Self-emulsifying drug delivery systems: In vivo evaluation of their potential for oral vaccination.

Oral Immunization remains a challenge as antigens are rapidly metabolized in the gastrointestinal tract. In numerous previous studies, Self-emulsifying drug delivery systems (SEDDS) have demonstrated to be a promising tool for oral delivery of biologics. In this study, the potential of SEDDS as vehicle for oral vaccination has been evaluated. At this purpose, the model antigen Bovine serum albumin (BSA) has been incorporated in SEDDS after ion pairing. Squalane and monophosphoryl lipid A (MPLA) were chosen as adjuvants and dissolved in SEDDS containing BSA (SEDDS-BSA-squalane and SEDDS-BSA-MPLA). Formulations were administered orally to BALB/c mice. As control unformulated BSA was administrated orally (BSA-oral) and subcutaneously (BSA-sc). Systemic (anti BSA IgG titre) and mucosal (anti BSA IgA titre) immugenicity of BSA loaded in SEDDS and of unformulated BSA administered orally and subcutaneously was assessed and compared with each other. SEDDS-BSA-squalane and SEDDS-BSA-MPLA induced both higher anti BSA-IgG titre and anti BSA-IgA titre than orally administered unformulated BSA. BSA-sc induced the highest systemic immune response, however, the highest mucosal immune response was achieved via oral administration of SEDDS-BSA-squalane and SEDDS-BSA-MPLA. In general, SEDDS-BSA-MPLA showed the most promising systemic and mucosal immune response. According to these results, SEDDS seems to be a promising carrier for oral delivery of vaccines. STATEMENT OF SIGNIFICANCE: Oral vaccination is still a great challenge, as orally administered antigens are easily degraded in the gastrointestinal (GI) tract by peptidases and proteases. During the last years, self-emulsifying drug delivery systems (SEDDS) consisting of a mixture of oils and surfactants have been developed for the oral administration of hydrophilic macromolecular drugs. In this study, Bovine serum albumin (BSA) was chosen as model antigen and incorporated into self-emulsifying drug delivery systems (SEDDS) after hydrophobic ion pairing. Lipid A from Salmonella Minnesota R595 (MPLA) and squalane were chosen as adjuvants. SEDDS-BSA-MPLA and SEDDS-BSA-squalane were administered orally to mice. SEDDS-BSA-MPLA induced the strongest systemic (anti BSA-IgG titre) and mucosal (anti BSA-IgA titre) immune response. Based on these results, SEDDS are a promising alternative carrier for oral vaccine delivery.

Highly mucus permeating and zeta potential changing self-emulsifying drug delivery systems: A potent gene delivery model for causal treatment of cystic fibrosis.

AIM: It was the aim of the study to develop self-emulsifying drug delivery systems (SEDDS) with the ability to change their zeta potential towards higher values at the adsorption membrane and in this way facilitate the release of the DNA-cetrimonium complex and enhance transfection. METHODS: Plasmid DNA was complexed via hydrophobic ion pairing utilizing various surfactants and the complex was incorporated into SEDDS achieving a payload of 1% (m/v). Log PSEDDS/water of the complex was determined. SEDDS were characterized regarding droplet size, zeta potential, stability and toxicity. Alkaline phosphatase presented in the sputum of cystic fibrosis patients was quantified using 4-nitrophenyl phosphate disodium salt and 5-bromo-4-chloro-1H-indol-3-yl phosphate dipotassium salt as substrates. SEDDS containing 0.4% (m/v) 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt were characterized regarding their zeta potential changing properties utilizing isolated alkaline phosphatase and cystic fibrosis sputum. The mucus permeating properties of SEDDS were evaluated via Transwell method using cystic fibrosis sputum. Finally, the transfection efficiency of incorporated plasmid DNA was investigated. RESULTS: Cetrimonium bromide showed the highest precipitation efficiency of 99.5 ±â€¯2.72% for the complexation of pDNA. SEDDS containing propylene glycol, Capmul PG-8, Captex 300, Captex 355, Captex 8000, Cremophor EL, Cremophor RH-40 and Brij O10 showed stable emulsions with a droplet size between 20 and 100 nm and zeta potential <-3 mV over 4 h. SEDDS demonstrated highly protective effect against enzymatic degradation and moderate cell viability on freshly obtained pulmonary tissue. The pDNA-cetrimonium complex incorporated into SEDDS revealed a log PSEDDS/water of about 2. A concentration of 0.879 ±â€¯0.103 U/g alkaline phosphatase was found in the sputum of cystic fibrosis patients. SEDDS containing 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt showed a high potential of changing the zeta potential by applying isolated alkaline phosphatase as well as cystic fibrosis sputum along with high mucus permeating properties. Formulation C demonstrated the highest transfection efficiency with a 7.2-fold increased fluorescence intensity compared to naked pDNA. CONCLUSION: The novel developed zeta potential changing SEDDS are opening versatile opportunities for the treatment of cystic fibrosis caused by gene mutation.

Will artificial intelligence solve the human resource crisis in healthcare?

Artificial intelligence (AI) has the potential to ease the human resources crisis in healthcare by facilitating diagnostics, decision-making, big data analytics and administration, among others. For this we must first tackle the technological, ethical and legal obstacles.The human resource crisis is widening worldwide, and it is obvious that it is not possible to provide care without workforce. How can disruptive technologies in healthcare help solve the variety of human resource problems? Will technology empower physicians or replace them? How can the medical curriculum, including post-graduate education prepare professionals for the meaningful use of technology? These questions have been growing for decades, and the promise of disruptive technologies filling them is imminent with digital health becoming widespread. Authors of this essay argue that AI might not only fill the human resources gap, but also raises ethical questions we need to deal with today.While there are even more questions to address, our stand is that AI is not meant to replace caregivers, but those who use AI will probably replace those who don't. And it is possible to prepare for that.

Amikacin-containing self-emulsifying delivery systems via pulmonary administration for treatment of bacterial infections of cystic fibrosis patients.

AIM: The aim of the study was to develop self-emulsifying delivery systems (SEDDS) exhibiting improved permeation rate for pulmonary delivery of amikacin for treatment of cystic fibrosis (CF) patients. MATERIALS & METHODS: Solubility of amikacin in lipids was improved by hydrophobic ion pairing with sodium myristyl sulfate. The complex was loaded into SEDDS. Drug-release studies were performed and the permeation properties of SEDDS through human CF mucus were examined. RESULTS: A total of 10% complex could be loaded into SEDDS. SEDDS exhibited sustained release. Up to twofold more amounts of amikacin permeated through the CF mucus compared with reference. CONCLUSION: The developed SEDDS with amikacin may be a promising tool for the treatment of certain bacterial infections of CF patients.

Self-emulsifying peptide drug delivery systems: How to make them highly mucus permeating.

AIM: It was the aim of this study to evaluate the mucus permeating properties of self-emulsifying drug delivery systems (SEDDS) exhibiting different size and zeta potential. METHODS: Various SEDDS were prepared and characterized regarding droplet size, zeta potential and stability. Desmopressin was incorporated as model peptide drug and log P (SEDDS/water) was determined. Thereafter, mucus permeation studies with freshly isolated porcine mucus via Transwell method were performed. Moreover, the impact of water movement on mucus permeation of SEDDS was investigated. Different types of nanocarriers including nanoparticles and liposomes served as references. RESULTS: SEDDS exhibited an initial droplet size of 25.0 ±â€¯2.2, 49.5 ±â€¯4.6, 123.5 ±â€¯12.1, 226.2 ±â€¯93.4 and 502.9 ±â€¯93.7 nm and a zeta potential of +24.4 ±â€¯4.6, +10.6 ±â€¯2.0, 0.2 ±â€¯3.8, -8.2 ±â€¯3.4 and -35.1 ±â€¯2.7 mV. Log P was in the range of 1.29-2.09 and mucus permeation studies with these SEDDS revealed a clear correlation between droplet size and permeation rate. The smaller SEDDS were, the higher their mucus permeating properties were. Negatively charged SEDDS demonstrated a higher permeation rate than positively charged SEDDS. In comparison to liposomes and solid nanocarriers SEDDS exhibited up to 5-fold higher mucus permeating properties. CONCLUSION: Small droplet size and negative zeta potential of SEDDS could be identified as key parameters for their mucus permeating properties.

Thiolated Hyaluronic Acid as Versatile Mucoadhesive Polymer: From the Chemistry Behind to Product Developments-What Are the Capabilities?

Within the last decade, intensive research work has been conducted on thiolated hyaluronic acids (HA-SH). By attaching sulfhydryl ligands onto naturally occurring hyaluronic acid various types of HA-SH can be designed. Due the ability of disulfide bond formation within the polymer itself as well as with biological materials, certain properties such as mucoadhesive, gelling, enzyme inhibitory, permeation enhancing and release controlling properties are improved. Besides the application in the field of drug delivery, HA-SH has been investigated as auxiliary material for wound healing. Within this review, the characteristics of novel drug delivery systems based on HA-SH are summarized and the versatility of this polymer for further applications is described by introducing numerous relevant studies in this field.

Inhibitory effect of emulsifiers in sedds on protease activity: Just an illusion?

AIM: Evaluation of inhibitory effect of emulsifiers on pancreatic trypsin and α-chymotrypsin. METHODS: The inhibitory effect of Cremophor EL, Cremophor RH 40, Brij O10, Tween 20, polyethylene glycol 8000, polyethylene glycol 400, Carbitol, Pemulen TR-1, Pemulen TR-2, Carbopol Ultrez 20 and Carbopol Ultrez 21 on pancreatic trypsin and α-chymotrypsin was tested. BAEE (Nα-Benzoyl-l-arginine ethyl ester), BTEE (N-Benzoyl-l-tyrosine ethyl ester), casein and insulin were used as substrates for trypsin and α-chymotrypsin. SEDDS containing Pemulen TR-2 were developed, loaded with insulin-DMPG (dimyristoylphosphatidylglycerol) complex, characterized and tested regarding the protective effect towards the proteolytic degradation of insulin. RESULTS: Cremophor EL, Cremophor RH 40, Brij O10, Tween 20, polyethylene glycol 8000, polyethylene glycol 400, Carbitol did not show any inhibitory effect towards trypsin and α-chymotrypsin, whereas Pemulen TR-1, Pemulen TR-2, Carbopol Ultrez 20 and Carbopol Ultrez 21 inhibited the enzymes in a concentration dependent manner. Moreover, Pemulen and Carbopol Ultrez emulsifiers exhibited comparable inhibitory properties (p>0.05). The incorporation of 0.34% w/w of Pemulen TR-2 in SEDDS decreased the degradation rate of the loaded insulin-DMPG complex compared to the blank formulation (p<0.05). CONCLUSION: The present study revealed that commonly used emulsifiers in SEDDS do not have inhibitory properties on the proteolytic activity of trypsin and α-chymotrypsin. Moreover, it was demonstrated that the incorporation of emulsifiers with inhibitory properties towards trypsin and α-chymotrypsin in SEDDS play a minor role in the protection of embedded drugs from enzymatic degradation.

Comparison of the protective effect of self-emulsifying peptide drug delivery systems towards intestinal proteases and glutathione.

AIM: The aim of this study was to evaluate the protective effect of self-emulsifying drug delivery systems (SEDDS) for therapeutic peptides towards intestinal proteases and reduced glutathione (GSH). METHODS: Sodium docusate was applied as anionic surfactant for hydrophobic ion pairing with leuprorelin (LEU), insulin (INS) and desmopressin (DES). The complexes were loaded into SEDDS that were characterized regarding droplet size distribution and zeta potential. The release profile of the peptides was examined by dialysis membrane method. Enzymatic digestion studies were performed by applying α-chymotrypsin, trypsin and elastase. Furthermore, the protective effect of SEDDS towards degradation through thiol-disulfide exchange reactions was examined by addition of GSH. RESULTS: SEDDS showed a mean droplet size of 0.27-3.9µm and a zeta potential of -25 to -33mV. All formulations provided a sustained release of the peptides over 6h. Degradation of the model peptides by intestinal proteases and GSH could only be observed in the release medium. In the oily phase of SEDDS neither any of the proteases nor GSH was soluble (≤0.1%). Furthermore, no degradation of the model peptides by proteases and GSH took place in the oily phase of SEDDS. CONCLUSION: SEDDS can provide a 100% protective effect towards protease degradation and deactivation by GSH. According to this, SEDDS might be promising tools for oral delivery of peptide drugs.

Combination of SEDDS and Preactivated Thiomer Technology: Incorporation of a Preactivated Thiolated Amphiphilic Polymer into Self-Emulsifying Delivery Systems.

PURPOSE: The aim of the study was to create novel mucoadhesive drug delivery systems by incorporating amphiphilic hydrophobically modified, thiolated and preactivated polymers (preactivated thiomers) into self-emulsifying drug delivery systems (SEDDS). METHODS: L-Cysteine methyl ester was covalently attached to the polymeric backbone of Pemulen TR-2 and preactivated using 2-mercaptonicotinic acid (2-MNA). These thiomers were incorporated in a concentration of 0.3% (w/v) into SEDDS. The size distribution and the zeta potential of the emulsions were evaluated by dynamic light scattering. Mucoadhesive properties of thiomers-SEDDS spiked with FDA (fluorescein diacetate) were examined utilizing rheological measurement, permeation studies and in vitro residence time study on porcine mucosa. Cell viability tests were additionally performed. RESULTS: 734 ± 58 µmol L-Cysteine methyl ester and 562 ± 71 µmol 2-MNA could be attached per gram polymer of Pemulen TR-2. Emulsions exhibited a droplet size range between 180 and 270 nm. Blank SEDDS possessed a zeta potential value between -5.7 and -8.6 mV, whereas thiomers-SEDDS between -14.6 and -17.2 mV. Viscous modulus of thiomer and preactivated thiomer containing SEDDS-mucus mixture was 8-fold and 11-fold increased in comparison to reference. The amount of FDA permeated the mucus layer was 2-fold lower in case of thiomers-SEDDS compared to blank SEDDS. A prolonged residence time was observed for thiomers-SEDDS over 45 min. During cell viability studies no severe toxic effects were detected. CONCLUSION: The novel developed SEDDS with incorporated thiomers might be a promising tool for mucoadhesive oral drug delivery.

Hydrophobic ion pairing: Key to highly payloaded self-emulsifying peptide drug delivery systems.

AIM: The aim of this study was the formation and characterization of various ion pairs of therapeutic peptides with different surfactants in order to reach a high payload in self-emulsifying drug delivering systems (SEDDS). METHODS: Hydrophobic ion pairs (HIP) were formed between the anionic surfactants sodium docusate, dodecylsulfate and oleate and the peptides leuprorelin (LEU), insulin (INS) and desmopressin (DES). The efficiency of HIP formation was evaluated by quantifying the amount of formed complexes, log P value determination in n-octanol/water via HPLC and zeta potential measurements. Solvents and surfactants were screened regarding their complex solubilizing properties. Subsequently, peptide complexes were incorporated into SEDDS followed by payload and stability determination. RESULTS: Independent from the type of peptide, docusate showed the most efficient HIP properties followed by dodecylsulfate and oleate. Ratios of 2:1 for LEU, 6:1 for INS and 1.5:1 for DES led to the highest quantity of formed complexes with docusate and log P increased at least by 3 units. The more docusate was added to each peptide, the more negative became the zeta potential of the resulting complex. Incorporating these optimized complexes into novel SEDDS containing Capryol 90, Labrafil M 2125 CS, Labrasol ALF, Peceol, propylene glycol, tetraglycol, Transcutol HP and Tween 20 allowed payloads of the LEU, DES and INS complexes above 10%. Moreover, SEDDS exhibited high stability and constant negative zeta potential over a 4h incubation time. CONCLUSION: Following the procedure described herein payloads >10% can be achieved for peptide drugs in SEDDS.

Drug release profiles and microstructural characterization of cast and freeze dried vitamin B12 buccal films by positron annihilation lifetime spectroscopy.

Solvent cast and freeze dried films, containing the water-soluble vitamin B12 as model drug were prepared from two polymers, sodium alginate (SA), and Carbopol 71G (CP). The proportion of the CP was changed in the films. The microstructural characterization of various samples was carried out by positron annihilation lifetime spectroscopy (PALS). The drug release kinetics of untreated and stored samples was evaluated by the conventionally applied semi-empirical power law. Correlation was found between the changes of the characteristic parameters of the drug release and the ortho-positronium (o-Ps) lifetime values of polymer samples. The results indicated that the increase of CP concentration, the freeze-drying process and the storage at 75% R.H. decreased the rate of drug release. The PALS method enabled the distinction between the micro- and macrostructural factors influencing the drug release profile of polymer films.

[Formulation aspects and ex-vivo examination of buccal drug delivery systems]. / Bukkális hatóanyag-leadó rendszerek formulálásának és ex vivo vizsgálatának lehetoségei.

Application of buccal dosage forms has several advantages. Buccal route can be used for systemic delivery because the mucosa has a rich blood supply and it is relatively permeable. This route of drug delivery is of special advantages, including the bypass of first pass effect and the avoidance of presystemic elimination within the GIT. Buccal delivery systems enable the systemic delivery of peptides and proteins. In our previous study the physiological background of this application and the excipients of the possible formulations were reviewed. In the present work the formulation and ex vivo examination aspects of buccal drug delivery systems are summarized.