Article

Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: Formulation development and bioavailability assessment

Authors:
  • Texas A&M University - College Station, Rangel College of Pharmacy
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Abstract

The goals of our investigations are to develop and characterize self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10 (CoQ10), using polyglycolyzed glycerides (PGG) as emulsifiers and to evaluate their bioavailability in dogs. Solubility of CoQ10 was determined in various oils and surfactants. SEDDS consisted of oil, a surfactant and a cosurfactant. Four types of self-emulsifying formulations were prepared using two oils (Myvacet 9-45 and Captex-200), two emulsifiers (Labrafac CM-10 and Labrasol) and a cosurfactant (lauroglycol). In all the formulations, the level of CoQ10 was fixed at 5.66% w/w of the vehicle. The in vitro self-emulsification properties and droplet size analysis of these formulations upon their addition to water under mild agitation conditions were studied. Pseudo-ternary phase diagrams were constructed identifying the efficient self-emulsification region. From these studies, an optimized formulation was selected and its bioavailability was compared with a powder formulation in dogs. Medium chain oils and Myvacet 9-45 provided higher solubility than long chain oils. Efficient and better self-emulsification processes were observed for the systems containing Labrafac CM-10 than formulations containing Labrasol. Addition of a cosurfactant improved the spontaneity of self-emulsification. From these studies, an optimized formulation consisting of Myvacet 9-45 (40%), Labrasol (50%) and lauroglycol (10%) was selected for its bioavailability assessment. A two-fold increase in the bioavailability was observed for the self-emulsifying system compared to a powder formulation. SEDDS have improved the bioavailability of CoQ10 significantly. The data suggest the potential use of SEDDS to provide an efficient way of improving oral absorption of lipophilic drugs.

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... Tolvaptan is classified as a BCS Class IV drug with low solubility (50 ng/mL, 25 • C, pH [2][3][4][5][6][7][8][9][10][11][12] in aqueous solution and low permeability. The bioavailability was extremely low, 0.63% and 2% in rats and dogs, respectively, after oral dosing of power prepared using a jet-mill [4]. ...
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... The statistical experimental model was designed using Design-Expert software (V. 10 lack-of-fit formulations, 4 replicate formulations, and 1 additional center point formulation, were arranged randomly (Tables 1 and 2). The dependent variables for determining the optimal SMEDDS formulation were the mean droplet size (Y1) and the percentage of drug dissolved at 15 min (Y2) and at 60 min (Y3). ...
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... Presence of high concentration of surfactant (tween 80) to stabilize oil-water interface in F8 might be contributing the smaller particle size. This result was in consistent with previous finding reported in Wei et al., (2005) [20], Kommuru and Gurley, (2001) [21] and Levy and Benita, (1990) [22]. ...
... Presence of high concentration of surfactant (tween 80) to stabilize oil-water interface in F8 might be contributing the smaller particle size. This result was in consistent with previous finding reported in Wei et al., (2005) [20], Kommuru and Gurley, (2001) [21] and Levy and Benita, (1990) [22]. ...
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... In addition, an increase in cosurfactant concentrations decreased the droplet size and PDI. This may be, at least in part, because the cosurfactant could lower the interfacial tension and fluidize the hydrocarbon region of the interfacial film, decreasing the bending stress of the interface [31]. The nano-sized droplets from the developed SNEDDS could provide a large interfacial surface area for rapid drug release [13]. ...
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... is lipophilic and has a poor bioavailability. Since it is less soluble in water (Kommuru et al., 2001;McClements, 2013), to boost CoQ10's solubility and bioavailability when delivered orally, a lipid-free nano-CoQ10 system was designed and modified with several surfactants (Zhou et al., 2014). ...
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... Notwithstanding, the observed enhanced bioavailability profiles of some of these formulations may be attributed to a probable increase in drug dissolution that might have resulted from a large surface area generated by micro emulsification. 36 It has been established that drug molecules that possess partition coefficient (log P) values greater than 5 and quantitative solubility values of more than 50 mg/ml in triglycerides constitute potential candidates for intestinal lymphatic transport mechanism. This assertion was investigated by comparing the lymphatic transport mechanisms of dichloro diphenyl tetrachloroethane -DDT (possessing log P 6.19) and hexachlorobenzene -HCB (possessing log P 6.53). ...
... Among the tested oil systems like oleic acid, olive oil and peanut oil exhibited less solubility of DAP (≤5 mg/mL) whereas capryol 90 and octanoic acid exhibited better solubility of DAP 15.5 ± 1.24 mg/mL and 15.8 ± 1.06 mg/mL, respectively. The spontaneous nanoemulsion formation of a SNEDDS is facilitated by the addition of a co-surfactant to the system, which helps to minimize the interfacial tension between the aqueous and oily phases [28,29]. PEG 400 has been incorporated as a co-surfactant in the liquid phase as it also exhibited desirable solubility of DAP (22.45 ± 1.12 mg/mL) to further improve the drug loading. ...
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... In the area of pharmaceuticals, emulsions have broader applications in drug delivery systems as most of the drug molecules are hydrophobic in nature, which poses solubility and bioavailability problems in drug delivery to the body. So, the emulsions can be of great importance in the rapid delivery of both hydrophilic and lipophilic drugs due to the presence of the characteristics of both water and lipids, which can be delivered either through the oral route or through the topical route (Ahmad et al., 2011;Kommuru, 2001). A pseudoternary phase diagram is a tool that optimizes the three components of any typical emulsion, i.e., water, oil, and surfactant, to obtain the concentration range of these components, which form a stable emulsion. ...
Chapter
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... In the area of pharmaceuticals, emulsions have broader applications in drug delivery systems as most of the drug molecules are hydrophobic in nature, which poses solubility and bioavailability problems in drug delivery to the body. So, the emulsions can be of great importance in the rapid delivery of both hydrophilic and lipophilic drugs due to the presence of the characteristics of both water and lipids, which can be delivered either through the oral route or through the topical route (Ahmad et al., 2011;Kommuru, 2001). A pseudoternary phase diagram is a tool that optimizes the three components of any typical emulsion, i.e., water, oil, and surfactant, to obtain the concentration range of these components, which form a stable emulsion. ...
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This chapter emphasizes the important tools of cheminformatics that are proven to be well organized for pharmaceutical data analysis and applications. Cheminformatics acts as an interface between physics, chemistry, biology, mathematics, biochemistry, statistics, and informatics. Cheminformatics refers to solving chemical and synthetic problems effectively by making use of information tools available in the wide space of the web. Each of the tools described in the chapter has been extensively discussed in many research publications but this work gives a complete overview of the major tools and techniques that are able to aid in the study of many important applications such as drug discovery processes and other biochemical applications. It connects molecular modeling with cheminformatics very well. This chapter discusses briefly almost all aspects of molecular modeling and drug designing that utilize cheminformatics tools, ranging from quantitative structure activity relationship analysis, similarity searching to deriving pharmacophores, and shortlisting datasets to forming combinatorial libraries. Cheminformatics aids in designing reactions and possible synthetic routes, structural elucidation of molecules isolated from various biological, and environmental sources or from reaction pathways.
... All rights reserved. lipids, which can be delivered either through the oral route or through the topical route (Ahmad et al., 2011;Kommuru, 2001). A pseudoternary phase diagram is a tool that optimizes the three components of any typical emulsion, i.e., water, oil, and surfactant, to obtain the concentration range of these components, which form a stable emulsion. ...
Book
Chemoinformatics and Bioinformatics in the Pharmaceutical Sciences brings together two very important fields in pharmaceutical sciences that have been mostly seen as diverging from each other: chemoinformatics and bioinformatics. As developing drugs is an expensive and lengthy process, technology can improve the cost, efficiency and speed at which new drugs can be discovered and tested. This book presents some of the growing advancements of technology in the field of drug development and how the computational approaches explained here can reduce the financial and experimental burden of the drug discovery process. This book will be useful to pharmaceutical science researchers and students who need basic knowledge of computational techniques relevant to their projects. Bioscientists, bioinformaticians, computational scientists, and other stakeholders from industry and academia will also find this book helpful.
... lipids, which can be delivered either through the oral route or through the topical route (Ahmad et al., 2011;Kommuru, 2001). A pseudoternary phase diagram is a tool that optimizes the three components of any typical emulsion, i.e., water, oil, and surfactant, to obtain the concentration range of these components, which form a stable emulsion. ...
Chapter
An emulsion is a biphasic dispersion of two immiscible liquids in which one phase is evenly distributed as a fine globule form (dispersed phase) into the other continuous phase (dispersion medium). Emulsions are thermodynamically unstable, which tend to separate into two phases, i.e., aqueous and oily phases on standing undisturbed; therefore requires special additives named emulsifying agents to be stable for longer time. Depending on the phases, emulsions may be classified as oil-in-water (O/W) emulsion and water-in-oil (W/O) emulsion. Complex forms of these two emulsions are called double emulsions or multiple emulsions. When an emulsion is emulsified with another phase, e.g., a W/O emulsion, and emulsified again with water, it produces a water-in-oil-in-water (W/O/W) emulsion. The globule size of the dispersed phase in an emulsion depends on many factors, such as the method of preparation, nature of oil used, and type of emulsifying agent. This categorizes the emulsion as a macroemulsion (0.1e10 mm), microemulsion (5e50 nm), and nanoemulsion (20e1000 nm), which further determine the stability of the emulsion. The larger the size of droplets of the dispersed phase, the smaller the stability because the large droplets tend to coalescence with each other, which leads to phase separation. Therefore macroemulsions are less stable than microemulsions over time. Addition of surfactants (emulsifying agents) reduces the interfacial tension at the oil and water interface and increases the miscibility of these two phases, which makes them stable for a prolonged time. The emulsifiers are amphiphilic molecules, which contain both polar and nonpolar groups that form micelles around the dispersed phase at the liquid interface and hold both liquids tightly to make them miscible.
... However, the modern SEDDS formulations design profoundly depends on the experimentation by the skills of independent researchers. The process of SEDDS formulation design includes three step as below: the determination of drug solubility in several oils, surfactants and cosurfactants; dissolve the mixture of oils, surfactants and cosurfactant into distilling water, and then draw the ternary phase diagram to identify the self-emulsion area; the evaluation of the SEDDS formulation by multiple characterization methods 9,10 . Therefore, current formulation development of SEDDS urgently need some effective methods to assist experimental design. ...
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Pioglitazone Hydrochloride (PGZ) suffers from poor aqueous solubility. The aim of this research was to design orally disintegrating tablets with self-nanoemulsifying properties (T-SNEDDS) to improve the Pioglitazone solubility and dissolution rate. Three liquid self-nanoemulsifying systems (L-SNEDDS) were formulated and evaluated for transmittance percentage, emulsification time, particle size, Poly dispersity index (PDI), percentage of content, solubility and stability. The optimum L-SNEDDS formula was converted to a solidified self-nanoemulsifying drug delivery system (S-SNEDDS) by adsorption on Syloid (SYL). Powder characterization tests, such as flowability tests, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and scanning electron microscopy (SEM), were performed for the selected S-SNEDDS formulation. Orally disintegrating tablets (ODT) were formulated by blending S-SNEDDS with tableting excipients. The ODT tablet batch composed of Prosolv was selected for tablet quality control tests, such as hardness, friability, disintegration time, content uniformity, weight variation, in vitro release, in vivo studies and accelerated stability studies. ODT tablets showed accepted mechanical properties and rapid disintegration time (<30 s). No drug degradation was observed at 3 months into the accelerated stability study. The optimized L-SNEDDS, S-SNEDDS and ODT (T-SNEDDS), showed significant enhancement of PGZ in vitro dissolution profiles compared to the pure drug (p > 0.05). In vivo pharmacokinetic and pharmacodynamic evaluation of ODTs showed better behavior compared to the raw drug suspension and the commercial tablet (p > 0.05). Orally disintegrating tablets revealed a promising potential to improve Pioglitazone poor aqueous solubility, dissolution profile and bioavailability.
... Moreover, it is well distributed within the skin layer and in vitro tests have proved it biocompatible with keratinocytes and fibroblasts, indicating its protective effect against oxidative damage and the potential for wound healing 25 . Previous reports have evaluated the use of nanocarriers for CoQ10 delivery such as a self-emulsifying drug delivery system (SEDDS) 26 , ethosomes 27 , transethosomes 28 , and microemulsion 29 . The use of transethosomes successfully encapsulated CoQ10 up to 97% in vesicles and produced > 95% drug deposition in different skin layers resulting in high efficacy for androgenic alopecia 28 . ...
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Coenzyme Q10 (CoQ10) is a naturally produced organic molecule which acts as an antioxidant agent, including in skin anti-ageing, and plays a major role in the social determinants of health. However, its level in the body will decrease during ageing. Therefore, an external supplement is required to repair damaged skin, especially the skin dermis layer. This study aims to evaluate the use of a protransfersomal emulgel to improve the skin delivery and stability of CoQ10 which demonstrates low water solubility, poor permeability and instability. CoQ10 was initially dissolved in oleic acid at a weight ratio of 1:56. Protransfersome was then loaded with CoQ10 (Protransf-CoQ10) and prepared using a composition of L-α-Phosphatidylcholine and Tween 80 at a molar ratio of 85:15. The Protransf-CoQ10 was dispersed in an emulgel base consisting of Tween 80 and Span 80 to produce Protransf-CoQ10 emulgel. The in vivo studies of anti-aging activity and irritability were further evaluated by applying daily 200 mg of emulgels twice a day to a 4 cm ² section on the back of a UV-ray aging-induced male Balb/c mouse 20 min before irradiation. The results showed that Protransf-CoQ10 could transform into transfersomal vesicles with particle sizes of approximately 201.5 ± 6.1 nm and a zeta potential of − 11.26 ± 5.14 mV. The dispersion of Protransf-CoQ10 into emulgel base resulted in stable Protransf-CoQ10 Emulgel during 28 days of observation at low temperatures. Moreover, the in vivo study revealed that Protransf-CoQ10 Emulgel successfully increases the collagen density and number of fibroblast cells in UV radiation skin-aged induced-mice which reflects its potential for repairing the skin ageing process. In addition, the 24-h topical application of Protransf-CoQ10 Emulgel showed that no erythema or skin rash was observed during the study. In conclusion, loading CoQ10 into protransfersomal Emulgel successfully enhanced the stability and anti-ageing efficacy enabling its potential use as anti-ageing cosmetics.
... It was noted that increasing the concentration of surfactant enhanced the rate of self-emulsification, and a percentage of surfactant below 60% showed poor emulsification in accordance with a previous study (Halder et al., 2018). A higher concentration of surfactant can stabilize the oil-water interface and form a fine emulsion of small droplet size with low viscosity (Kommuru et al., 2001). PEG 400 as a co-surfactant can improve the dispersibility by reducing interfacial tension between oil and water, possibly leading to the acceleration of drug absorption in the gastrointestinal tract (Chen, 2008). ...
Article
The present study was designed to develop a self‐emulsifying drug delivery system (SEDDS) of (R)‐α‐lipoic acid (RLA) to improve the physicochemical and nutraceutical properties of RLA. RLA/SEDDS was prepared using medium‐chain triglycerides, tween 80, and polyethylene glycol 400 as oil, surfactant, and co‐surfactant, respectively. The preferable composition of SEDDS was selected according to a pseudo‐ternary phase diagram for improved emulsification properties, and its physicochemical and pharmacokinetic properties were evaluated. RLA/SEDDS showed the immediate formation of fine micelles with a mean droplet size of approximately 260 nm when introduced into aqueous media. In simulated gastric fluid, this system could significantly improve the dissolution behavior of RLA and prevent the degradation of RLA, possibly due to the encapsulation of RLA into the emulsion structure. Following the oral administration of RLA/SEDDS (10 mg RLA/kg) in rats, systemic exposure to RLA and dihydrolipoic acid (DHLA), a reduced form of RLA, increased by 7‐ and 3‐fold, respectively. The improved dissolution and gastric stability of RLA could contribute to enhancing systemic exposure to RLA and DHLA after oral administration. From these findings, RLA/SEDDS might be an efficacious dosage option for improving the oral bioavailability as well as nutraceutical properties of RLA.
... Prepared SNEDDS must be dispersed spontaneously in an aqueous medium on mild shaking. The emulsification time of the drug-loaded L-SNEDDS formulations was evaluated according to USP (United State Pharmacopeia) by dissolution apparatus II [44]. For sample preparation, 1 ml of L-SNEDDS was diluted with 100 ml of double-distilled water (1:100 dilutions), 0.1 N HCl and 6.8 pH phosphate buffer in separate glass beakers. ...
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Curcumin (CUR) and piperine (PIP) are very well-known phytochemicals that claimed to have many health benefits and have been widely used in foods and traditional medicines. This study investigated the therapeutic efficacy of these compounds to treat Alzheimer’s disease (AD). However, poor oral bioavailability and permeability of curcumin are a major challenge for formulation scientists. In this research study, the researcher tried to enhance the bioavailability and permeability of curcumin by a nanotechnological approach. In this research study, we developed a CUR–PIP-loaded SNEDDS in various oils. Optimised formulation NF3 was subjected to evaluate its therapeutic effectiveness on AD animal model in comparison with untreated AD model and treated group (by market formulation donepezil). On the basis of characterisation results, it is confirmed that NF3 formulation is the best formulation. The optimised formulation shows a significant dose-dependent manner therapeutic effect on AD-induced model. Novel formulation CUR–PIP solid-SNEDDS was successfully developed and optimised. It is expected that the developed S-SNEDDS can be a potential, safe and effective carrier for the oral delivery of curcumin to the brain. To date, this article is the only study of CUR–PIP-loaded S-SNEDDS for the treatment of AD.
... 58 Various studies have shown that surfactants with an HLB value of greater than 10 generally stabilize oil-in-water nanoemulsions. 59,60 Herein, the HLB was adjusted to 12 according to the previous optimized study. 41 ...
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Self-assembled nanoparticles present unique properties that have potential applications in the development of a successful drug delivery system. Doxorubicin (DOX) is an important anti-neoplastic anthracycline chemotherapeutic drug widely described. However, it suffers from serious dose-dependent cardiotoxicity. d-Limonene is a major constituent of numerous citrus oils that is considered a specific monoterpene against free radicals producing antioxidant activity. Herein, we aimed to design three types of self-assembled nanodelivery systems (nanoemulsion, niosomes, and polylactide nanoparticles) for loading both DOX and d-limonene to enhance the solubilization of d-limonene and provide antioxidant activity with excellent anticancer activity. As confirmed by dynamic light scattering and transmission electron microscopy, the nanoparticles were prepared successfully with diameter sizes of 52, 180, and 257 nm for the DOX-loaded nanoemulsion, niosomes, and polylactide nanoparticles, respectively. The zeta potential values were above -30 mV in all cases, which confirms the formation of stable nanoparticles. The loading efficiency of DOX was the highest in the case of the DOX-loaded nanoemulsion (75.8%), followed by niosomes (62.8%), and the least was in the case of polylactide nanoparticles with a percentage of 50.2%. The in vitro release study of the DOX-loaded nanoparticles showed a sustained release profile of doxorubicin with the highest release in the case of DOX-loaded PDLLA nanoparticles. The kinetic release model for all developed nanoparticles was the Peppas-Sahlin model, demonstrating DOX release through Fickian diffusion phenomena. Moreover, all developed nanoparticles maintain the antioxidant activity of d-limonene. The cytotoxicity study of the DOX-loaded nanoparticles showed concentration-dependent anticancer activity with excellent anticancer activity in the case of the DOX-loaded nanoemulsion and polylactide nanoparticles. These nanoparticles will be further studied in vivo to prove the cardioprotective effect of d-limonene in combination with DOX.
... Brookfield Viscometer (LVDV-E Model) is used to find the viscosity of optimized SMEDDS at spindle #63, at 10 rpm for 5 min. [30] Dynamic light scattering with Zeta sizer HSA 3000 (Malvern Instrument Ltd., HAS 3000) is used for the size analysis of the SMEDDS. Samples were placed in square glass cuvettes and droplet size analysis was carried out for SMEDDS formulations. ...
... Isopropyl myristate and Nigella oil as an oily phase, and Cremophor as a surfactant, determined the lower size of ME-2-OA in respect to ME-1.OA. The droplet size of the microemulsion is greatly affected by the oily phase, type of surfactant and cosurfactant and their ratio [57,58]. The addition of surfactants to the microemulsion systems causes the interfacial film to stabilize and condense, while the addition of cosurfactant causes the film to expand [58]. ...
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Oleanolic acid (OA) is the main triterpenic acid of olive leaves known for numerous pharmacological properties, including antioxidant activity. However, it is poorly soluble in water and consequently with low bioavailability, which limits its pharmacological application. Microemulsions (MEs) are dispersed systems consisting of two immiscible phases that promote rapid solubilization and absorption in the gastrointestinal tract. To improve both solubility and intestinal permeability of this molecule, OA has been formulated in two different microemulsions (ME-1 and ME-2). A solubility screening was carried out to select the ME components, and pseudoternary phase diagrams were constructed to evaluate the region of existence and select the appropriate amount of the constituents. ME-1 was prepared using Capmul PG-8/NF as the oily phase, and Transcutol and Tween 20 (7:3) as surfactants, while ME-2 contained Nigella oil and Isopropil myristate as the oily phase, and Transcutol HP and Cremophor EL (2:1) as surfactants. The OA solubility was increased by 1000-fold and 3000-fold in ME-1-OA and ME-2-OA, respectively. The MEs’ droplet size and the PdI were evaluated, and the stability was assessed for 8 weeks by monitoring chemical and physical parameters. The parallel artificial membrane permeability assay (PAMPA) also demonstrated an enhanced intestinal permeability of both OA formulations compared with free OA. The potential ability of both MEs to enhance the bioactivity of OA against LPS-induced oxidative stress in RAW 264.7 murine macrophages was also investigated. Overall, this study suggests that both MEs promote a bio-enhancement of the protective action of OA against the LPS-induced pro-oxidant stress in macrophages. Overall, this study suggests that MEs could be an interesting formulation to improve OA oral bioavailability with potential clinical applications.
... The higher hydrophilicity of PG (short chain) compared to the other tested co-surfactants can explain its greater success. It was proved that a surfactant/co-surfactant mixture with higher hydrophilicity or hydrophilic lipophilic balance (HLB value) will help the formation of O/W type nanoemulsions [37]. The use of PG as a co-surfactant has previously proved a success in the preparation of this type of nanocarrier [38,39]. ...
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β-Sitosterol glucoside (SG), isolated from Senecio petasitis (Family Asteraceae), was loaded in self-nanoemulsifying drug delivery systems (SEDDS) in a trial to enhance its solubility and biological effect. Various co-surfactants were tested to prepare a successful SEDDS. The selected SG-loaded SEDDS had a droplet size of 134 ± 15.2 nm with a homogenous distribution (polydispersity index 0.296 ± 0.02). It also demonstrated a significant augmentation of SG in vitro release by 4-fold compared to the free drug suspension. The in vivo insulin sensitivity and antidiabetic effect of the prepared SG-loaded SEDDS were further assessed in streptozotocin-induced hyperglycemic rats. The hypoglycemic effect of SG-loaded nanosystem was evidenced by decreased serum glucose and insulin by 63.22% and 53.11%, respectively. Homeostasis model assessment-insulin resistance (HOMA-IR) index demonstrated a significant reduction by 5.4-fold in the diabetic group treated by SG-loaded nanosystem and exhibited reduced glucagon level by 40.85%. In addition, treatment with SG-loaded nanosystem significantly decreased serum MDA (malondialdehyde) and increased catalase levels by 38.31% and 64.45%, respectively. Histopathological investigations also supported the protective effect of SG-loaded nanosystem on the pancreas. The promising ability of SG-loaded nanosystem to ameliorate insulin resistance, protect against oxidative stress, and restore pancreatic β-cell secretory function warrants its inclusion in further studies during diabetes progression.
... The mean values of z for three independent samples were documented. [12] ...
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The current study aims to formulate an anti-hypertensive drug manidipine self-nanoemulsifying drug delivery system (SNEDDS) employing different novel polymers to enhance solubility and drug release manidipine. The optimal concentration of excipients chosen based on solubility study further confirmed by self-emulsification region of pseudo ternary phase diagram. Manidipine SNEDDS optimized employing box-behnken design (BBD) through the study of factors - the amount of capryol 90(A), cremophor RH40 (B) and triacetin (C) and responses -droplet size (Y1), zeta potential (Y2), and cumulative percentage of drug release after 60 minutes (Y3). All formulations were evaluated for particle size, zeta potential, polydispersity index, entrapment efficiency, drug content, and in-vitro drug release. The optimized formulation was characterized for FTIR, SEM, and stability studies. The study indicates that manidipine optimized formulation MF11 comprising of capryol 90 (40.0%), cremophor RH40 (10.0%) and triacetin (30.0%) exhibited minimum droplet size (76.5 ± 2.87), best zeta potential (-24.7 ± 1.31mV) and entrapment efficiency (98.23 ± 1.74%) content uniformity (99.12 ± 1.28%) maximum drug release (98.79 ± 1.68%). The fourier transform infrared spectroscopy (FTIR) studies of MF11 indicated no significant interaction amid the drug and formulation excipients. The scanning electron microscopy (SEM) data revealed that particle size is in the nanometer range with a zeta potential value >5 mV indicating higher absorption and stability. Accelerated stability studies indicated the formulation to be stable for 3 months. Hence the results revealed that application of SNEDDS formulation technique for manidipine increased solubility and drug release.
... To achieve our goal of enhancing the mucosal permeation of the drug, one of the re-emerging trends in the field of drug delivery, i.e., utilization of SEDDS (a commonly known carrier for lipophilic drugs) was employed [28][29][30]. SEDDS may follow variable mechanisms to increase bioavailability but before being in contact with the gastrointestinal fluids, SEDDS form oil in water emulsion as a result of the agitation produced naturally due to the peristaltic movement of the gastrointestinal system [31]. The selection of the ingredients for the formulations was based upon the previous studies regarding SEDDS [20,32,33], with some modifications, in particular the co-solvent. ...
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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.
... It is estimated that around 40% of the newly discovered Chemical Entities (NCEs) by the researchers and even many of the existing entities are water-immiscible and existence of the lipophilic compounds leads to low oral bioavailability, high Intra-and Intersubject Inconsistency in oral drug absorption and low-dose proportionality. In order to overcome the problem in existing drugs which are having low water solubility, numerous formulation techniques are listed in the pharmaceutical literature which includes the use of permeation enhancers, surfactants, nanoparticles, micronization, lipids and cyclodextrins [6]. In the coming years, the ability to deliver drugs which are poorly soluble will increase significantly as many pharma industry researchers are depending upon NCEs for a bigger stake of revenues in the market. ...
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Modern mode of drug delivery system has been constructed to defeat the main issues linked with the traditional drug delivery system. This particular review will give an idea about the retinoid based nanoemulsion system. The main focus is to briefly explain the different aspects of nanoemulsion formulations, procedure of preparation, portrayal procedures with special focus on different utilizations of nanoemulsion in various area. Nanoemulsions are colloidal dispersion system that are composed of two non-miscible mixtures mixed along with surfactants and co-surfactants emulsifier to develop a single phase which is thermodynamically balanced. Nanoemulsion droplet sizes commonly fall in the range of 20-200 nm and show thin size distributions. Nanoscale dispersions of droplets of one liquid in another insoluble liquid can be achieved by using extreme emulsification procedures. Retinoid, better known as vitamin A are lipophillic in nature. They are vastly used for therapeutic purpose in skin disorders. Retinoid are among one of the fundamental compound found in cosmeceuticals. They are the most investigated compound with sufficient information supporting them. Retinoid include natural or synthetic derivatives that decrease hyperpigmentation and limit collagen breaking enzymes. Nanoemulsions comprise of tiny oil-in-water globules, havingless than 100 nm diameter. They are delicate frameworks by nature. Traditional formulations are restricted becauseof irritation, poor aqueous solubility and high instability of retinoid. But administration of retinoid in aqueous mediais enabled due to nanoemulsion based formulation, decreasing degradation, controlled release, high stability,improve targeting and enhance efficacy. Nanoemulsion show incredible guarantee for the future of beauty careproducts, diagnostics, treatments, and biotechnologies. The unique properties of nanoemulsions such as highstability, translucent appearance and efficient drug delivery attribute has attracted researchers interest which is oneof the reason why the usage of nanoscale emulsion has grown rapidly during the recent decades. Nanoemulsionformulation might be considered as viable, safe and with enhanced bioavailability. Comparing to the conventionaltopical formulation, nanoemulsion possess advance transdermal permeation of various drugs such as gels andemulsions. Nanoemulsion is significantly important in modern pharmaceutical industry and provide many benefitsin drug delivery systems. This review is focused on the most recent literature on developments of retinoid basednanoemulsions.
... Several CoQ10 incorporation and delivery methods have been investigated to enhance its applications in aqueous-based products, increase its bioavailability, and protect it from the outside environment. For example, self-emulsifying drug delivery system [14], binary solid dispersion [15], emulsification [16], lipid carrier [17], direct dispersion of CoQ10 into a polysaccharide (amylomaize starch and its dextrin) aqueous solution [18], and encapsulation [19] are some of the approaches investigated. ...
Article
Supercritical adsorptive precipitation (SAP) can be employed to load hydrophobic bioactives onto aerogels formed using the Pressurized Gas eXpanded liquid (PGX) technology to prepare novel delivery systems. The objective of this study was to investigate the effects of SAP parameters on the coenzyme-Q10 (CoQ10) loading onto PGX-processed sodium alginate (PGX-SA) and its physicochemical properties. Within the ranges tested, higher recirculation time (50 min) and flow rate (262 mL/min), lower pressure (200 bar), and higher surface area biopolymer resulted in higher CoQ10 loading (46.9±3.0% w/w). Helium ion microscopy revealed a rather uniform coating of PGX-SA fibrils, covering the porous structure. Thermal and crystallinity analyses demonstrated a decrease in CoQ10 crystallinity. CoQ10-loaded PGX-SA suspension in water remained stable for 50 days at 4 oC. These findings demonstrate the potential of PGX Technology combined with SAP for developing delivery systems for hydrophobic bioactives to increase water dispersibility and suspension stability, which can boost their bioavailability.
... [17] Neoral spontaneously forms a transparent & thermo-dynamically stable dispersion with droplet size below 100 nm when introduced into an aqueous medium. [18,19] SEDDS may be solid or liquid in nature and they may be formulated into tablets, capsules, pellets, solid dispersions, microspheres, nanoparticles or dry emulsions. ...
Article
Low aqueous solubility and thereby low oral bioavailability is a major concern for formulation scientist as many recent drugs are lipophillic in nature and their lower solubility and dissolution is a major drawback for their successful formulation into oral dosage forms. Aqueous solubility of drugs can be increased by different methods such as salt formation, solid dispersion, complex formation but Self Emulsifying Drug Delivery System (SEDDS) is gaining more attention for improving the solubility of lipophillic drugs. SEDDS are ideally isotropic mixtures of drug, oil, surfactant and/or co surfactant. They spontaneously form emulsion on mixing with water with little or no energy input. Generally SEDDS are prepared using triglycerides and non ionic surfactants. The present review provides an updated account of the advancements in SEDDS with regard to the selection of lipid systems for current formulations, dosage forms for SEDDS, solidification techniques, characterization and their applications. © 2011 IGJPS. All rights reserved
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Biomass-based surfactants have excellent surface activities, showing the common characteristics of natural biomass including biocompatibility, biodegradability and non-toxicity, which are environmental-friendly and accord with the green development direction. In this study, a keratin based quaternary ammonium salt surfactant (denoted as E-K) was prepared by cationic modification of keratin with epoxypropyldodecyldimethylammonium chloride (EPDDMAC). The characterization of E-K by FTIR and the conversion rate of -NH2 in keratin confirmed the successful preparation of E-K. Subsequently, surface activity such as surface tension (γcmc) and critical micelle concentration (cmc), physicochemical properties such as HLB value, isoelectric point, foaming property and emulsifying property, as well as antibacterial activity and biodegradability were investigated. The results show that E-K possesses good surface activity, acceptable emulsifying and foaming ability. The HLB of E-K is 14-15, and it has excellent compatibility with commercial surfactants commonly used in hair care products. Particularly, E-K is a betaine zwitterionic surfactant, and its isoelectric point increases from 3.8 to 9.2 due to cationization. This means that the quaternized keratin hydrolysate is easily adsorbed on the hair surface, and makes the hair surface smoother and denser, which was proved by the adsorption test and SEM observation. Furthermore, E-K has outstanding antibacterial activity against E. coli and S. aureus, and the BOD5/CODCr value indicated that it is easily biodegradable. Therefore, the prepared biomass-based surfactant (E-K) has great potential application in hair care products and other products related to antibacterial and biodegradable surfactants.
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The objective of present study was to improve solubility and dissolution rate of rosuvastatin by formulating it as a self micro emulsifying drug delivery system (SMEDDS). The SMEDDS were prepared by using capmul McM and capryol 90 as oils Polaxomer 407 as surfactant and Transcutol hP and Soluphor P as co-surfactants. The liquid SMEDDS were then converted into free flowing powder by adsorbing onto solid carriers like magnesium aluminium silicate. The prepared SMEDDs were further evaluated for particle size, phase separation, droplet size, drug content and for in vitro drug release. From the results, it was observed that the SMEDDs were found to be stable. Among the prepared SMEDDS the formulations prepared with oil to co-surfactant ratios of 1:3 showed highest rates of dissolution. The FTIR and DSc analysis on optimised formulations revealed that there were no major interactions between drug and excipients.
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Excess reactive oxygen species can cause oxidative stress and lead to the progression of cardiovascular diseases. Pandanus tectorius fruit (PTF) is a promising source of herbal medicine with antioxidant activity. However, the oral administration is hindered due to the semi-polar properties of the extract. The solubility of the extract can be potentially improved through synthesis of a self-nanoemulsifying drug delivery system (SNEDDS). This study aims to formulate nanoemulsion of the extract by means of self-nanoemulsification approach using caprylic triglycerides, kolliphor RH40, and propylene glycol. It was found that when tested in water, simulated gastric, and intestinal fluid, PTF-SNEDDS had emulsification times of 38.17, 49.44, and 45.29 sec, indicating grade A formulation. The clarity level of PTF-SNEDDS, particle size, and zeta potential was at 99.3%, 41.5 ± 1.1 nm, and -25.9 mV. The antioxidant activity of PTF-SNEDDS was 1.6 times higher than PTF extracts. It can be concluded that PTF extract can be formulated into SNEDDS and stable in gastrointestinal conditions.
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Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability. Simvastatin-induced effects were prevented by co-incubation with mevalonic acid. When myotubes were incubated with 60 μM simvastatin, mitochondrial CoQ content decreased while co-incubation with CoQ nanodisks (ND) increased mitochondrial CoQ levels and improved cell viability. Incubation of myotubes with simvastatin also led to a reduction in oxygen consumption rate (OCR). When myotubes were co-incubated with simvastatin and CoQ ND, the decline in OCR was ameliorated. The data indicate that CoQ ND represent a water soluble vehicle capable of delivering CoQ to cultured myotubes. Thus, these biocompatible nanoparticles have the potential to bypass poor CoQ oral bioavailability as a treatment option for individuals with severe CoQ deficiency syndromes and/or aging-related CoQ depletion.
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Senescent cells accumulation can contribute to the development of several age-related diseases, including cancer. Targeting and eliminating senescence cells, would allow the development of new therapeutic approaches for the treatment of different diseases. The 4N1Ks peptide, a 10 amino acid peptide derived from TSP1 protein, combines both features by targeting the CD47 receptor present in the surface of senescent cells and demonstrating senolytic activity, thereby representing a new strategy to take into account. Nonetheless, peptide drugs are known for their biopharmaceutical issues, such as low short half-life and tendency to aggregate, which reduces their bioavailability and limits their therapeutic potential. In order to overcome this problem, herein we propose the use of biodegradable and biocompatible sphingomyelin nanosystems (SNs), decorated with this peptide for the targeting of senescent cells. In order to efficiently associate the 4N1Ks peptide to the nanosystems while exposing it on their surface for an effective targeting of senescent cells, the 4N1Ks peptide was chemically conjugated to a PEGylated hydrophobic chain. The resulting SNs-4N1Ks (SNs-Ks), were extensively characterized for their physicochemical properties, by dynamic light scattering, multiple-angle dynamic light scattering, nanoparticle tracking analysis and atomic force microscopy. The SNs-Ks demonstrated suitable features in terms of size (∼ 100 nm), association efficiency (87.2 ± 6.9%) and stability in different biorelevant media. Cell toxicity experiments in MCF7 cancer cells indicated an improved cytotoxic effect of SNs-Ks, decreasing cancer cells capacity to form colonies, with respect to free peptide, and an improved hemocompatibility. Lastly, senescence escape preliminary experiments demonstrated the improvement of SNs-Ks senolytic activity of in chemotherapy-induced senescence model of breast cancer cells. Therefore, these results demonstrate for the first time the potential of the combination of SNs with 4N1Ks peptide for the development of innovative senolytic therapies to battle cancer.
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Current article is focused on recent advances in the formulation and characterization of Self Emulsifying Nanoemulsions in Drug Delivery. Self-Emulsifying Drug Delivery Systems (SEDDS) are the isotropic mixtures of oil, surfactant, co surfactant and drug that form oil in water Nanoemulsion when introduced into aqueous phase under gentle agitation. Nanoemulsions are novel drug delivery systems consisting of emulsified oil and water systems with mean droplet diameters ranging from 50 to 1000 nm. Usually, the average droplet size is between 100 and 500 nm and can exist as oil-in-water (o/w) or water-in-oil (w/o) form, where the core of the particle is either oil or water, respectively. A lot of techniques are available for enhancing absorption of poorly water-soluble drugs. One such approach is the use of lipid-based systems. Thus enhancement of aqueous solubility in such case is a valuable goal to successfully formulate them into bioavailable dosage forms. Nanoemulsions can be prepared by high-and low-energy methods. Both high-energy and low energy methods can produce stable Nanoemulsions. Nanoemulsion can be formulated for delivery of drugs through various routes. Nanoemulsions are well tolerated orally and on the skin and mucous membranes when used to deliver topically active drugs. Nanoemulsion globules can fuse with membranes of lipid-containing organisms facilitating penetration and transfer. Less amount of surfactant is required in Nanoemulsions compared to other emulsion systems. This can increase the bioavailability of poorly soluble drugs since small particles easily cross the absorption membrane. Furthermore, very small size provides large surface area which eases the solubilization and penetration through the skin or epithelial layer.
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The aim of this study was to enhance the solubility of Aceclofenac with a new polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soloplus ®) and formulate it in controlled release (CR) tablet dosage form by direct compression method with HPMC K-15. Solid dispersions were prepared in different ratio of Aceclofenac and Soloplus ® as F1, F2 and F3 with different polymer ratios i.e. 30%, 50%, and 70% respectively. All the quality control tests were performed for the prepared controlled release tablets. Drug polymer interaction studies of Aceclofenac and Soloplus ® were carried using FTIR and XRD. Dissolution study was carried out against Alkaris ® as a standard reference. The formulation F3 showed optimum results and followed zero order kinetics. The Soloplus ® improved the solubility of the drug and the CR formulation enhanced the delivery in a sustained manner. Hence, the CR formulation enhanced the delivery of aceclofenac in a sustained manner, thereby an efficient drug delivery may lead to an effective anti-inflammatory activity.
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Background: Despite the vast utility of polymeric nanocarriers in drug delivery, their promising role in formulating efficient transdermal drug delivery systems for managing various dis-eases has not been explored properly. Introduction: Polymeric nanocarriers have increased the interest of researchers with respect to im-proving intradermal and transdermal delivery of drugs having ominous penetration and solubility issues. Therefore, a range of invasive and noninvasive approaches have been extensively explored in transdermal delivery systems for the safe and effective transportation of drugs across the skin into the systemic circulation. Accordingly, this review emphasizes the recently used, effectively appli-cable invasive and noninvasive methodologies for formulating transdermal systems in the form of polymeric films/patches, microneedles, and nanocarriers for better penetration and bioavailability. Conclusion: Various novel methodologies for transdermal drug delivery systems offer countless benefits over conventional methods, but still, a safe and effective delivery system is the major chal-lenge in terms of reproducible pharmacokinetic and pharmacodynamic results.
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Coenzyme Q10(CoQ10) is a well-known lipophilic antioxidant with good prospects for practical application of different fields including foods and pharmaceutics but has the drawback of low oral bioavailability because of its water insolubility and instability. Pinus koraiensis nut oil(PNO) is excellent in nutritional content and contains a great amount of unsaturated fatty acids that are helpful to the human body. It is easily oxidized, however, due to the high degree of unsaturation in its own structure, which limits its application. The present study aimed to formulate and characterize a CoQ10 loaded nanoemulsion based on PNO to overcome these problems of CoQ10 and PNO. Simultaneously, the physiological effects of the CoQ10 and PNO can work together in a synergistic way. In this study, coenzyme Q10 nanoemulsion(CoQ10-NE) with good stability was prepared by high pressure homogenization(HPH) technology. The CoQ10-NE was evaluated by TEM, FTIR, encapsulation rate, stability and release behavior in vitro. The bioavailability and the relationship between cellular oxidative stress and anticancer of CoQ10-NE was studied by pharmacokinetic and activity of malondialdehyde(MDA), superoxidedismutase(SOD) and glutathione peroxidase(GPx) about mouse colon cancer cells(CT26. WT). The area under the curve(AUC0-ꝏ) of CoQ10-NE was 3.25 folds higher than that of CoQ10 suspension, indicating that the bioavailability and absorption of CoQ10-NE are greatly increased. Also, at the same time, CoQ10-NE has a protective effect on CT26. WT cell damage induced by H2O2 compared with CoQ10 suspension and blank nanoemulsion. The final formulation solved the insolubility and instability of CoQ10 during use, along with providing a new technology for preparing CoQ10-NE with a long-term stability and good antioxidants in the prevention of colon cancer.
Article
Oral anticancer therapy faces several drawbacks of low aqueous solubility, poor and irregular absorption from gastro-intestinal sites, high first-pass metabolism, food-influenced absorption, non-targeted delivery, severe systemic and local adverse effects, etc. Enhancement of oral bioavailability could reduce the drug load and associated adverse effects. Self-emulsifying drug delivery systems (SEDDS) can enhance in-vivo solubility and drug absorption from the gastrointestinal tract, bypass liver metabolism by lymphatic absorption and inhibit efflux transport. All these phenomena ultimately result in improved oral bioavailability. Anticancer drug delivery using the SEDDS has shown promising results for bioavailability and pharmacodynamic response. A handful number of researches have produced evidence of the successful loading of anticancer agents in SEDDS-based formulations. Various potent and established chemotherapeutic agents such as docetaxel, paclitaxel, etoposide, 5 Fluorouracil, doxorubicin etc. have been successfully formulated and evaluated. Improved bioavailability and reduction of dose might be possible by SEDDS. It could be effective for low-dose drugs. But, excessive surfactant-cosurfactant concentration, lacking predictive in-vitro models and adequate IVIVC, unavailability of toxicity data are certain challenges for future researchers. To date, no clinical trials have been recorded with anticancer drug loaded SEDDS. To avail the benefits of anticancer SEDDS, overcoming the challenges and further progression to clinical studies are required. Methods Hospital based retrospective, observational study in which all the confirmed cases of CSC (272) seen between 2010 and 2019 were included. Supplementary data was collected on follow up visits or through telephonic calls. Results The male: female ratio was 17:1; low socio-economic status was (155; 73.45%), and occupations such as drivers (61; 28.9%) and outdoor laborers (59; 27.96%) were the most commonly affected. The majority (78.05%; 185) were single expatriates. Financial worries (105; 50.72%) constituted the leading cause of stress. The usage of corticosteroids (83; 30.51%), nasal decongestants (14.70%) or both (17; 6.25%) within one year was common; mostly (82; 30.14%) for rhinitis/respiratory states, though grossly under-recognized. Muscle relaxants and psychotropic medications were the other major medications used by 24 (8.82%) and 25 (9.19%) cases prior to CSC. Seven of 15 women had at least one condition that alters the endocrinal milieu: Pregnancy (3), recent child birth (1), erratic oral contraceptive intake (1), menopause with liver dysfunction (1), hormone replacement therapy for menopause and endometriosis (1), ovarian cyst and infertility (1) hypothyroidism (3), and Cushing syndrome (1). Chronic/ recurrent forms were seen in 31.08%. There were too few glaucoma patients despite both CSC and glaucoma being common among our patients.
Article
Background Nanoemulsions (NEs) have been explored as nanocarriers for the delivery of many drugs and cosmeceuticals. The extraordinary expansion of using NEs is due to their capability to conquer the main challenges of conventional delivery systems such as short residence time with low patient acceptance, poor stability, low aqueous solubility, permeability, and hence bioavailability. Methods This review recapitulated the most recent pharmaceutical and cosmeceutical applications of NEs as effective delivery nanocarriers. The outputs of our research studies and the literature review on the latest NEs applications were assessed to highlight the NEs components, preparations, applications, and the improved quality and elegance of the used product. Results NEs are stable submicronic translucent dispersions with narrow droplet size distribution. They exhibited excellent ability to efficiently encapsulate therapeutics of diverse nature of drugs and cosmeceuticals. NE formulations showed superiority over conventional delivery approaches with overabundances of advantages through different routes of administration. This novel technology exhibited better aesthetic appeal, higher bioavailability, and a longer duration compared to the conventional delivery systems. Conclusion This novel technology holds promise for different therapeutics fields. However, the success of NEs use advocated the development of robust formulations, proper choice of equipment, ample process characterization, and assurance of their efficacy, stability, safety and cosmetic appeal.
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Tadalafil (TAD) is a poorly soluble, phosphodiesterase inhibitor used to treat erectile dysfunction. The primary goal of this project was to prepare nano-emulsions using ultrasonic technology to address TAD bioavailability concerns. The Box–Behnken design was employed to find prominent correlations between factors impacting the sono-emulsification process. The emulsifier concentration, amplitude level, and ultrasonication time were the independent factors, whereas the average droplet size (ADS) and polydispersity index (PDI) were designated as the response variables. TAD-loaded nano-emulsions (93–289 nm) were generated and the emulsifier concentration showed a crucial role in directing emulsion droplet size. The model desirability function was utilized to optimize a nano-emulsion with a small ADS (99.67 ± 7.55 nm) and PDI (0.45 ± 0.04) by adjusting the emulsifiers concentration, amplitude level, and ultrasonication time at 9.85%, 33%, 49 s, respectively. The optimized nano-emulsions did not demonstrate any precipitation or phase separation after stability stress tests. TAD jellies were formulated based on the optimized nano-emulsion and subjected to in vitro evaluation for physical characteristics; TAD content, pH, spreadability, viscosity, syneresis, and taste-masking ability. An optimized nano-emulsion-based jelly (NEJ) formulation showed more than 96% drug dissolution in 30 min relative to 14% for the unprocessed TAD. In vivo assessment of NEJ in experimental rats demonstrated a significant enhancement (p < 0.05) of TAD bioavailability with an AUC0–24h of 2045 ± 70.2 vs. 259.9 ± 17.7 ng·h·mL−1 for the unprocessed TAD. Storage stability results revealed that NEJ remained stable with unremarkable changes in properties for 3 months. Overall, NEJ can be regarded as a successful therapeutic option for TAD administration with immediate-release properties and improved bioavailability.
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By dissolving drug molecules in these solutions, a unit dosage form for oral administration can be generated for oral administration. Self-emulsifying drug delivery system (SEDDS) is utilized to address the inadequate bioavailability of poorly soluble and highly permeable drugs, according to the literature. These methods can disseminate and deliver hydrophobic medications as a unit dose form for oral administration in this fashion. SEDDS formulations self-emulsify (micro/nano) after being discharged into the intestinal lumen and coming into contact with the gastrointestinal (GI) fluid. Several factors must be considered to make the oral drug administration difficult, including poor water solubility and limited permeability. Self-emulsifying drug delivery can increase the solubility of biopharmaceutical classification system (BCS) II medicines. The SEDDS is a drug delivery system that enhances the solubility of lipophilic medications. It has risen in popularity over time. Under moderate agitation and subsequent dilution, GI fluids are categorized as hydrophilic liquid mixes that are isotropic. This research looks at a variety of uses as well as recent advancements in SEDDS composition, evaluation, dosage forms, and novel techniques to convert liquid SEDDS to solids. Final Thoughts Determining whether or not it is feasible to construct a BCS Category 2 medication formulation based on SEDDS represents a significant contribution of this effort. Medicines with solubility issues and low and variable bioavailability will benefit from the connected technologies.
Article
Curcumin (CU) possesses diverse pharmacological activities while being relatively safe; nevertheless, its clinical application is limited due to its physico-chemical characteristics. This study aimed to synthesize cinnamic acid based glyceride for use in a self-nanoemulsifying drug delivery system (SNEDDS) to enhance CU anticancer activity and oral bioavailability. The synthesized glyceride was characterized by ESI-mass spectrometry, ¹H-NMR spectroscopy, and ¹³C-NMR spectroscopy. The potential of synthesized glyceride as an oil component in SNEDDS was explored in combination with surfactant and co-surfactant. The concentration of SNEDDS components was optimized through a ternary phase diagram. The composition of 40% surfactant, 10% co-surfactant, and 50% synthetic glyceride as oil was selected as the optimized formulation. The optimized formulation was characterized through Zeta sizer, atomic force microscope (AFM) and FTIR, and was then evaluated for dilution and thermodynamic stability. The CU-loaded SNEDDS revealed nano-size droplets (182.06 ±6.90 nm) with -20.96 ± 0.61 mV surface negativity. The optimized SNEDDS was highly stable and maintained the chemical nature of the drug. The anticancer activity of CU was enhanced upon encapsulation in novel SNEDDS. Similarly, the CU bioavailability improved significantly upon oral administration in novel SNEDDS. It can be safely concluded that the novel synthetic glyceride based SNEDDS can significantly improve CU bioavailability and anticancer activity.
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Coenzyme Q10 (CoQ10), a highly lipophilic compound present in the inner mitochondrial membrane, is essential for production of cellular energy in the form of ATP. CoQ10 is used as an antioxidant and also in the treatment of various cardiovascular disorders. The relative bioavailabilities of powder filled capsule (I) and oil-based formulation (II) of CoQ10 were compared in beagle dogs in an open, randomized, multiple dose, cross-over design. Poor and slow absorption characteristics were observed for both the formulations. The AUC, Cmax, and Tmax for formulation I and II are comparable (p < 0.05) where the values for formulation I are 22.84 +/- 6.3 micrograms ml-1 h, 0.51 +/- 0.11 microgram/ml, and 6.1 +/- 2.0 h whereas the values for formulation II are 24.32 +/- 5.6 micrograms ml-1 h, 0.55 +/- 0.16 microgram/ml, and 6.6 +/- 2.3 h, respectively. Stability of CoQ10 at various temperature and humidity conditions and its photostability were studied. Various antioxidants were evaluated to determine the type and amount of antioxidant(s) required to improve the stability of CoQ10. Large extent of degradation was observed at 45 degrees C and 55 degrees C. The effect of humidity conditions on degradation was insignificant. Among the various antioxidants studied, mixture of ascorbic acid (5%) and EDTA (0.1%) offered better protection than phenolic antioxidants such as butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), or propyl gallate (PG). Further, increasing concentrations of phenolic antioxidants (from 0.1 to 0.3%) accelerated the degradation.
Article
Cyclosporin (cyclosporin A) has been used as an immunosuppressive agent after organ transplantation for more than 15 years. The bioavailability of cyclosporin in its conventional oral formulation ‘Sandimmun’ displays considerable inter- and intra-patient variability. Absorption is also bile dependent. Recently, a new galenic formulation of cyclosporin was introduced, ‘Neoral’, which is a water-free microemulsion of cyclosporin. The microemulsion creates micelles which are absorbed in the small bowel without the presence of bile. Pharmacokinetic studies in healthy volunteers clearly demonstrate an increased bioavailability of the microemulsion formulation of cyclosporin, measured as an increase in maximum drug concentration (Cmax) and area under the drug concentration-time curve, and a reduced time to Cmax. These findings have been confirmed in kidney, liver and heart transplant recipients. With the microemulsion formulation, an improved prediction of cyclosporin concentrations has probably attributed to the decrease found in the variability of cyclosporin absorption. This could probably enable easier and more reliable monitoring of cyclosporin concentrations after transplantation. So far, data on the effects of conversion from the conventional to the microemulsion formulation of cyclosporin are only available in a limited number of patients and with a limited follow-up period. The main questions are related to what the long term consequences of the improved bioavailability of the microemulsion formulation will be. Further long term studies are needed in order to answer these questions. In the present review, we report on the pharmacokinetic properties of, and on clinical experience after solid organ and bone marrow transplantation with, the microemulsion formulation.
Article
The use of natural and synthetic lipids has generated much academic and commercial interest as a potential formulation strategy for improving the oral bioavailability of poorly water soluble drugs. Lipid-based formulations can reduce the inherent limitations of slow and incomplete dissolution of poorly water soluble drugs, and facilitate the formation of solubilised phases from which absorption may occur. The attainment of an appropriate pre-absorptive solubilised phase will not necessarily arise directly from the administered lipid, but most likely from the intraluminal processing to which lipids are subjected. This review attempts to provide a framework for the assessment of lipid based formulations by describing how aspects of GI physiology, and the choice of lipids and their formulation attributes, impact on dose form performance. Lipid digestion is briefly described and the various colloidal phases present within the GI tract during lipid digestion are highlighted. This is followed by selected examples where lipids have been investigated for improving the absorption of poorly water soluble drugs. Finally, some perspectives are offered such that the design of lipid-based dose forms may become less phenomenological than has been the traditional practice.
Article
The ability of polyglycolyzed glycerides (PGG) with varying fatty acid and polyethylene glycol (PEG) chain lengths to produce the self-emulsification of oil in water has been investigated. The quality of the resulting emulsions depends on the oil and emulsifier pair selected. These self-emulsifying drug delivery systems (SEDDS) were prepared using various concentrations of PGG as emulsifiers. Two oils, a medium-chain triglyceride (Neobee M5) and Peanut Oil, were chosen as the vehicle for the drug. A lipophilic drug with excellent oil solubility was selected for this study. The droplet size distribution, the release rate of the drug and the oil/water partition coefficient (PCo/w) of the drug in these systems were evaluated for the SEDDS obtained. The results indicate that PGG are effective emulsifiers for SEDDS. Droplet particle size in combination with droplet polarity in the emulsion are prerequisites for efficient SEDDS. The PCo/w of the drug from these SEDDS is helpful in evaluating these properties. A phase diagram was used to obtain the optimum concentrations of drug, oil and emulsifying agent. The results obtained with PGG were compared with previously reported SEDDS for the efficiency of drug release (Bachynsky et al., (1989) AAPS Annual Meeting). In vitro dissolution and in vivo absorption of a lipophilic drug from SEDDS are compared with those properties of other dosage forms.
Article
The effects of various nonionic and ionic surfactants and two bile salts (sodium cholate and sodium taurocholate) on the GI absorption of β-lactam antibiotics were investigated using the in situ rat GI perfusion technique. Addition of 10 mM polyoxyethylene-23-lauryl ether in the perfusion solution reduced the absorption of propicillin by the stomach and markedly increased the absorption of propicillin and cefazolin by the small intestine. Ester-type nonionic surfactants and bile salts exerted no significant influence on the intestinal absorption of these antibiotics.
Article
The level of solubilization of the drug testosterone propionate into 2% w/w oil-in-water (o/w) microemulsions, stabilized by the nonionic surfactant polyoxyethylene 10-oleyl ether (Brij 96) and containing a range of oils, has been determined. Although testosterone propionate was readily soluble in the ethyl esters ethyl oleate, ethyl caprylate, and ethyl butyrate, and the triglycerides soybean oil, Miglyol 812, and tributryin, and the alkene 1-heptene, only microemulsions containing the ethyl esters and the triglyceride oils exhibited a significant increase in solubilization over the corresponding micellar solution (i.e., surfactant solution in the absence of oil). Furthermore, the increase in drug solubility observed in the microemulsion systems was not related to the solubility of the drug in the bulk oil. That is, while the smaller molecular volume oils, such as ethyl butyrate, exhibited a greater capacity for the drug, microemulsions containing these oils were only marginally better at solubilizing the drug than the corresponding micellar solution. In contrast, microemulsions containing the larger molecular volume oil, Miglyol 812, gave levels of drug solubilization almost three times those containing ethyl butyrate, yet the bulk capacity for drug in this oil was less than half that of ethyl butyrate. Light scattering and phase inversion temperature studies suggested that the structure of the microemulsion was sensitive to the oil being used, in that, at the low oil concentrations used in this study, the smaller molecular volume oils generally penetrated the interfacial surfactant monolayer in much the same way as a cosurfactant, causing an alteration, presumably a dilution, of the relatively concentrated polyoxyethylene region close to the hydrophobic core, thereby destroying one of the main loci of drug solubilization and counteracting any advantages encountered due to the high solubility of the drug in the bulk oil.
Article
Self-emulsifying drug delivery systems (SEDDSs) represent a possible alternative to traditional oral formulations of lipophilic compounds. In the present study, a lipophilic compound, WIN 54954, was formulated in a medium chain triglyceride oil/nonionic surfactant mixture which exhibited self-emulsification under conditions of gentle agitation in an aqueous medium. The efficiency of emulsifi-cation was studied using a laser diffraction sizer to determine particle size distributions of the resultant emulsions. An optimized formulation which consisted of 25% (w/w) surfactant, 40% (w/w) oil, and 35% (w/w) WIN 54954 emulsified rapidly with gentle agitation in 0.1 N HCl (37C), producing dispersions with mean droplet diameters of less than 3 m. The self-emulsifying preparation was compared to a polyethylene glycol 600 (PEG 600) solution formulation by administering each as prefilled soft gelatin capsules to fasted beagle dogs in a parallel crossover study. Pharmacokinetic parameters were determined and the absolute bioavailability of the drug was calculated by comparison to an i.v. injection. The SEDDS improved the reproducibility of the plasma profile in terms of the maximum plasma concentration (C max) and the time to reach the maximum concentration (t max). There was no significant difference in the absolute bioavailability of WIN 54954 from either the SEDDS or the PEG formulations.
Article
A series of mixtures comprising Imwitor 742 and Tween 80 have been prepared and their self-emulsifying properties studied using a method of visual examination. The particle size distributions of emulsions prepared from these mixtures at 25°C, 37°C in water and 37°C in 0.1 M HCl have been measured. A marked decrease in mean particle size was observed for 30 and 40% Imwitor 742/Tween 80 mixtures at 25°C with a decrease in particle size also being noted for the majority of Imwitor 742/Tween 80 compositions at higher temperatures. Low frequency dielectric spectroscopy was performed on the pure components and on binary systems to which water had been added to make 50% v/v mixtures. Evidence was shown for the formation of liquid crystalline phases at concentrations corresponding to those shown to be efficient self-emulsifying systems. The study therefore suggests that self-emulsification may be associated with liquid crystal formation and that low frequency dielectric spectroscopy may be of considerable use in understanding the factors leading to self-emulsification.
Article
Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, sometimes including cosolvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal tract. Hydrophobic drugs can often be dissolved in SEDDS allowing them to be encapsulated as unit dosage forms for peroral administration. When such a formulation is released into the lumen of the gut it disperses to form a fine emulsion, so that the drug remains in solution in the gut, avoiding the dissolution step which frequently limits the rate of absorption of hydrophobic drugs from the crystalline state. Generally this can lead to improved bioavailability, and/or a more consistent temporal profile of absorption from the gut. Ultra-low oil-water interfacial tension and/or substantial interfacial disruption are required to achieve self-emulsification. SEDDS are usually formulated with triglyceride oils and ethoxylated nonionic surfactants, usually at surfactant concentrations greater than 25%. In practice, disruption of the oil-water interface is caused by penetration of water into the formulation or diffusion of cosolvents away from the formulation. Both of these phenomena can be studied using equilibrium phase diagrams, which in combination with particle size measurements allow the optimisation of performance of SEDDS. The precise mechanisms of emulsification remain the subject of speculation but there is an empirical link between self-emulsification, liquid crystal formation, oil-water phase-inversion temperature and enhanced solubilization of water by oily formulations, and these phenomena are indicators of the efficiency of emulsification. This article describes strategies used for formulation of SEDDS, methods used for assessment of efficiency of emulsification and practical considerations regarding the use of SEDDS for enhancement of the bioavailability of drugs from the gastro-intestinal tract.
Article
The in vitro release of diazepam from a submicron o/w emulsion was evaluated using the dialysis bag technique diffusion and the bulk-equilibrium reverse dialysis bag technique. Irrespective of the nature of the sink solution used, the release rate of diazepam from different emulsion dosage forms remained slow and incomplete as compared to a diazepam hydroalcoholic solution using the dialysis bag technique. This was attributed to a marked decrease in the aqueous drug gradient of drug available for membrane diffusion in the presence of the oily internal phase, rendering the permeation through the dialysis membrane the rate-limiting step in the overall kinetic process. It can definitely be deduced that the dialysis bag technique could not be considered an appropriate method to evaluate the true release mechanism of a drug from a colloidal carrier. An in vitro kinetic model is therefore proposed where the colloidal drug carrier suspension is directly placed in the release solution and has the opportunity to release the drug content under maximum dilution and perfect sink conditions. The drug released sampling is performed through immersed dialysis bags previously filled and equilibrated with the sink solution in the receptor compartment. The release profiles of diazepam from the actual submicron emulsion was similar to that observed from marketed aqueous and emulsion dosage forms correlating well with pharmacokinetic results reported in the literature. It was found that the release rate from the oily nanodroplets was faster than the permeation rate through the dialysis membrane which should be the slowest step governing the overall kinetic process despite rapid and complete diffusion of dissolved drug within less than 1 h. In view of the overall results it can be concluded that the release of diazepam from submicron emulsion is very rapid under perfect sink conditions.
Article
The intestinal lymphatic system is an alternate pathway to the portal blood by which orally administered drug molecules can gain access to the systemic circulation. The potential advantages of intestinal lymphatic transport include: (i) avoidance of first pass effect; (ii) delivery of selected drugs to the lymphatics; and (iii) controlled rate of entry to the systemic circulation. Highly lipophilic drugs and xenobiotics (logarithm of partition coefficient of at least 5–6 at physiological pH) transported by the intestinal lymphatics are associated with lipoproteins (primarily chylomicrons) formed by the enterocyte during lipid absorption and transport. This article describes the factors involved in the transport of highly lipophilic drugs by the intestinal lymphatics and discusses potential means for the promotion of intestinal lymphatic transport of lipophilic molecules.
Article
The purpose of this study was to improve the solubility and enhance the bioavailability of poorly water-soluble cyclosporin A loaded in o/w microemulsion systems. Microemulsions with varying weight ratios of surfactant to cosurfactant were prepared using caprylic/capric triglyceride (Captex 355®) as an oil, polyoxyethylated castor oil (Cremophor EL®) as a surfactant, Transcutol® as a cosurfactant and saline. The area of o/w microemulsion region in pseudo-ternary phase diagram was increased with increasing ratio of Cremophor EL® to Trancutol®. The solubility of cyclosporin A in microemulsion systems reached the maximum with 2:1 mixture of Cremophor EL® and Trancutol®. The dispersion rate of oil–surfactant–cosurfactant mixture with varying ratios of Cremophor EL® to Trancutol® in aqueous media assuming the condition of gastric fluid decreased with the increase of Cremophor EL® to Trancutol® weight ratio. The droplet size of microemulsion without cyclosporin A was decreased with the increase of Cremophor EL® content. The droplet size increased on increasing the incorporation of cyclosporin A. The droplet size of cyclosporin A loaded microemulsion was minimized with microemulsions prepared with 2:1 mixture of surfactant to cosurfactant (Cremophor EL®:Transcutol®:Captex 355®, 10:5:4). The maximal blood concentration (Cmax) of cyclosporin A and the area under the drug concentration-time curve (AUC) after oral administration of this cyclosporin A loaded microemulsion was 3.5 and 3.3 fold increased compared with Sandimmun®. No significant difference of Cmax and AUC was observed between this microemulsion system and Sandimmun Neoral®. The absolute bioavailability of cyclosporin A loaded in this microemulsion system was increased about 3.3 and 1.25 fold compared with Sandimmun® and Sandimmun Neoral®. The enhanced bioavailability of cyclosporin A loaded in this microemulsion system might be due to the reduced droplet size of microemulsion systems.
Article
Bioavailabilities (BA) of the lipophilic compound, L-683,453, from several formulations were determined in fasted and fed purpose-bred Beagle dogs following oral administration and an i.v. reference dose. The compound is poorly soluble in water (∼0.001 mg/mL) and exhibited very low BA, 0.2%, from suspensions in methyl cellulose, in fasted dogs. Addition of sodium dodecyl sulfate (SDS) into suspensions increased BA significantly to 0.6% in fasted (P = 0.05) and to 1.7% in fed animals (P < 0.01). A more dramatic enhancement in BA, up to 13.7%, was achieved from a self-emulsifying formulation composed of mono- and di-glycerides of caprylic/capric acids (MDG) and surfactants. It was found that tolerability and efficacy of MDG-based formulations at 16 mg/kg depend not only on the dose but also on the dosing volume. A volume of 2 mL/kg caused emesis, while a volume of 1 mL/kg was well tolerated. In contrast to its effect on suspensions, food had no statistically significant effect on BA of self-emulsifying formulations at dosing volumes of 1 mL/kg and 0.25 mL/kg. However, peak plasma concentrations were achieved faster in fed than in fasted animals.
Article
Monolayers of a well differentiated human intestinal epithelial cell line, Caco-2, were used as a model to study passive drug absorption across the intestinal epithelium. Absorption rate constants (expressed as apparent permeability coefficients) were determined for 20 drugs and peptides with different structural properties. The permeability coefficients ranged from approximately 5 x 10(-8) to 5 x 10(-5) cm/s. A good correlation was obtained between data on oral absorption in humans and the results in the Caco-2 model. Drugs that are completely absorbed in humans had permeability coefficients greater than 1 x 10(-6) cm/s. Drugs that are absorbed to greater than 1% but less than 100% had permeability coefficients of 0.1-1.0 x 10(-6) cm/s while drugs and peptides that are absorbed to less than 1% had permeability coefficients of less than or equal to 1 x 10(-7) cm/s. The results indicate that Caco-2 monolayers can be used as a model for studies on intestinal drug absorption.
Article
To the Editor: The use of solid dispersions and solid solutions in pharmaceutical dosage forms to improve the dissolution rate of sparingly water-soluble drugs has been investigated extensively. However, as discussed earlier, very few of the formulations have been marketed due to problems associated with their processing and stability. Some of the problems associated with processing (e.g., pulverization, compression, etc.) of a solid dispersion may be avoided by encapsulating the formulation directly in hard or soft gelatin capsules as a liquid melt. The melt solidifies at room temperature. Complete dissolution of a poorly water-soluble drug from such a system may be obtained if a surface-active vehicle is used. In the present report, the human bioavailability of α-pentyl-3-(2-quinolinylmethoxy)benzenemethanol (REV 5901; 1), a 5-lipoxygenase inhibitor orally active against hypersensitivity diseases, from a conventional tablet formulation and a solid dispersion in a surface-active vehicle is compared. There are very few reports in the literature on the comparative bioavailability of solid dispersions and conventional dosage forms (e.g., tablets, powder-filled capsules, etc.) in humans. Griseofulvin is the only drug for which the human bioavailability of a solid dispersion has been compared with that of a tablet. The extensive literature on the solid dispersions of other compounds deals mostly with their in vitro dissolution rates and, in some cases, with the bioavailability in animal models. Therefore, it is important that the enhanced bioavailability of 1 from solid dispersions observed in dogs be confirmed in humans.
Article
Co-enzyme Q10 (ubiquinone) is a naturally occurring substance which has properties potentially beneficial for preventing cellular damage during myocardial ischemia and reperfusion. It plays a role in oxidative phosphorylation and has membrane stabilizing activity. The substance has been used in oral form to treat various cardiovascular disorders including angina pectoris, hypertension, and congestive heart failure. Its clinical importance is now being established in clinical trails worldwide.
Article
The intestinal absorption of cyclosporine was measured in situ in rats using an olive oil emulsion prepared by either stirring or homogenization. The surface area of the homogenized dosage form was twice that of the stirred dosage form. The apparent permeability of cyclosporine from the homogenized emulsion was about twice that of the emulsion prepared by stirring. The examination of absorption in different intestinal segment lengths suggested the presence of an "absorption window." The absorption of cyclosporine appeared to be concentration independent and, therefore, non-carrier mediated. The dependence of absorption upon the intestinal perfusion rate suggested that the stagnant aqueous layer is the rate-limiting barrier in cyclosporine absorption. These results indicate that the bioavailability of cyclosporine administered in an emulsion can possibly be increased by enhancing its rate of absorption through the reduction of droplet size.
Article
Sodium salts of medium chain fatty acids (MCFAs) enhance the absorption of hydrophilic drugs across the intestinal mucosa, but the mechanism behind the effect is largely unknown. In this study, the dose-dependent effects of the sodium salts of four MCFAs, C6 (caproate), C8 (caprylate), C10 (caprate) and C12 (laurate), on the permeability of the hydrophilic marker molecule [14C]mannitol were studied in monolayers of the human intestinal epithelial cell line, Caco-2, grown on permeable supports. C8, C10 and C12, but not C6, enhanced the permeability of [14C]mannitol in a dose-dependent manner. Comparison of the cellular effects of the MCFAs at concentrations that gave comparable (8.1- to 8.5-fold) absorption enhancement showed that: 1) C8 was active as absorption enhancer only when the tonicity of the medium was increased; 2) absorption enhancement mediated by C10 was related to a redistribution of the cytoskeleton and structural dilatations in the tight junctions; and 3) C12 was without effect on the cytoskeleton and cellular morphology. Studies on C10 under anisotonic conditions showed that deviations from isotonicity enhanced its effect. These results suggest that structurally similar MCFAs display dramatic differences in their mechanism of action. In addition, the effects of osmolality provide an explanation for the previously reported variability in the efficacy of MCFAs as absorption enhancers.
Article
The oral route is most preferred for chronic drug therapy. Poor oral bioavailability has the consequences of more variable and poorly controlled plasma concentrations and drug effects, in addition to possibly increased product cost. In this review, the most common causes of low oral bioavailability are categorized, and formulation strategies to improve bioavailability are summarized. Various methods that can be used to help identify the cause of low bioavailability are discussed. The focus of this article is on poor membrane permeation and presystemic degradation problems; solubility/dissolution rate problems are discussed only briefly. Poor membrane permeation and presystemic degradation problems are typically encountered in the efforts to develop oral proteins, peptides, and peptide mimics. Formulation strategies reviewed include the use of metabolism inhibitors, membrane permeation enhancers, ion pairing and complexation, and particulate carriers. Also reviewed are lipid and surfactant formulations, which have been shown to increase bioavailability by various mechanisms and which are only beginning to be understood and optimized.
Article
This review highlights the state-of-the-art in pharmaceutical microemulsions with emphasis on self-emulsifying systems, from both a physical and biopharmaceutical perspective. Although these systems have several pharmaceutical applications, this review is primarily focused on their potential for oral drug delivery and intestinal absorption improvement. Physicochemical characteristics and formulation design based on drug solubility and membrane permeability are discussed. Case studies in which lipid microemulsions have successfully been used to improve drug solubilization/dissolution and/or intestinal absorption of poorly absorbed drugs/peptides are presented. Drug development issues such as commercial viability, mechanisms involved, range of applicability, safety, scale-up and manufacture are outlined, and future research and development efforts to address these issues are discussed.
Article
It has recently been reported that the permeability of peptides across Caco-2 cells, an in vitro model of the intestinal mucosa, was limited by an apically polarized efflux mechanism. Since surfactants (e.g. Cremophor EL, Polysorbate 80) have been reported to inhibit similar efflux systems in tumor cells, we determined whether they could enhance the permeability of peptides across monolayers of Caco-2 cells. The transport studies of [3H]-mannitol and [14C]-model peptides were carried out across the Caco-2 cell monolayers. TEER values were determined using Voltohmmeter with STX-2 electrode and the equilibrium dialysis studies were conducted using side-by-side dialysis apparatus with cellulose ester membranes. Initially, [3H]-mannitol flux studies were conducted to find concentrations of the surfactants that did not cause damage to the cell monolayer. Based on these studies, Polysorbate 80 and Cremophor EL were selected for further study. The fluxes of [14C]-AcfNH2 (a nonsubstrate for this efflux system) and [14C]-Acf(N-Mef)2NH2 (a substrate for this efflux system) were then measured in the absence and presence of the two surfactants. The permeability of [14C]-AcfNH2 was not affected by the surfactants, while that of [14C]-Acf(N-Mef)2NH2 increased with increasing concentrations of surfactants and then decreased. For example, the Pe values for [14C]-Acf(N-Mef)2NH2 were 3.75 x 10(-6), 8.58 x 10(-6), 10.29 x 10(-6), 7.48 x 10(-6), and 1.46 x 10(-6) cm/sec with Cremophor EL concentrations of 0, 0.01, 0.1, 1 and 10% w/v, respectively. This bimodal effect of surfactants on the Caco-2 cell permeability of this peptide was shown to be due to the interactions between the peptide and micelles at higher concentrations of surfactants, which were demonstrated by the equilibrium dialysis experiments. These results suggest that surfactants, which are commonly added to pharmaceutical formulations, may enhance the intestinal absorption of some drugs by inhibiting this apically polarized efflux system.
Article
Cyclosporin (cyclosporin A) has been used as an immunosuppressive agent after organ transplantation for more than 15 years. The bioavailability of cyclosporin in its conventional oral formulation 'Sandimmun' displays considerable inter- and intra-patient variability. Absorption is also bile dependent. Recently, a new galenic formulation of cyclosporin was introduced, 'Neoral', which is a water-free microemulsion of cyclosporin. The microemulsion creates micelles which are absorbed in the small bowel without the presence of bile. Pharmacokinetic studies in healthy volunteers clearly demonstrate an increased bioavailability of the microemulsion formulation of cyclosporin, measured as an increase in maximum drug concentration (Cmax) and area under the drug concentration-time curve, and a reduced time to Cmax. These findings have been confirmed in kidney, liver and heart transplant recipients. With the microemulsion formulation, an improved prediction of cyclosporin concentrations has probably attributed to the decrease found in the variability of cyclosporin absorption. This could probably enable easier and more reliable monitoring of cyclosporin concentrations after transplantation. So far, data on the effects of conversion from the conventional to the microemulsion formulation of cyclosporin are only available in a limited number of patients and with a limited follow-up period. The main questions are related to what the long term consequences of the improved bioavailability of the microemulsion formulation will be. Further long term studies are needed in order to answer these questions. In the present review, we report on the pharmacokinetic properties of, and on clinical experience after solid organ and bone marrow transplantation with, the microemulsion formulation.
Article
The transport of the model peptide Acf(NMef)2NH2 across Caco-2 cell monolayers was studied in the apical (AP) to basolateral (BL) and the BL to AP direction in the presence of Polysorbate 80 or Cremophore EL in the AP compartment. Increasing surfactant concentrations resulted in increasing AP-->BL peptide permeability and decreasing BL-->AP permeability. In either direction, limiting permeabilities were achieved at concentrations less than the critical micellar concentrations (cmc's) of the surfactants, and remained constant at much higher concentrations. These plateau permeabilities were not equivalent in the two directions. This residual assymetry was abolished by increasing the peptide concentration. Altogether, the observations support the presence of at least two pumps in Caco-2 cells for this peptide, polarized in the BL-->AP direction. These experimental results were analyzed within the context of a quantitative biophysical model incorporating concurrent passive diffusion across the AP and BL membranes accompanied by surfactant-inhibitable active polarized efflux across the AP membrane. The model was also used to locate the additional transport activity at the BL membrane as an uptake pump. Under conditions of complete inhibition, the intrinsic passive diffusional permeability of Acf(NMef)2NH2 was found to be 13 x 10(-6) cm/s, essentially identical with results reported earlier with this peptide utilizing verapamil as an inhibitor. With respect to the mechanism of surfactant inhibition of the apical efflux transport, the monomeric species was found to be responsible with no contribution from micelles. Modeling the mode of inhibition as a noncompetitive Michaelis-Menten process gave identical Kis of 0.5 microM for the two surfactants. Finally, increase of either surfactant beyond 750 microM resulted in a decrease of peptide permeability in the AP-->BL direction. This was attributed to weak association of the peptide with micelles in the AP compartment, which effectively decreased the thermodynamic activity of the peptide at surfactant concentrations greater than 20 times their cmc. Both the experimental approach and accompanying theoretical model demonstrated in this work will allow for further characterization of the inhibitory potencies of surfactants for the nonpassive efflux pathway in vitro and in vivo.
Article
Ontazolast is a potent inhibitor (IC50 = 1 nm) of calcium ionophore A23187-stimulated leukotriene B4 (LTB4) biosynthesis in human peripheral blood leukocytes. The compound is practically insoluble in water (0.14 microgram/mL) and previous studies in animals have demonstrated extensive presystemic drug clearance through hepatic first-pass metabolism. Bioavailability of a suspension formulation in rats was less than 1%, but increased to approximately 9% when administered as a 20% soybean oil-in-water emulsion. The emulsion formulation and three additional lipid-based formulations were administered by gavage to conscious, minimally restrained rats in a novel, double-cannulated model to determine the effects of formulation on systemic blood absorption and mesenteric lymph transport of ontazolast. The bioavailability of ontazolast was significantly and substantially enhanced by all of the lipid-based formulations. While these formulations also significantly increased the amount of ontazolast transported by the lymph, the total amounts transported were insufficient to account for the improvement in bioavailability, which may be due to the elimination or reduction of the barriers of poor aqueous solubility and slow dissolution to absorption of ontazolast from the gastrointestinal tract, or the effects of lipid on the gastrointestinal membrane permeability, transit time, or metabolism of ontazolast. Semisolid SEDDS formulations, composed of Peceol and Gelucire 44/14, produced bioavailability similar to the emulsion formulation. The total amount of ontazolast transported by the lymph varied directly with the amount of concurrent triglyceride transport and appeared to be favored by formulations that prolong gastric emptying time or promote rapid absorption of ontazolast from the gastrointestinal tract.
Article
P-glycoprotein (P-gp) actively pumps out a number of anticancer drugs, such as epirubicin, from tumor cells. P-gp is also expressed in the small intestine under normal physiological conditions. Inhibition of intestinal P-gp function using MDR reversing agents may enhance the oral bioavailability of some chemotherapeutic agents. Human colon adenocarcinoma (Caco-2) cell line expresses many characteristics of differentiated cells of the normal small intestine. Using Caco-2 as an in vitro intestinal model, the overall goal of the present study was to evaluate the MDR-reversing effects of some commonly used nonabsorptive pharmaceutical surfactants, such as Tween 20, Tween 80 and acacia on the intracellular accumulation of epirubicin by flow cytometry. Tween 20, Tween 80 or acacia all significantly increased intracellular accumulation of epirubicin with the highest enhancing effect for acacia and the lowest for Tween 20. Apart from progesterone, the enhancing effects of surfactants were better than those of non-surfactant MDR reversing agents such as verapamil, trifluoperazine and reserpine. In conclusion, our results demonstrate that progesterone, acacia, Tween 20 and Tween 80 are potent MDR modifiers of epirubicin in Caco-2 at concentrations that could be achieved in vivo. Use of surfactants in excipients may increase the intestinal absorption of some drugs through P-gp inhibition and thus improve drug bioavailability for P-gp substrate.