach the absorption membrane in intact form.

Surface design of nanocarriers: Key to more efficient oral drug delivery systems.

As nanocarriers (NCs) can improve the solubility of drugs, prevent their degradation by gastrointestinal (GI) enzymes and promote their transport across the mucus gel layer and absorption membrane, the oral bioavailability of these drugs can be substantially enhanced. All these properties of NCs including self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, polymeric nanoparticles, inorganic nanoparticles and polymeric micelles depend mainly on their surface chemistry. In particular, interaction with food, digestive enzymes, bile salts and electrolytes, diffusion behaviour across the mucus gel layer and fate on the absorption membrane are determined by their surface. Bioinert surfaces limiting interactions with gastrointestinal fluid and content as well as with mucus, adhesive surfaces providing an intimate contact with the GI mucosa and absorption enhancing surfaces can be designed. Furthermore, charge converting surfaces shifting their zeta potential from negative to positive directly at the absorption membrane and surfaces providing a targeted drug release are advantageous. In addition to these passive surfaces, even active surfaces cleaving mucus glycoproteins on their way through the mucus gel layer can be created. Within this review, we provide an overview on these different surfaces and discuss their impact on the performance of NCs in the GI tract.

Oral delivery of calcitonin-ion pairs: In vivo proof of concept for a highly lipophilic counterion.

Hydrophobic ion pairing and subsequent incorporation into self-emulsifying drug delivery systems (SEDDS) is a promising strategy to orally deliver hydrophilic macromolecular drugs. Within this study, hydrophobic ion pairs (HIP) between salmon calcitonin (sCT) and highly lipophilic sulfosuccinate counterions were formed and compared to frequently applied commercially available counterions. Bis(isotridecyl) sulfosuccinate resulted in HIPs of the highest lipophilicity and in significantly higher solubility in lipophilic co-solvents. Thus, bis(isotridecyl) sulfosuccinate allowed efficient solubilization of sCT in a SEDDS preconcentrate based on a lipophilic co-solvent and an indigestible lipid, but omitting hydrophilic co-solvents. In addition to the increased solubility in the lipidic matrix, markedly reduced dissociation in biorelevant media resulted in high distribution coefficients between oil droplet and FaSSGF or FaSSIF (logD) of 2.98 ± 0.12 or 2.77 ± 0.14, respectively. The composition of the lipidic matrix preserved integrity of the oil droplets after emulsification and subsequent lipolysis, allowing to fully exploit the potential of the HIP attributed to the high logD. Oral administration of the HIP-loaded SEDDS resulted in an excellent relative pharmacological activity of 13.8 ± 5.6 % measured as hypocalcaemic effect in rats.

Charge-reversal nanoemulsions: A systematic investigation of phosphorylated PEG-based surfactants.

Surfactants bearing monophosphate esters with PEG of increasing chain length and different lipophilic tail structures were investigated to improve the effectiveness of enzyme triggered charge-converting nanoemulsions. The surfactants PEG-8-stearate, PEG-22-tocopheryl succinate (TPGS), PEG-3-oleate, PEG-9-oleate and PEG-9-lauryl ether were phosphorylated and incorporated in a self-emulsifying drug delivery system (SEDDS) exhibiting a defined PEG corona. To provide a positive zeta potential increasing amounts of the cationic surfactant benzalkonium chloride (BA) were incorporated. The effect of these PEG monophosphate esters (P-PEG-surfactants) was evaluated based on enzyme induced phosphate release and change in zeta potential. Significant enzyme induced charge conversion was observed for all P-PEG-surfactants, showing shifts from Δ3 mV to Δ31 mV. Surfactants comprising the shortest and longest PEG chain showed similar amplitudes (P-PEG-3-oleate: Δ11.9 mV; P-PEG-22-TPGS Δ10.2 mV), whereas P-PEG-8-stearate, P-PEG-9-oleate and P-PEG-9-lauryl ether bearing similarly long PEG chains but different lipophilic tail structures resulted in pronounced differences in amplitudes of Δ10.3 mV, Δ14.5 mV and Δ18.1 mV, respectively. Furthermore, an indirect correlation between the lipophilicity of P-PEG-surfactants and the obtained charge-reversing effect was observed. With the exception of P-PEG-lauryl ether, this charge-reversal effect decreased with increasing BA concentrations. In conclusion, the enzyme induced amplitude of charge conversion of P-PEG-surfactants depends to a high extent on their lipophilic tail structure. Based on this knowledge potent charge-reversal nanoemulsions can be designed.