Self-emulsifying Drug Delivery System Formulation Research Articles

Effects of polymeric surfactants with low HLB values on drug and excipient release from self-emulsifying drug delivery systems

In this study, we evaluated the effects of polymeric surfactants with low hydrophile–lipophile balance values (PSLH) lauryl PEG-8 dimethicone (LP8D) and Pluronic L121 (P121) on drug and excipient release from self-emulsifying drug delivery systems (SEDDS). Valsartan (logKOW 1.5) was used as a model drug, whereas oleic acid (logKOW 7.64) was loaded in SEDDS as a model excipient. Diffusion of valsartan from oil phase to aqueous phase was significantly reduced when adding 5 % LP8D or P121 into the oil phase consisting of isopropyl myristate:Capmul MCM 4:1 m/m. Drug diffusion reached plateau phases after 72 h compared to 3 h in case of the non-PSLH oil phase. Adding 10 % either LP8D or P121 further decreased drug diffusion to aqueous phase. P121 showed a more controlled drug diffusion profile than LP8D at the same loading level. PSLH were loaded in SEDDS preconcentrates at different concentrations in the ranges of 0–15 % LP8D and 0–10 % P121 m/m to yield emulsion with size ∼200 nm and polydispersity index <0.3 upon dilution. The burst release phases from PSLH loaded SEDDS were suppressed and better controlled with higher PSLH loading ratios. The presence of PSLH in the oil phase could increase intermolecular interactions such as hydrogen bonding and London dispersion forces between PSLH and drug or excipient molecules as shown by FTIR difference spectra. Furthermore, PSLH can accumulate at the oil-water interfacial barrier and increase the activation energy level for solute molecules diffusion, i.e. adding 10 % LP8D led to a 3-fold increase in activation energy for oleic acid. Therefore, incorporation of PSLH in SEDDS formulation could be a potential approach to reduce drug diffusion coefficients, enhance drug affinity to oil phase and control drug release rate.

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.

Improvement of dissolution profile of eplerenone with solidified self-emulsifying drug delivery systems (S-SEDDS)

Context Eplerenone is a member of antihypertensives used individually or in combination with other medicines. Eplerenone exhibits poor solubility and is considered a class II drug. Objective Increasing the solubility of eplerenone by using both liquid and solid self-emulsifying drug delivery systems as an alternative to its marketed tablet product. Methods Solubility studies of eplerenone were done with different oils, surfactants, and co-surfactants to determine which one has the highest solubility for eplerenone and determine the preference in the formulations of liquid self-emulsifying drug delivery system. The solidification process was carried out with the adsorption to solid carrier method. Optimal ratios of components were specified with the pseudo-ternary phase diagram technique. Self-emulsifying drug delivery system formulations were characterized in terms of chemical interaction, droplet size/distribution, crystallization behaviors, and rheological evaluation. In vitro drug release studies were conducted and compared to pure drugs and marketed products. Results The solubility screening results showed high solubility of EPL in triacetin (11.99 mg/mL) as oil, Kolliphor®EL (≈ 2.65 mg/mL), and Tween80 (≈ 1.91 mg/mL) as surfactant and polyethylene glycol 200 (PEG200) (≈ 8.50 mg/mL), dimethyl sulfoxide (≈ 7.57 mg/mL), TranscutolP (≈ 6.03 mg/mL) as co-surfactant, respectively. Rheology studies revealed that liquid self-emulsifying drug delivery formulations exhibited non-Newtonian pseudoplastic flow. Conclusion Solid self-emulsifying drug delivery systems prepared with Aerosil and Neusilin have shown tremendous improvement in terms of eplerenone dissolution by releasing the entire dose with boosted effect within 5 and 30 min respectively compared to the marketed product and pure eplerenone (p < 0.05).

Pembuatan dan Karakterisasi Self Emulsifying Drug Delivery Systems(SEDDS) Ibuprofen Secara Oral

Self emulsifying drug delivery systems (SEDDS) dikembangkan sebagai metode untuk meningkatkan kelarutan obat lipofilik seperti ibuprofen, serta untuk meningkatkan absorpsi dan laju disolusi obat. Oleh karena itu penelitian ini bertujuan untuk mengembangkan formulasi SEDDS ibuprofen yang memenuhi syarat secara farmasetik dan meningkatkan bioavailabilitas ibuprofen. Formula SEDDS diperoleh dari uji kelarutan ibuprofen dan optimasi formula pada berbagai konsentrasi minyak, surfaktan dan kosurfaktan. Asam oleat, cremophor RH 40 dan propilenglikol masing-masing terpilih sebagai minyak, surfaktan dan kosurfaktan dengan perbandingan fase minyak : (surfaktan + kosurfaktan) 1:9 dan pebandingan surfaktan : kosurfaktan (3:2). Formula SEDDS optimum dievaluasi meliputi pengukuran persen transmitan, pengujian dispersibilitas, pengujian robustness, pengujian stabilitas (sentrifugasi, heating cooling cycle, freeze thaw cycle), penentuan ukuran partikel dan uji laju disolusi. Formula SEDDS ibuprofen terbaik memenuhi persyaratan persen transmitan (99,7% ± 0,872), waktu dispersibilitas (41,48 detik ± 1,3), stabil pada pengujian robustness, tidak terjadi pemisahan fasa pada pengujian stabilitas, serta memiliki ukuran globul dalam kisaran mikrometer yaitu 114,7 ± 0,692 nm. Hasil uji laju disolusi in vitro pada menit ke-10 menunjukkan bahwa sediaan SEDDS ibuprofen lebih tinggi dibandingkan dengan serbuk ibuprofen murni, yaitu masing-masing sebesar 90,04 ± 1,764% dan 59,30 ± 1,638%.

A stability indicating RP-HPLC method for determination of the COVID-19 drug molnupiravir applied using nanoformulations in permeability studies

Antiviral drugs have gained much more attention in recent years due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and many drug candidates are currently under investigation in order to end pandemic. Molnupiravir, a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, is one of the promising candidates for SARS-CoV-2 treatment. In this study, a RP-HPLC method was developed for the determination of Molnupiravir and applied for in vitro permeability studies of self-emulsifying drug delivery system (SEDDS) formulations using Caco-2 cell line. Discovery® HS C18 Column (75 ×4.6 mm, 3 µm) was used at 30 °C. Isocratic elution was performed with ACN:water (20:80 v/v) mixture. The flow rate was 0.5 mL/min and UV detection was at 240 nm. Molnupiravir eluted within 5 min. Molnupiravir was exposed to thermal, photolytic, hydrolytic, and oxidative stress conditions. Peak homogeneity data of Molnupiravir in the stressed samples peak obtained using photodiode array detector, in the stressed sample chromatograms, demonstrated the specificity of the method for their estimation in presence of degradants. The developed method was validated according to the International Council for Harmonisation (ICH) guidelines and found to be linear within the range 0.1–60.0 μg/mL. The method was simple, rapid, selective, sensitive, accurate, precise, robust and rugged. Thus, it was applied successfully for permeability quantitation of Molnupiravir in nanoformulations. The apparent permeability of Molnupiravir in SEDDS formulations, which have droplet size under 350 nm, was calculated as 3.20 ± 0.44 × 10−6 cm/s.

Improved anti-inflammatory effect of curcumin by designing self-emulsifying drug delivery system

Purpose of present study was to prepare and evaluate self-emulsifying drug delivery system (SEDDS) of curcumin (Cur) to enhance its solubility and percentage release for the evaluation of anti-inflammatory effect. Curcumin loaded SEDDS formulation was prepared, and zones of self-emulsification were recognized by dilution method for the construction of phase diagram. Lauroglycol FCC, Tween 80 (surfactant), and Transcutol HP (co-surfactant) were selected based on their solubility and highest emulsion region in phase diagram. Thermodynamic stability of Cur-SEDDS was calculated through globule size, zeta potential, polydispersity index (PDI), viscosity and pH. Cur-SEDDS were also characterized by encapsulation efficiency (EE %), FT-IR, in vitro release, and in vivo anti-inflammatory effect. Results revealed that droplet size of Cur-SEDDS was 19.77 ± 0.03 nm with their PDI 0.22 ± 0.19, zeta potential -19.33 ± 0.94 and viscosity 25.68 ± 0.86 cp. EE % of Cur-SEDDS was found to be 94.99 ± 0.38%, percentage release 65.83% compared with pure curcumin powder. The designed formulation possesses significant anti-inflammatory activity in paw edema when compared with positive control in carrageenan induced rat paw edema assay. Newly developed Cur-SEDDS with enhanced curcumin solubility, percentage release and better anti-inflammatory action may be an alternative source of oral delivery of curcumin.

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide.

Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. As a model therapeutic peptide, octreotide (OCT) was converted to thedocusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. LS formulation improved thesolubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Ileo-Colon Targeting of the Poorly Water-Soluble Drug Celecoxib Using a pH-Dependent Coating in Combination with Self-Emulsifying Drug Delivery or Solid Dispersion Systems.

Targeting celecoxib to the ileo-colonic region could be beneficial for the treatment and prevention of colon cancer. Ileo-colonic targeting can be achieved by using pH-dependent coating systems such as ColoPulse. Celecoxib has poor aqueous solubility, which may jeopardize optimal treatment. Therefore, we combined a pH-dependent coating with self-emulsifying drug delivery systems (SEDDS) or with solid dispersion systems (SD); two approaches that are often used to improve the dissolution behavior of lipophilic drugs. The dissolution behavior of various formulations of both systems was investigated. Optimized formulations with and without precipitation inhibitors were coated with the ColoPulse and the release of celecoxib was tested under non-sink conditions using an in vitro dissolution system, simulating the pH gradient of the gastrointestinal tract. The dissolution behavior of SDs with and without precipitation inhibitor (sodium dodecyl sulfate) and the SEDDS without precipitation inhibitor was negatively impacted by the coating. Control experiments indicated that components of the coating released in the dissolution medium acted as precipitation mediators. However, the SEDDS formulation with HPMC 4000 cps as a precipitation inhibitor showed excellent dissolution behavior. We hypothesize that HPMC accumulates at the oil/water interface of the emulsion thereby stabilizing the emulsion resulting in maintenance of the supersaturated state.

In-Vitro Dissolution and Characterization of Self-Emulsifying Drug Delivery System of Artemisinin for Oral Delivery

Artemisinin is a compound extracted from Artemisia Annua. Artemisinin is used globally as the first-line antimalarial drug. Despite its high efficacy against the malaria parasite, artemisinin has low bioavailability because it has low solubility in water. This present study was conducted to prepare and characterize the self-emulsifying drug delivery system of artemisinin to increase the dissolution profile of artemisinin. The stability of the resulting emulsion was observed visually for 6 hours. Droplet size, polydispersity index, and zeta potential of the emulsion were measured using Nano Particle Analyzer. The optimum formulation was evaluated with the dissolution test and compared with the artemisinin crystal. Several formulations have good stability of the resulting emulsions where no creaming or flocculation was formed during the observation. Droplet sizes of the resulting emulsions ranged from 114.17-247.93 nm and the polydispersity index of the emulsions ranged from 0.35- 0.56. Zeta potential values of the selected formulations were found in the range of -23.23 - -2.33 mV. Fourier Transform Infrared Spectroscopy spectra of self-emulsifying drug delivery system showed the presence of artemisinin in the formulation with lactone and peroxide peaks. The dissolution of artemisinin in the self-emulsifying drug delivery system was significantly increased compared to artemisinin crystal. Artemisinin was released up to 98,6 %in 150 minutes in self-emulsifying drug delivery system formulation.

Role of Biorelevant Media in the Estimation of In Vitro Lipolysis and Food Impact on Self-emulsifying Drug Delivery Systems

Self-emulsifying drug delivery systems (SEDDS) include self-microemulsifying drug delivery system (SMEDDS) and self-nanoemulsifying drug delivery system (SNEDDS) whose major benefits are reduction of inter/intrasubject variability and food effect that results in a better pharmacological response of the drug. Oral intake of these formulations triggers the digestion process because of pancreatic lipase which emulsifies/digests the lipidic ingredients of the formulation leading to precipitation of the drug. As a tool to foresee in vivo medicament precipitation, in vitro lipolysis models are established. Biorelevant media play an important role to study the effect of in vitro lipolysis and food impact on the bioavailability of SEDDS formulations. It is vital to generate the composition of fluids for both fed and fasting conditions of gastric, small intestine and colon to investigate the impact of in vitro lipolysis and food on drug’s release behavior from the formulation. Fed/Fasted state simulated gastric fluid (Fe/FaSSGF), and Fed/Fasted state simulated gastric fluid (Fe/FaSSIF) (Phosphate buffers) are first-generation. While Fa/FeSSIF-V2 (maleate) are second- generation biorelevant media utilized for these studies. FaSSIF-V3 belongs to the thirdgeneration which differs from other generations in the composition and source of bile salts. With updates in physiological data, it is vital to incorporate changes in dissolution media composition to make it more biorelevant. This review paper mainly emphasized the compositions of biorelevant media of gastric and small intestine for both fed and fasting conditions. Besides, applications of biorelevant media to investigate the effect of in vitro lipolysis and food on SEDDS are discussed with some recent research reports.

Optimization of self-emulsifying drug delivery system of cefuroxime axetil

Abstract Overcoming solubility problems is the greatest challenge during formulation of poorly soluble active pharmaceutical ingredients (API’s) into oral solid dosage forms. Different formulation approaches were used to surpass this problem and enhance their solubility in the gastrointestinal (GI) fluids, in order to achieve a faster dissolution and better absorption, which will directly influence their therapeutic effect. In this paper, an evaluation of the potential of a self-emulsifying drug delivery system (SEDDS) to improve the solubility of the active ingredient cefuroxime axetil (CA) was done. Screening of the solubility of the API in different excipients was done, and Tween 80, PEG 400, and Olive oil as a surfactant, co-solvent, and oil, respectively, were chosen as the most convenient system constituents. An optimal self-emulsification and solubilization ability of this system was assessed using mixture experimental design statistical tools based on the response surface methodology (RSM). The prepared CA-SEDDS were evaluated for droplet size (d10, d50, d90 in µm), droplet size distribution (Span factor), and absorbance. As a complementary approach, for better representation of the non-linear relationship between the formulation compositions and the observed dispersion characteristics an artificial neural network (ANN) was used. Optimal formulation that consists of 10% (w/w) Tween 80 as surfactant, 80% (w/w) PEG 400 as co-solvent and 10% (w/w) Olive oil, was obtained. Both, mixture experimental design and ANN were combined for a comprehensive evaluation of CA-SEDDS and the obtained results suggested that formulation of SEDDS is a useful approach for improving the solubility of the CA. Keywords: self-emulsifying drug delivery systems (SEDDS), cefuroxime axetil, design of experiment, artificial neural network (ANN)

Self-emulsifying Drug Delivery System for Improved Dissolution and Oral Absorption of Quetiapine Fumarate: Investigation of Drug Release Mechanism and In-vitro Intestinal Permeability.

In this study, we focused on quetiapine fumarate (QTF), a class II BCS drug. QTF is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorders. Our objective was to develop a new QTF-loaded self-emulsifying drug delivery system (SEDDS) to improve the dissolution and absorption of the drug. An experimental design approach was used to develop and optimize QTF-loaded SEDDS. The optimized formulation was characterized for droplets size, zeta potential, PDI, and stability. It was then evaluated using an in-vitro combined test for dissolution and Everted gut sac technique. Mathematical modeling and Transmission electron microscopy (TEM) were used to elucidate the mechanism of release.The optimal formulation was type IIIB SEDDS, constituted of 9.1% of oleic acid, 51.6% of Tween®20, and 39.3% of Transcutol® P. It showed a droplets size of 144.8 ± 4.9nm with an acceptable PDI and zeta potential. For in-vitro evaluation tests, we noticed an enhancement of the dissolution rate of the optimal QTF-loaded SEDDS compared to the free drug (98.82 ± 1.24% for SEDDS after 30 min compared to 85.65 ± 2.5% for the pure drug). The release of QTF fitted with the Hopfenberg model indicating the drug was released by water diffusion and erosion mechanism. This result was confirmed by TEM images which showed a smaller droplet size after release. We also found an amelioration of the permeability of QTF of 1.69-fold from SEDDS compared to the free drug. Hence, the SEDDS formulation represented a new way to improve the dissolution and absorption of QTF.

Insights into Novel Excipients of Self-Emulsifying Drug Delivery Systems and Their Significance: An Updated Review.

Self-emulsifying drug delivery system (SEDDS), a category of lipid-based technology, has gained interest in the recent years for enhancement of solubility and bioavailability of poorly water-soluble drugs. With the progress of research in this field, novel excipients have been developed with enhanced properties. But excipient selection is the key hurdle in the formulation of SEDDS. The objective of this review is to summarize different types of oils, surfactants, co-surfactants which are the key components of liquid SEDDS (L-SEDDS), various carriers utilized in the conversion of L-SEDDS to solid SEDDS (S-SEDDS), their description, properties, grades, and applications in pharmacy. This article provides an overview of solidification techniques to transform L-SEDDS to S-SEDDS which are more stable and have better patience compliance. This review presents numerous literature reports on various excipients used and the discussion on how these excipients affect the final results.

Development, optimization and evaluation of losartan potassium loaded Self Emulsifying Drug Delivery System

In the current research work, losartan potassium (LP) loaded Self Emulsifying Drug Delivery System (SEDDS) was formulated using various ratios of lipids, surfactants and co-surfactants to prevent its first pass metabolism. A pseudo-ternary phase diagram was plotted to establish the emulsification region. Total of eight batches (F1 to F8) were prepared and subjected to different characterizations (thermodynamic study, phase separation, zeta potential and particle size) studies to obtain the optimized formulation. The optimized SEDDS (F8) with 40% oil, 60% surfactant and co-surfactant mixture (Smix) (6:1 ratio) was found to be a thermodynamically stable emulsion, with droplet size at around 204.7 ± 5.0 nm, surface charge −13.38 ± 1.5 mV and polydispersity index 0.221 ± 0.03. The SEM study confirmed the spherical shape and even surface of the droplets. The In-vitro drug release profile of optimized formulation exhibited a similar rate and extent of dissolution as compared to the marketed formulation. Further, the optimized formulation had shown equivalent therapeutic efficacy (anti-hypertensive) with respect to the marketed tablet at half of the dose of the drug in SEDDS formulation.

Improving solubility and oral bioavailability of a novel antimalarial prodrug: comparing spray-dried dispersions with self-emulsifying drug delivery systems

To improve the solubility and oral bioavailability of a novel antimalarial agent ELQ-331(a prodrug of ELQ-300), spray-dried dispersions (SDD) and a self-emulsifying drug delivery system (SEDDS) were developed. SDD were prepared with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) polymer carrier and Aeroperl® 300 Pharma and characterized by differential scanning calorimetry, powder X-ray diffraction. For SEDDS, solubility in oils, surfactants, and co-surfactants was determined and ternary phase diagram was constructed to show self-emulsifying area. SEDDS were characterized for spontaneous emulsification and droplet size distribution. The amorphous ELQ-331 SDD improved the solubility to 10× in fast-state simulated intestinal fluid and addition of sodium lauryl sulphate externally to SDDs further improved the solubility to ∼28.5× versus non-formulated drug. SEDDS had good self-emulsifying characteristics with small emulsion droplet sizes and narrow particle distribution. Oral pharmacokinetic studies for SDD and SEDDS formulations were performed in rats. The ELQ-331 rapidly converted to ELQ-300 soon after oral administration in rats. Exposure levels of ELQ-300 were about 1.4-fold higher (based on AUC) in SEDDS than SDD formulations. Poorly soluble drugs like ELQ-331 can be formulated using SDD or SEDDS to improve solubility and oral bioavailability.

Zeta potential changing self-emulsifying drug delivery systems utilizing a novel Janus-headed surfactant: A promising strategy for enhanced mucus permeation

AimThe aim of this study was to develop zeta potential changing self-emulsifying drug delivery systems (SEDDS) utilizing a Janus-headed surfactant in order to improve mucus permeation. Methods12-Amino-1-dodecanol (12-AD) was phosphorylated by utilizing phosphorus pentoxide (P2O5) and incorporated in a concentration of 2% into a SEDDS formulation (10% Glycerol 85, 30% Campul MCM, 30% Cremophore EL, 30% Captex 355). The phosphorylated 12-AD (p-12-AD) loaded SEDDS were characterized regarding their size and zeta potential. Phosphate release studies from SEDDS having been diluted 1:100 in HEPES buffer were performed with isolated alkaline phosphatase (10 U/mL) as well as cell-associated intestinal alkaline phosphatase (AP). In parallel, the resulting change in zeta potential as well as the increase in amino group concentration on the surface of SEDDS were monitored. The effect of zeta potential change on mucus permeation was evaluated by Transwell method with freshly isolated porcine mucus utilizing fluorescein diacetate (FDA) as a marker. ResultsSize and zeta potential of SEDDS were 61 ± 3.8 nm and −9.37 mV, respectively. The amount of phosphate release was 29.91 μmol/g and 1.22 μmol/g in the presence of isolated AP and Caco-2 cell monolayer, respectively. SEDDS showed a shift in zeta potential from −9.37 mV to +0.5 mV in the presence of isolated AP within 6 h. The mucus permeation results demonstrated that negatively charged SEDDS permeate the mucus gel layer to a 6.5-fold higher extent than SEDDS having already changed their zeta potential to positive because of phosphate cleavage. ConclusionSEDDS containing a Janus-headed phosphorylated surfactant might be a promising strategy for mucosal drug delivery.

Improved Intestinal Mucus Permeation of Vancomycin via Incorporation Into Nanocarrier Containing Papain-Palmitate

The aim of this study was to improve intestinal mucus permeation of a peptide antibiotic via incorporation into papain-palmitate–modified self-emulsifying drug delivery systems (SEDDS) as nanocarrier. Vancomycin as a peptide antibiotic was lipidized by hydrophobic ion pair formation using sodium bis-2-ethylhexyl-sulphosuccinate before incorporation in SEDDS comprising Capmul MCM, propylenglycol, and Kolliphor EL (2:1:2). As mucolytic agent, 0.5% papain-palmitate was introduced in SEDDS formulation containing the vancomycin-sodium bis-2-ethylhexyl-sulphosuccinate ion pair. The formulation was evaluated regarding droplet size, zeta potential, and cytotoxicity using Caco-2 cells previous to intestinal mucus permeation studies using Transwell diffusion and rotating tube method. The hydrophobic ion pair product yielded from surfactant to drug ratio of 3:1 provided a 25-fold increase in lipophilicity, drug payload in SEDDS of 5%, and log DSEDDS/release medium of 2.2. The formulation exhibited a droplet size and zeta potential of 221.5 ± 14.8 nm and −4.2 ± 0.8 mV, respectively. Cytotoxicity study showed that SEDDS formulations were not toxic. Introducing 0.5% papain-palmitate increased the mucus permeability of SEDDS 2.8-fold and 3.3-fold in Transwell diffusion and rotating tube studies, respectively. According to these results, papain decorated SEDDS might be a potential strategy to improve the mucus permeating properties of peptide antibiotics.

In vitro evaluation of a self-emulsifying drug delivery system (SEDDS) for nasal administration of dimenhydrinate

The objective of the study was the development and in vitro characterization of a self-emulsifying drug delivery system (SEDDS) for the nasal application of dimenhydrinate. Final composition of SEDDS was established based on drug solubility and stability studies. Dimenhydrinate was loaded into the SEDDS pre-concentrates to 7.5% (m/v). The droplet size of the final SEDDS formulations was in a range between 60 and 220 nm. Permeability, as well as tissue toxicity, of the formulations was investigated using bovine nasal mucosa. Enhancement in permeation up to 2.8-fold compared to pure dimenhydrinate was confirmed. Furthermore, toxicity studies did not reveal any serious tissue damages related to the SEDDS. Additionally, irritation potential of SEDDS was evaluated in ciliary beat frequency measurements. Incorporation of dimenhydrinate into SEDDS might therefore be considered as a promising approach within the field of nasal delivery of antiemetics by utilizing permeation enhancement strategy.

Development of self-emulsifying drug delivery systems (SEDDS) for ciprofloxacin with improved mucus permeating properties

The aim of this study was to develop a self-emulsifying drug delivery system (SEDDS) containing the fluoroquinolone antibiotic ciprofloxacin (CIP) exhibiting highly mucus permeating properties and antimicrobial activity in in vitro models. Various SEDDS formulations were developed and evaluated regarding droplet size, polydispersity index, zeta potential and formulation stability. Furthermore, SEDDS permeating properties were investigated in porcine intestinal mucus, as well as in cystic fibrosis (CF) sputum freshly collected from CF patients using Transwell® setup and single particle tracking (SPT), respectively. In order to evaluate antibacterial activity in an in vitro model against Staphylococcus aureus and other pathogens, minimum inhibitory concentrations (MIC) and time-kill curves were determined. In addition, in vitro release of ciprofloxacin and cytotoxicity studies were conducted. The preselected formulations F1 and F11 exhibited a mean droplet size of 79 nm and 25 nm, respectively, and a negative zeta potential. SEDDS containing CIP exhibit improved ability to permeate porcine intestinal mucus and CF sputum. After 4 h, F1-CIP formulation resulted in a 1.6 - fold and F11-CIP a 2.0 - fold higher amount of permeated ciprofloxacin through the sputum layer with respect to free CIP. Moreover, the antimicrobial activity of F11-CIP against S. aureus was higher than that of free CIP. According to these results, SEDDS formulations should be taken into consideration as promising delivery systems for the treatment of pulmonary infections accompanied by mucus dysfunction.