Preparation of Squalene Oil-Based Emulsion Adjuvants Employing a Self-Emulsifying Drug Delivery System and Assessment of Mycoplasma hyopneumoniae-Specific Antibody Titers in BALB/c Mice

Bastola, Rakesh; Seo, Jeong-Sun; Keum, Taekwang; Noh, Gyubin; Choi, Jae Woong; Shin, Jong Il; Kim, Ju Hun; Lee, Sang Kil

doi:10.3390/pharmaceutics11120667

Cited by 8 publications

(4 citation statements)

References 24 publications

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“… 52–54 SNEDDS technology is a lipid-based drug delivery system that has attracted the attention of the pharmaceutical industry and is considered to be a promising drug carrier for improving the oral bioavailability of poorly soluble drugs. 55 To date, many commercial SNEDDS drugs have been approved by FDA, such as kaletra ® (Ritonavir/Lopinavir), Aptivus ® (Tipranavir), Sandimmune ® (cyclosporine). 17 , 56 Given the advantages of the SNEDDS technology and its application in medicine, this study used it to increase the solubility and enhance the bioavailability of GKA.…”

Section: Discussionmentioning

confidence: 99%

Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

Yin¹,

Yin²,

Ouyang³

et al. 2021

DDDT

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Purpose The aim of the present study was to develop an optimized Genkwanin (GKA)-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation to enhance the solubility, intestinal permeability, oral bioavailability and anti-colitis-associated colorectal cancer (CAC) activity of GKA. Methods We designed a SNEDDS comprised oil phase, surfactants and co-surfactants for oral administration of GKA, the best of which were selected by investigating the saturation solubility, constructing pseudo-ternary phase diagrams, followed by optimizing thermodynamic stability, emulsification efficacy, self-nanoemulsification time, droplet size, transmission electron microscopy (TEM), drug release and intestinal permeability. In addition, the physicochemical properties and pharmacokinetics of GKA-SNEDDS were characterized, and its anti-colitis-associated colorectal cancer (CAC) activity and potential mechanisms were evaluated in AOM/DSS-induced C57BL/6J mice model. Results The optimized nanoemulsion formula (OF) consists of Maisine CC, Labrasol ALF and Transcutol HP in a weight ratio of 20:60:20 (w/w/w), in which ratio the OF shows multiple improvements, specifically small mean droplet size, excellent stability, fast release properties as well as enhanced solubility and permeability. Pharmacokinetic studies demonstrated that compared with GKA suspension, the relative bioavailability of GKA-SNEDDS was increased by 353.28%. Moreover, GKA-SNEDDS not only significantly prevents weight loss and improves disease activity index (DAI) but also reduces the histological scores of inflammatory cytokine levels as well as inhibiting the formation of colon tumors via inducing tumor cell apoptosis in the AOM/DSS-induced CAC mice model. Conclusion Our results show that the developed GKA-SNEDDS exhibited enhanced oral bioavailability and excellent anti-CAC efficacy. In summary, GKA-SNEDDS, using lipid nanoparticles as the drug delivery carrier, can be applied as a potential drug delivery system for improving the clinical application of GKA.

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Section: Discussionmentioning

confidence: 99%

Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

Yin¹,

Yin²,

Ouyang³

et al. 2021

DDDT

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“…The measured droplet size shows that the emulsion contained droplets (358.57–811.60 nm) of similar or slightly smaller size compared to other squalene-based oil-in-water emulsions 41 ( Table 2 ). In general, the droplet size of emulsion used in the pharmaceutical products ranges from 0.1 to 10 µm, 15 , 42 suggesting that prepared emulsions (F1–F15) were of suitable sizes for use as an adjuvant.…”

Section: Discussionmentioning

confidence: 75%

“…A previous study reported the use of two types of non-ionic surfactants, Span ® 80 and Cremophor ® ELP, for 3%, 5%, and 10% of squalene-based oil-in-water emulsions as adjuvants for the delivery of a combination vaccine containing a porcine circovirus type 2 (PCV2) antigen and inactivated Mycoplasma hyopneumoniae (J101 strain) antigen. 41 As a result, a particle size of up to 2.5 µm was obtained, and the zeta potential exhibited values ranging from -43 mV to +11 mV. 41 Our emulsions (Span ® 85, Kolliphor ® RH40, and CMC) showed droplet sizes in the nano range and maintained zeta potential values between −30 mV to -10 mV for 4 weeks, indicating good physical stability as a vaccine adjuvant.…”

mentioning

confidence: 98%

“…41 As a result, a particle size of up to 2.5 µm was obtained, and the zeta potential exhibited values ranging from -43 mV to +11 mV. 41 Our emulsions (Span ® 85, Kolliphor ® RH40, and CMC) showed droplet sizes in the nano range and maintained zeta potential values between −30 mV to -10 mV for 4 weeks, indicating good physical stability as a vaccine adjuvant.…”

mentioning

confidence: 98%

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Development of Squalene-Based Oil-in-Water Emulsion Adjuvants Using a Self-Emulsifying Drug Delivery System for Enhanced Antigen-Specific Antibody Titers

Chae¹,

Kim²,

Jin³

2022

IJN

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Introduction A recombinant protein cannot induce sufficient immune response by itself. Various substances, including cytokine and mineral, have been used as adjuvants to enhance the immunogenicity and efficacy of vaccines; however, most of them induce excessive immune responses or exhibit cytotoxicity. In this study, a self-emulsifying drug delivery system (SEDDS), an isotropic mixture of oil, surfactant, and solvent, was designed for oil-in-water emulsions as a non-toxic adjuvant to increase immune response to antigens. Methods Squalene-based oil-in-water emulsions were prepared by SEDDS to assess its value as an adjuvant. Fifteen emulsions (F1–F15) were prepared by stirring two types of surfactants (Span ® 85 and Kolliphor ® RH40), and squalene and carboxymethyl cellulose (CMC) were added at different ratios. The physical properties and viscosity of the 15 emulsions were evaluated by measuring droplet size, zeta potential, and polydispersity index. The toxic effect of emulsions was assessed by acute toxicity test in mice. Mice were immunized twice with 1:1 mixtures of antigen and adjuvant (15 emulsions, phosphate-buffered saline, and commercial alum-based adjuvant). Antigen-specific antibody titers from immunized mice serum were measured by an indirect enzyme-linked immunosorbent assay. Results All emulsions exhibited droplet sizes ranging from 322 to 812 nm and maintained zeta potential values between −30 mV to –10 mV for 4 weeks, indicating good physical stability as a vaccine adjuvant. Additionally, all emulsions were non-toxic, and they induced humoral immunity at a similar level compared to commercial alum-based adjuvant in the first immunization. However, 12% squalene-based oil-in-water emulsion containing 0.5% of ultra-high viscosity CMC (F15) showed significantly higher immune response than a commercial adjuvant in the second immunization. Conclusion Squalene-based oil-in-water emulsions could be conveniently prepared using SEDDS technique and are non-toxic and stable at room temperature storage. Moreover, squalene-based oil-in-water emulsions show enhanced immune induction with antigen; hence, they can possibly be used as effective adjuvants.

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Effects of excipients on the interactions of self-emulsifying drug delivery systems with human blood plasma and plasma membranes

Le-Vinh,

Le,

Phan

et al. 2024

Drug Deliv. and Transl. Res.

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Due to its versatility in formulation and manufacturing, self-emulsifying drug delivery systems (SEDDS) can be used to design parenteral formulations. Therefore, it is necessary to understand the effects of excipients on the behavior of SEDDS formulations upon parenteral administration, particularly their interactions with blood plasma and cell membranes. In this study, we prepared three neutrally charged SEDDS formulations composed of medium-chain triglycerides as the oil phase, polyoxyl-35 castor oil (EL35) and polyethylene glycol (15)-hydroxystearate (HS15) as the nonionic surfactants, medium-chain mono- and diglycerides as the co-surfactant, and propylene glycol as the co-solvent. The cationic surfactant, didodecyldimethylammonium bromide (DDA), and the anionic surfactant, sodium deoxycholate (DEO), were added to the neutral SEDDS preconcentrates to obtain cationic and anionic SEDDS, respectively. SEDDS were incubated with human blood plasma and recovered by size exclusion chromatography. Data showed that SEDDS emulsion droplets can bind plasma protein to different extents depending on their surface charge and surfactant used. At pH 7.4, the least protein binding was observed with anionic SEDDS. Positive charges increased protein binding. SEDDS stabilized by HS15 can adsorb more plasma protein and induce more plasma membrane disruption activity than SEDDS stabilized by EL35. These effects were more pronounced with the HS15 + DDA combination. The addition of DDA and DEO to SEDDS increased plasma membrane disruption (PMD) activities, and DDA (1% w/w) was more active than DEO (2% w/w). PMD activities of SEDDS were concentration-dependent and vanished at appropriate dilution ratios. Graphical abstract

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Preparation of Squalene Oil-Based Emulsion Adjuvants Employing a Self-Emulsifying Drug Delivery System and Assessment of Mycoplasma hyopneumoniae-Specific Antibody Titers in BALB/c Mice

Cited by 8 publications

References 24 publications

Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

Development of Squalene-Based Oil-in-Water Emulsion Adjuvants Using a Self-Emulsifying Drug Delivery System for Enhanced Antigen-Specific Antibody Titers

Effects of excipients on the interactions of self-emulsifying drug delivery systems with human blood plasma and plasma membranes

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