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.

Preparation and Evaluation of Charge Reversal Solid Lipid Nanoparticles.

The aim of this study was to design and investigate solid lipid nanoparticles (SLN) providing an intestinal alkaline phosphatase (IAP) triggered charge reversion. SLN containing the monophosphate ester bearing surfactant P-PEG-9-lauryl ether and the cationic surfactant benzalkonium chloride were prepared via step-wise hot microemulsion method enabling P-PEG-9-lauryl ether to accumulate the phosphate moiety on the surface of the particles accessible for IAP. Charge reversal SLN were characterized in vitro and ex vivo. SLN containing 10% of P-PEG-9-lauryl ether and 1% of cationic surfactant displayed a z-average of 92 nm and a PDI of 0.33 remaining stable over one year stored at 2-8 °C. An enzyme induced charge reversion from -18.4 mV to +16.5 mV correlated with the cleavage of 82% of the incorporated phosphate. SLN maintained their size during charge reversion, as no significant difference in z-average was observed. Mucin interaction studies revealed a higher interaction between SLN and mucins in the presence of IAP causing an increase in z-average from 190 nm to 2500 nm as well as a decrease in zeta potential from -26 mV to -17 mV. No significant change in z-average and zeta potential was observed when IAP was absent indicating lower mucin interaction of negatively charged particles. In contrast, higher interaction with cell membrane was evidenced by 85% hemolysis when SLN were pretreated with IAP, whereas control SLN without IAP resulted in 16% hemolysis. To investigate the phosphate cleavage by membrane bound IAP, SLN were incubated on excised rat intestinal mucosa and a significant higher release of phosphate was observed in comparison to samples treated with an enzyme inhibitor. Charge reversal SLN might be promising drug delivery systems for alkaline phosphatase bearing membranes that are covered by a mucus gel layer such as the intestine.

Lysine-Based Biodegradable Surfactants: Increasing the Lipophilicity of Insulin by Hydrophobic Ion Paring.

AIM: The aim of this study was to evaluate biodegradable cationic surfactants based on lysine. METHODS: Lysine was esterified with cholesterol, oleyl alcohol and 1-decanol resulting in cholesteryl lysinate (CL), oleyl lysinate (OL) and decyl lysinate (DL). Esters were investigated regarding their log Dn-octanol/water, critical micelle concentration (CMC) and biodegradability. Hemolytic potential of CL, OL, DL and the already established hexadecyl lysinate (HL) was determined and complexes with insulin (INS) were formed by hydrophobic ion pairing (HIP). Lipophilic characteristics of ion-pairs were examined by analyzing their log Pn-butanol/water. RESULTS: Successful synthesis of CL, OL and DL was confirmed by IR, NMR and MS. Log D analysis revealed amphiphilic properties for the esters and a CMC of 0.01 mM, 2.0 mM and 6.0 mM was found for CL, OL and DL, respectively. Biodegradability was proven, as over 99% of OL and DL were degraded by isolated enzymes within 30 min and after 3 h 97% of CL was cleaved by membrane bound enzymes. OL as well as DL displayed no hemolytic effect and for CL cytotoxicity was significantly reduced in comparison to HL. INS/CL complex exhibited highest lipophilicity. CONCLUSION: Cholesterol-amino acid based surfactants seem to be promising agents for HIP.