Nor-LAAM loaded PLGA microparticles for treating opioid use disorder.

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 µm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

Construction of injectable micron-sized polymorphic vesicles for prolonged local anesthesia with weekly sustained release of ropivacaine.

Currently, to overcome the short half-life of the local anesthetic ropivacaine, drug delivery systems such as nanoparticles and liposomes have been used to prolong the analgesic effect, but they are prone to abrupt release from the site of administration or have poor slow-release effects, which increases the risk of cardiotoxicity. In this study, injectable lipid suspensions based on ropivacaine-docusate sodium hydrophobic ion pairing (HIP) were designed to significantly prolong the duration of analgesia. The resulting ion-paired lipid suspension (HIP/LIPO) had a micrometer scale and a high zeta potential, which facilitates stable in situ retention. The strong interaction between docusate sodium and ropivacaine was verified using thermal and spectroscopic analyses, and the formation of micron-sized polymorphic vesicles was attributed to the mutual stabilizing interactions between ropivacaine-docusate sodium HIP, docusate sodium and lecithin. The HIP/LIPO delivery system could maintain drug release for more than 5 days in vitro and achieve high analgesic efficacy for more than 10 days in vivo, reducing the side effects associated with high drug doses. The stable HIP/LIPO delivery system is a promising strategy that offers a clinically beneficial alternative for postoperative pain management and other diseases.

QbD Approach-Based Preparation and Optimization of Hydrophobic Ion-Pairing Complex of Lysozyme with Sodium Dodecyl Sulphate to Enhance Stability in Lipid-Based Carriers.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods.

Comparative Analysis of PEG-Free and PEG-Based Self-Emulsifying Drug Delivery Systems for Enhanced Oral Bioavailability of Therapeutic (Poly) Peptides.

This study aims to compare the potential of Polyethylene glycol (PEG-free and PEG-based self-emulsifying drug delivery systems (SEDDS) for the oral administration of insulin glargine (IG). Hydrophobic ion pairs (HIPs) of IG are formed using various counterions. HIPs are assessed for log P octanol/water and dissociation behavior. They are incorporated into SEDDS based on polyglycerol (PG) and zwitterionic surfactant (ZW) using response surface methodology and compared to conventional PEG-SEDDS in size, stability, and log D SEDDS/release medium. Oral IG bioavailability in PG/ZW-SEDDS and PEG-SEDDS is evaluated in rats. Among the various counterions studied, IG-BIS (bis(isotridecyl)sulfosuccinate) HIPs demonstrated the highest log P and an improved dissociation profile. PG/ZW-SEDDS and PEG-SEDDS have similar ≈40 nm sizes and are stable over 24 h. Both formulations have log D > 4 in water and >2 in 50 mM phosphate buffer pH 6.8. PG/ZW-SEDDS yielded an oral bioavailability of 2.13 ± 0.66% for IG, while the employment of PEG-SEDDS resulted in an oral bioavailability of 1.15 ± 0.35%. This study highlights the prospective utilization of PEG-free SEDDS involving the concurrent application of PG and ZW surfactants, an alternative to conventional PEG surfactants, for improved oral therapeutic (poly) peptide delivery.

Variations in the inner core affect the pharmacokinetics of indomethacin-encapsulated polymeric micelles.

Hydrophobic ion pairing (HIP) is a drug encapsulation technology that uses electrostatic interactions between a drug and an additive. However, although polymeric micelles can encapsulate hydrophobic drugs in the core, the encapsulated drug often leaks. Therefore, we designed polymeric micelles with HIP functionalized in a hydrophobic inner core using three diblock copolymers comprising polypeptides with different ratios of polar and hydrophobic amino acids and polyethylene glycol (PEG) to encapsulate indomethacin (IND). The three IND-encapsulated HIP micelles showed different area under the curve (AUC) values as an index of blood retention after intravenous injection in mice. Despite having the same PEG shell, IND-PEG-poly(H/F)n showed a 1.56-fold higher AUC than IND-PEG-poly(D/F)n. PEG interface morphologies were evaluated to determine the differences in pharmacokinetic parameters caused by changes in inner core HIP patterns. The micellarized diblock copolymer was desorbed from IND-PEG-poly(D/F)n due to electrostatic repulsion between IND and the diblock copolymer comprising aspartic acid. Our results suggest that changes in the HIP patterns of the micelle inner core affected the PEG interface morphologies, such as PEG density and diblock copolymer desorption from micelles. These phenomena might lead to changes in the interaction of plasma proteins and drug dispositions.

Hydrophobic ion pairing and microfluidic nanoprecipitation enable efficient nanoformulation of a small molecule indolamine 2, 3-dioxygenase inhibitor immunotherapeutic.

Blockade of programmed cell death-1 (PD-1) is a transformative immunotherapy. However, only a fraction of patients benefit, and there is a critical need for broad-spectrum checkpoint inhibition approaches that both enhance the recruitment of cytotoxic immune cells in cold tumors and target resistance pathways. Indoleamine 2, 3-dioxygenase (IDO) small molecule inhibitors are promising but suboptimal tumor bioavailability and dose-limiting toxicity have limited therapeutic benefits in clinical trials. This study reports on a nanoformulation of the IDO inhibitor navoximod within polymeric nanoparticles prepared using a high-throughput microfluidic mixing device. Hydrophobic ion pairing addresses the challenging physicochemical properties of navoximod, yielding remarkably high loading (>10%). The nanoformulation efficiently inhibits IDO and, in synergy with PD-1 antibodies improves the anti-cancer cytotoxicity of T-cells, in vitro and in vivo. This study provides new insight into the IDO and PD-1 inhibitors synergy and validates hydrophobic ion pairing as a simple and clinically scalable formulation approach.

Histidine-based ionizable cationic surfactants: novel biodegradable agents for hydrophilic macromolecular drug delivery.

The aim of this study was to design surfactants based on histidine (His) for hydrophobic ion-pairing and evaluate their safety and efficacy. Lauryl, palmitoyl and oleyl alcohol, as well as 2-hexyl-1-decanol were converted into surfactants with histidine as head-group via esterification. The synthesized His-surfactants were characterized regarding pKa, critical micellar concentration (CMC), biodegradability, toxicity on Caco-2 cells, and ability to provide endosomal escape. Furthermore, the suitability of these agents to be employed as counterions in hydrophobic ion pairing was evaluated. Chemical structures were confirmed by 1H-NMR, FT-IR, and MS. The synthesized surfactants showed pKa values ranging from 4.9 to 6.0 and CMC values in the range of 0.3 to 7.0 mM. Their biodegradability was proven by enzymatic cleavage within 24 h. Below the CMC, His-surfactants did not show cytotoxic effects on Caco-2 cells (cell viability > 80%). All His-surfactants showed the ability to provide endosomal escape in a pH-dependent manner in the range of 5.2 to 6.8. Complexes formed between His-surfactants and heparin or plasmid DNA (pDNA) via hydrophobic ion pairing showed at least 100-fold higher lipophilicity than the correspondent model drugs. According to these results, His-surfactants might be a promising safe tool for delivering hydrophilic macromolecular drugs and nucleic acids.

MCT Nanoemulsions for the Efficient Delivery of siRNA.

In this study, an oil-in-water (o/w) nanoemulsion is used to deliver siRNA targeting Twist1, a protein that contributes to tumor metastasis in a variety of cancers. The FDA-approved oil, medium chain triglycerides (MCT), is used as the hydrophobic phase for the nanoemulsion. The siRNA is paired with dioleoyl-3-trimethylammonium-propane (DOTAP) to form a hydrophobic salt that is soluble at high concentrations in MCT. The resulting MCT/siRNA-DOTAP solution is formulated into a nanoemulsion with an average particle size of 140 nm. The nanoemulsion displays long term stability over the course of 195 days. In an in vivo murine tumor model, the nanoemulsion facilitates a 46% decrease in Twist1 mRNA after 48 h.

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.

Quality by Design-Based Development of Solid Self-Emulsifying Drug Delivery System (SEDDS) as a Potential Carrier for Oral Delivery of Lysozyme.

For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: -4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (-0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.

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.

Preparation and characterisation of self-emulsifying drug delivery system (SEDDS) for enhancing oral bioavailability of metformin hydrochloride using hydrophobic ion pairing complexation.

AIM: The aim of this study was preparation of a self-emulsifying drug delivery system (SEEDS) containing metformin hydrochloride. METHODS: Hydrophobic ion paired complexes were prepared by electrostatic interaction between metformin and sodium lauryl sulphate (SLS). The nanodroplets were optimised using two-level full factorial methodology and their morphology were examined. In vitro release of metformin from SEDDS was evaluated in simulated gastric and intestinal fluids. Finally, the ex-vivo efficacy of the optimised formulation in enhancing the intestinal permeability of metformin was evaluated using non-everted intestinal sac. RESULTS: The data revealed that in weight ratio 1:4(metformin: SLS), the highest recovery was achieved. The physico-chemical properties of the optimised nano-droplets including size, polydispersity index (PdI), zeta potential, and loading efficiency (%) were 192.33 ± 9.9 nm, 0.275 ± 0.051; -1.52 mV, and 93.75 ± 0.77% (w/w), respectively. CONCLUSIONS: The data obtained from the intestinal transport study demonstrated that SEDDS can significantly enhance the oral permeability of the compound.

Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles.

Hydrophobic ion pairing (HIP) can successfully increase the drug loading and control the release kinetics of ionizable hydrophilic drugs, addressing challenges that prevent these molecules from reaching the clinic. Nevertheless, polymeric nanoparticle (PNP) formulation development requires trial-and-error experimentation to meet the target product profile, which is laborious and costly. Herein, we design a preformulation framework (solid-state screening, computational approach, and solubility in PNP-forming emulsion) to understand counterion-drug-polymer interactions and accelerate the PNP formulation development for HIP systems. The HIP interactions between a small hydrophilic molecule, AZD2811, and counterions with different molecular structures were investigated. Cyclic counterions formed amorphous ion pairs with AZD2811; the 0.7 pamoic acid/1.0 AZD2811 complex had the highest glass transition temperature (Tg; 162 °C) and the greatest drug loading (22%) and remained as phase-separated amorphous nanosized domains inside the polymer matrix. Palmitic acid (linear counterion) showed negligible interactions with AZD2811 (crystalline-free drug/counterion forms), leading to a significantly lower drug loading despite having similar log P and pKa with pamoic acid. Computational calculations illustrated that cyclic counterions interact more strongly with AZD2811 than linear counterions through dispersive interactions (offset π-π interactions). Solubility data indicated that the pamoic acid/AZD2811 complex has a lower organic phase solubility than AZD2811-free base; hence, it may be expected to precipitate more rapidly in the nanodroplets, thus increasing drug loading. Our work provides a generalizable preformulation framework, complementing traditional performance-indicating parameters, to identify optimal counterions rapidly and accelerate the development of hydrophilic drug PNP formulations while achieving high drug loading without laborious trial-and-error experimentation.

Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus.

To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.

An ameliorated anti-hTNF-α therapy for arthritis via carrier-free macromolecular nanoparticles consisted of infliximab.

Infliximab (INF) is intravenously used for the clinical treatment of rheumatoid arthritis. However, it can cause serious side effects, which are mainly associated with systemic exposure and high doses. Here, we developed a modified hydrophobic ion-pairing complexes (INF HIPC) through the sequential introduction of bovine lactoferrin (BLF) and hyaluronic acid (HA) with opposite charges into the INF solution. INF and BLF were found to be not only integrally responsible for the structural integrity of HIPC but also were determined to have respective biological activities by binding human tumor necrosis factor-alpha (hTNF-α) or promoting the proliferation of osteoblasts. The INF HIPC had good stability, high drug-loading efficiency, and long-term retention effects. Whether via knee joint injection or intravenous injection, INF HIPC resulted in lower hTNF-α levels and less cartilage destruction than INFs in the transgenic mouse model. At the same time, INF HIPC could reduce toxicity based on body weight changes in transgenic mice. Our findings provide a simple and promising avenue to develop advanced delivery systems for other antibodies and macromolecules.

Hydrophobic ion pairing-based self-emulsifying drug delivery systems: a new strategy for improving the therapeutic efficacy of water-soluble drugs.

INTRODUCTION: Self-emulsifying drug delivery systems (SEDDS) are formulations consisting of oil phase, emulsifiers, and co-emulsifiers, which can be spontaneously emulsified in the body to form O/W microemulsion. Traditionally, SEDDS are used commercially for the improvement of oral absorption and in vivo performances for poorly water-soluble drugs. However, SEDDS formulations were rarely reported for the delivery of water-soluble drugs. Recent studies have found that SEDDS have the potential for water-soluble macromolecular drugs by the application of the hydrophobic ion pairing (HIP) technology. AREAS COVERED: This review summarized the characteristics of HIP complexes in SEDDS and introduced their advantages and discussed the future prospects of HIP-based SEDDS in drug delivery. EXPERT OPINION: Hydrophobic ion pairing (HIP) is a technology that combines lipophilic structures on polar counterions to increase the lipophilicity through electrostatic interaction. Recent studies showed that HIP-based SEDDS offer an effective way to increase the mucosal permeability and improve the chemical stability for antibiotics, proteases, DNA-based drugs, and other water-soluble macromolecular drugs. It is believed that HIP-based SEDDS offer a potential and attractive method capable of delivering hydrophilic macromolecules with ionizable groups for oral administration.

A Comprehensive Insight on Recent Advancements in Self-emulsifying Drug Delivery Systems.

A large proportion of new chemical moieties are poorly water-soluble. As a result, the biggest challenge for researchers is to enhance the solubility and oral bioavailability of lipophilic drugs. Self-emulsifying systems offer immense potential for improving lipophilic drugs' oral bioavailability and solubility through various mechanisms such as: inhibiting efflux transporters, absorption of the lipophilic drug through the lymphatic system, and bypassing hepatic first-pass metabolism. These systems dissolve hydrophobic drugs, allowing them to be delivered in a unit dose form for oral administration. Despite much potential, issues like stability, low drug loading, packaging, etc., are associated with the self-emulsifying technique. This review discusses conventional Self-Emulsifying Drug Delivery Systems (SEDDS), which deliver poorly water-soluble drugs. Recent advancements in self-emulsifying systems to solve the issues associated with conventional SEDDS are described exhaustively, including their methodologies and excipients utilized for preparation. The current article also furnishes a literature review on recent advancements in self-emulsifying systems. Recent advances in SEDDS are a great option for overcoming oral bioavailability, stability, and solubility issues of lipophilic drugs. Solid-self emulsifying system can be used to improve the stability of the formulation, hydrophobic ion-pairing for improving mucus permeation properties, while supersaturated self-emulsifying systems with a low concentration of surfactant to overcome issues such as precipitation of drug after dilution and gastrointestinal related side effects. The day will come when medicine companies will see the value of selfemulsifying system developments and adopt this technology for next-generation product releases.

Biodegradable arginine based steroid-surfactants: Cationic green agents for hydrophobic ion-pairing.

The aim of this study was to evaluate the safety and efficacy for hydrophobic ion-pairing of surfactants based on arginine (Arg). The prepared Arg-cholesteryl ester (ACE) and Arg-diosgenyl ester (ADE) were characterized regarding solubility, pKa, critical micellar concentration (CMC), biodegradability as well as membrane- and aquatic toxicity using DOTAP as reference. The ability for hydrophobic ion-pairing was evaluated and the lipophilicity of formed complexes was determined. NMR, FT-IR and MS confirmed successful synthesis of Arg-surfactants. The slightly soluble single-charged Arg-surfactants (pH < pKa3 (ACE = 10.42 ± 0.52; ADE = 10.38 ± 0.27)) showed CMCs of 27.17 µM for ACE and 35.67 µM for ADE. CMCs of the sparingly soluble double-charged species (pH < pKa2 (ACE = 5.30 ± 0.20; ADE = 5.55 ± 0.06)) were determined at concentrations of ≥ 250 µM for ACE and ≥ 850 µM for ADE. The enzymatic- and environmental biodegradability was proven by an entire cleavage of Arg-surfactants within 24 h, whereas DOTAP remained stable. Arg-surfactants exhibited lower membrane- (> 2-fold) and aquatic toxicity (> 15-fold) than DOTAP. The complexes formed with Arg-surfactants and insulin showed higher lipophilicity than the DOTAP-complex. According to these results, Arg-surfactants might be a promising safe tool for the delivery of peptide drugs.

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.

Papain-Decorated Mucopenetrating SEDDS: A Tentative Approach to Combat Absorption Issues of Acyclovir via the Oral Route.

The aim of the current study was to enhance the oral bioavailability of Acyclovir (ACV) based on the papain-functionalized self-emulsifying drug delivery systems (SEDDS). The optimum control SEDDS formulation comprised of kolliphore (40%), transcutol (30%), propylene glycol (20%) and oleoyl chloride (10%). However, in the targeted SEDDS formulation, oleoyl chloride was replaced with oleoyl chloride-papain (OC-PAP) conjugate that was synthesized via an amide bond formation between the acyl halide groups of oleoyl chloride and the amino group of papain. Prior to adding in the SEDDS formulation, the newly synthesized conjugate was evaluated quantitatively by a Bradford assay that demonstrated 45 µg of papain contents per mg of the conjugate. Moreover, the conjugate formation was qualitatively confirmed through FTIR analysis and thin layer chromatography. ACV (a BCS class III drug) was incorporated into the SEDDS formulations after being hydrophobically ion paired with sodium deoxycholate, thereby making it lipophilic. The drug-loaded formulations were emulsified in the 0.1 M phosphate buffer (pH 6.8) and evaluated in vitro with respect to drug release and rabbit mucosal permeation studies. Both the formulations illustrated a very comparable drug release over a period of 4 h, afterwards, the OC-PAP-based formulation demonstrated a more sustaining effect. The extent of mucus diffusion evaluated via the silicon tube method demonstrated a 4.92-fold and a 1.46-fold higher penetration of the drug, a 3.21-fold and a 1.56-fold higher permeation through the rabbit intestinal mucus layer, and a 22.94-fold and a 2.27-fold higher retention of the drug over the intact mucosa of rabbit intestine, illustrated by OC-PAP-based nanoemulsions compared to the drug-free solution and controlled nanoemulsion, respectively. According to these in vitro results, papain-functionalized SEDDS is a promising approach for the oral delivery of ACV and many other drugs with oral bioavailability issues, however, in vivo studies in this respect have to be employed before making a comprehensive conclusion.