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Enhancement of oral bioavailability of repaglinide by self-nanoemulsifying drug delivery system
Abstract
Repaglinide is considered the drug of choice for diabetic patients with impaired kidney function as it is excreted mainly in the bile. Unfortunately, it possesses low oral bioavailability of approximately 56%. Therefore, nano-sized globules containing the drug are expected to enhance its bioavailability and sustain its glucose lowering action. Self nano-emulsifying drug delivery systems (SNEDDS) of repaglinide have been prepared for improving the water solubility and oral bioavailability of the drug. Various compositions of SNEDDS were prepared using four types of oils (oleic acid, isopropyl myristate IPM. Labrafil 1944 and 2125), surfactants (chromophore El35, chromophore RH 40, Labrasol and Span 20) and a variety of co-surfacatnts. Low energy emulsification was adopted as the method of preparation for its feasibility and low cost. The prepared nano-emulsions showed small average droplet size (13.5-20 nm) and low polydispersity index (0.10 - 0.30). In-vitro dissolution studies indicated that the drug release from some of the prepared nanoemulsion droplets reached 75% within the first 30 minutes. The in-vivo data demonstrated that repaglinide in the nano-emulsion formulations F8 (IPM, Cremophor EL35 and Propylene glycol) and F16 (Oleic acid, Cremophor RH40 and Lauroglycol FCC) lowered the plasma glucose level (< 110 mg/dL) of experimental rabbits in a similar trend to that of the commercial product (Novonorm®. © 2014, International Journal of Pharmacy and Pharmaceutical Sciences. All rights reserved.
... The PDI indicates the width of a particle distribution. The samples were diluted to an acceptable scattering intensity using double distilled water prior to testing [29,30]. ...
... After removing excess fluid using filter paper, the grid was stained for 30 seconds in a 1 percent phosphotungstic acid solution. SMEDDS microstructure and morphology can be studied using transmission electron microscopy [29]. ...
... Every time the withdrawn volume was refilled, a new dissolution media was used. A UV spectrophotometer was used to determine the medication concentration [29]. ...
The goal of this study was to design Cefpodoxime Proxetil SMEDDS (self-microemulsifying drug delivery system), to improve solubility and permeability which could improve therapeutic performance and drug loading capacity. Castor oil, Tween 80, PEG 400 were used as the oil, surfactant, and, co-surfactant respectively. A ternary phase diagram was used to choose the best formulations. Selected formulations were evaluated for various parameters. According to the findings, all SMEDDS formulations had nano-sized globules, good stability, and rapid dispersibility of microemulsions, which were clear and slightly bluish in colour, and no symptoms of phase separation, creaming or, cracking Intestinal permeability studies of SMEDDS formulations show that the drug diffused through a biological membrane is more when given in form of SMEDDS. The present investigation has shown that it is possible to enhance the solubility and permeability of poorly soluble drugs.
... Dissolution media of 900ml with an aid of rotating paddle at 50 rpm and temperature of 37ºC ±0.5º is used. Samples of 5 ml from the dissolution medium are withdrawn after specific time intervals and replaced with fresh 0.1N HCl and samples are assessed spectrophotometrically to calculate the cumulative percentage release (Ammar et al.,2014). ...
... Filter paper is used to remove excess fluid and then the grid is stained in 1% phosphotungstic acid solution for 30 seconds. Transmission electron microscopy (TEM) enables in knowing the morphology of SEDDS by giving information on the porosity and microstructure (Ammar et al., 2014). ...
... Nanoparticle distribution is a formulation of dispersed particles in nanometres or thousandths of a micron. This ability of nanoparticles usually increases the bioavailability of poorly soluble drugs in the systemic circulation, such as quercetin and repaglinide [9,10]. ...
Objective: This research aims to perform Self Nano-Emulsifying Drug Delivery System (SNEDDS) formulation of combined ethanolic extract of benalu batu (Begonia medicinalis) herbs and kelor (Moringa oleifera) leaves, determine the optimal concentration based on physicochemical characteristics as well as the phytochemical contents and in vitro anticancer activity. Methods: Surfactant and co-surfactant concentrations were determined by Design Expert v.13 software with Simplex Lattice Design (SLD) method. The phytochemical contents were measured by using a UV-Vis spectrophotometer, and the inhibition activity on HeLa cancer cells was tested by using the MTT method. Results: Design Expert with the SLD method produces five design formulas. The most optimal SNEDDS formula based on the SLD method was formula 5, which contains a combination of extract of benalu batu herbs and kelor leaves with a concentration ratio of 1:1 (100 mg: 100 mg), 12% Virgin Coconut Oil (VCO), 64% tween 80, and 16% propylene glycol. The optimal formula has the characteristics of an emulsification time of 39.30±3.055 seconds, a transmittance percentage of 92.25%±0.004, a particle size of 14.43 nm±0.306 with a Polydispersity Index (PI) of 0.237, pH of 4.70±0.031 and viscosity of 355 cps±2.6. It also contains a total phenolic content of 5.517±0.382 mg/g GAE, total flavonoids of 8.501±0.695 mg/g QE, and total saponins of 17.991±0.052 mg/g EE. In addition, it also possesses a high percentage of cell death of Hela cancer, which is 84.334% at a concentration of 200 µg/ml. Conclusion: Formula 5 has the potential for anticancer activity with good characteristics as SNEDDS formula.
... According to [36], the use of a 7:2 concentration of cosurfactant combination surfactant can reduce interfacial tension because surfactants will enclose oil droplets when emulsified in water so that they will form a nanometer size. The particle size of SNEDDS is in the range of less than 100 nm with a polydispersity index (PI) value of nano-emulsion droplets less than 1 [24,37,38]. A polydispersity index value close to 0 indicates homogeneous particle size dispersion, while a polydispersity index of more than 0.5 indicates high heterogeneity. ...
Objective: Sesewanua leaves contain alkaloid compounds as antioxidants, and its leaves can be used to formulate SNEDDS dosage forms, which can effectively deliver the medicine. This study intended to determine the variation of surfactant concentration (Tween 80) and cosurfactant (PEG 400) towards pH, viscosity, nano-emulsion duration and characterization using PSA method (particle size and polydispersity index). Methods: This study employed a quasi-experimental method and the independent variables in this study were variations in the concentration of surfactant (Tween 80) and cosurfactant (PEG 400), which consist of 3 formulas, such as SFS 1 (6:3), SFS 2 (7:2), and SFS 3 (8:1). The dependent variables in this study including pH, viscosity, nano-emulsion time, particle size and polydispersity index which utilized One Way Anova Post Hoc LSD (p>0.05) and Tamhane (p<0.05) tests as the data analysis. Results: The pH test SFS1-SFS3 has a pH value of 7.92, 8.30 and 8.35, followed by Viscosity test SFS1-SFS3, which has a viscosity value of 1.00 cP, 1.38 cP and 2.91 cP. Further, the SFS1-SFS3 nano emulsified time test had nano emulsified time in gastric and intestinal fluids 35.18s and 43.96s, 43.54s and 47.13s and 44.00s and 50.29s. Characterization of SFS1-SFS3 particle size in gastric and intestinal fluids 23.9 nm and 23.0 nm, 18.5 nm and 22.7 nm and 19.1 nm and 22.9 nm, while characterization of SFS1-SFS3 polydispersity index in gastric and intestinal fluids were 0.433 and 0.348, 0.451 and 0.440 and 0.568 and 0.462. Conclusion: The increase of variations in surfactant concentration and decreased cosurfactant significantly affected pH, viscosity, nano-emulsion time, and particle size of SFS preparations. However, the polydispersity index was not considerably affected.
... Repaglinide (RG) is a new oral anti-diabetic drug of BCS-II in the Biopharmaceutical Classification System [7], used to treat type 2 diabetes. It has low oral bioavailability (56%), low aqueous solubility, and a short terminal elimination half-life (1 h) but is quickly and totally absorbed from the digestive tract [8,9]. Because of its short plasma half-life and high dosing frequency, the immediate-release tablet is taken before each meal to maintain its therapeutic plasma levels. ...
Objective: The recent study's objective was to optimize and formulate a controlled-release gastro-retentive floating tablet of RG using a central composite design, which provides continuous release of Repaglinide for up to 24 h. Methods: Repaglinide gastro-retentive floating tablet (RG-GRF Tablet) was prepared by direct compression method. The optimization was carried out using a three-factor and three-level Central Composite design. The amount of Eudragit RSPO (A), HPMC K-100M (B) and Sodium bicarbonate (C) were selected as independent variables and the Cumulative % drug release in 1.5 h (DR1.5), Cumulative % drug release in 8 h (DR8), Cumulative % drug release in 24 h (DR24) and Floating lag time (FLT) were used as dependent variables. Results: CCD analysis results shows that predicted and experimental values for optimized formulation were found to be almost similar. Optimized amounts of Eudragit RSPO, HPMC K-100M, and NaHCO3 were 14.351 mg, 44.438 mg, and 10 mg, respectively, with the highest possible desirability value of 0.898. The experimental values at optimized preparation conditions were found to be DR1.5 is 30.68%, DR8 is 64.90%, DR24 is 96.54%, and FLT is 4.41 min. The release data from the optimized formulation were closely matched with the Korsmeyer-Peppas model and in vitro drug release studies indicated that the RG-GRF Tablet continuously releases the drug for 24 h in a controlled manner. Conclusion: Current research concludes that RG-GRF Tablets provide drug release for up to 24 h, and the derived central composite design can be used for forecasting the DR1.5, DR8 and DR24 as well. RG can also be made more bioavailable by extending the gastric residence time.
... The prepared SNEDDS showed 13-20 nm-sized droplets, PDI at 0.10-0.30, and dissolution at 75% within 30 min and lowered the plasma glucose levels < 110 mg/dL in experimental rabbits [103]. ...
The self-generating nano-emulsifying drug delivery system (SNEDDS) is among the most effective approaches to enhance the oral bioavailability of a therapeutic agent, especially of a hydrophobic or poorly-water soluble drug. The methodology for SNEDDS preparation has been established on a number of therapeutic agents from several pharmacological classes. The requisite studies have validated the concept, and detailed experimentations in pharmaceutical, pharmacokinetics, and pharmacodynamics evaluations have corroborated the feasibility of SNEDDS formulation in providing higher levels of drug uploading, transport, dissolution, and intestinal permeation together with enhanced bioavailability at the site, and enhanced therapeutic effectiveness of the drug administered through oral route. The anti-cancer and anti-diabetic drugs having solubility issues, poor absorption, unwanted toxicity, and low bioavailability at the site of action have been dealt-with by the SNEDDS technology. The present review encompasses the SNEDDS technology applications primarily in these segments of drugs, and natural bioactive agents as well as synthetic agents for several bioactivities. It analyses the SNEDDS formulation approaches both in liquid and solid-SNEDDS based formulations, the absorption differences, bioavailability, and overall therapeutic effectiveness of these SNEDDS based products in comparison to the free drug behavior and other forms of drug delivery modalities as well as administration routes.
... The concentration of oil was found to be a rate-limiting factor and in all aspects, high oil concentration resulted in poor emulsion region. [28] The black boundary covers the micro-emulsion region. At any point beyond this boundary, micro-emulsion if formed initially, become turbid on further dilution of solution. ...
Self-emulsifying drug delivery systems are a promising aptemsproach for the formulation of drug compounds with poor aqueous solubility. The main objective of this work was to formulate liquid and solid-self emulsifying drug delivery systems for poorly soluble aripiprazole. Aripiprazole is an atypical anti-psychotic drug used in the management of schizophrenia. The maximum solubility of aripiprazole was found in oleic acid (oil), Tween 80 (surfactant) and Transcutol P (co-surfactant). The L-SMEDDS were formulated in different ratios of oil: s-mix (surfactant: co-surfactant) from 1:9 to 9:1. For the formulation of stable SMEDDS, micro-emulsion region was identified by constructing pseudo-ternary phase diagram by phase titration method. The optimized F4 formulation was at the ratio of 4 (oil): 6 (s-mix). In-vitro drug release of F4 was significantly higher (99.89%) when compared to the pure drug (43.63%) in 1 hour. The F4 formulation had a droplet size of 115.9 nm and zeta potential of -24.9 mV. The pre-compression and post-compression parameters of the optimized S-SMEDDS formulation (SS1) containing Neusilin US2 as solid adsorbent were within the limits as per the official requirements of the Pharmacopoeia. SS1 formulation showed a better drug release (97% in 20 minutes) when compared to the marketed drug (59.75%) and pure drug (19.77%). In conclusion, this study illustrated that adsorption to solid carrier technique could be a useful method to prepare the solid SMEDDS tablets from liquid SMEDDS, which can enhance the solubility and improve the in-vitro drug release of aripiprazole.
... It has melting point of 130-131°C and molecular weight 452.58. Topical preparation of repaglinide may be beneficial to the patient since it reduces adverse effects and avoids the hepatic first-pass metabolism [20][21][22]. ...
Objective: In the present study, an attempt was made to develop polymeric blend transdermal patch of repaglinide using hydroxypropyl methyl cellulose (HPMC) K4M and kondagogu gum.Methods: A series of repaglinide drug-incorporated HPMC K4M-kondagogu gum matrix films were prepared by solvent casting method. The prepared transdermal films were evaluated for various parameters such as thickness, tensile strength, folding endurance, % elongation, % moisture content, % moisture uptake, % drug content, in vitro drug release, and drug excipient compatibility.Results: The Fourier-transform infrared spectra of the pure drug as well as drug-incorporated formulation indicated that no chemical interaction occurred between the drug and the polymers used. Differential scanning calorimetry thermograms of the pure drug and prepared formulation indicated that the drug has dispersed in micron level in the prepared films. In vitro release study data of prepared formulations were fitted into various mathematical models, and the best-fit model was found to be Higuchi model.Conclusion: Among all the formulations studied, the formulation F4 was found to be an optimized composition for efficient transdermal delivery of repaglinide for 24 h study period. Stability studies of the drug formulations concluded that the drug was stable in the optimized formulation for the study period.
The aim of the present study was to investigate the potential of a nanoemulsion formulation for transdermal delivery of aceclofenac. Various oil-in-water nanoemulsions were prepared by the spontaneous emulsification method. The nanoemulsion area was identified by constructing pseudoternary phase diagrams. The prepared nanoemulsions were subjected to different thermodynamic stability tests. The nanoemulsion formulations that passed thermodynamic stability tests were characterized for viscosity, droplet size, transmission electron microscopy, and refractive index. Transdermal permeation of aceclofenac through rat abdominal skin was determined by Franz diffusion cell. The in vitro skin permeation profile of optimized formulations was compared with that of aceclofenac conventional gel and nanoemulsion gel. A significant increase in permeability parameters such as steady-state flux (J(ss)), permeability coefficient (K(p)), and enhancement ratio (E(r)) was observed in optimized nanoemulsion formulation F1, which consisted of 2% wt/wt of aceclofenac, 10% wt/wt of Labrafil, 5% wt/wt of Triacetin, 35.33% wt/wt of Tween 80, 17.66% wt/wt of Transcutol P, and 32% wt/wt of distilled water. The anti-inflammatory effects of formulation F1 showed a significant increase (P < .05) in percent inhibition value after 24 hours when compared with aceclofenac conventional gel and nanoemulsion gel on carrageenan-induced paw edema in rats. These results suggested that nanoemulsions are potential vehicles for improved transdermal delivery of aceclofenac.
A novel oil-in-water nanoemulsion system for transdermal delivery of amlodipine was studied. Pseudoternary phase diagrams were developed and various nanoemulsion formulations were prepared using oleic acid (oil phase), Tween 20 (surfactant) and Transcutol P (co-surfactant). The effects of content of oleic acid and surfactant/co-surfactant ratio (S(mix)) on skin permeation of amlodipine were evaluated through excised rat skin using a Franz diffusion cell. Highest permeation rate and permeability coefficient was found at low oil and S(mix) concentration. On increasing the same, fluxes were further decreased, probably due to increased globule size and decreased thermodynamic activity of drug at higher surfactant mixture concentration. The optimum nanoemulsion formulation consisted of 2% oil (oleic acid), 20% surfactant (Tween 20), 10% co-surfactant (S(mix) 2 : 1) and water exhibited highest skin permeation rate of 49.681 +/- 1.98 microg/cm/h and permeability coefficient of 0.497 +/- 0.056 cm2/h. The optimized nanoemulsion was characterized for globules size, morphology, viscosity, and pH. The result suggests that nanoemulsions are potential vehicles for improved transdermal delivery of amlodipine.
In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.
A series of modified phospholipids (m-PC) possessing different acyl chains in position 2, from butanoyl to hexadecanoyl, were prepared by partial synthesis from soybean lysolecithin. They were used with soybean lecithin to construct phase diagrams containing ethanol as cosolvent, water and medium chain triglycerides (MCT) or isopropyl myristate (IPM) as oils. The weight ratios lecithin:m-PC and surfactants:ethanol were kept constant at 1:1. The results indicate that the m-PCs have a strong effect on the microemulsion (L) and liquid crystalline (LC) domains in the water-rich/oil-poor part of the phase diagrams, although all diagrams correspond to a single lecithin:m-PC ratio. On decreasing the acyl chain length, and thus increasing the hydrophilicity of the surfactant, there was a corresponding increase in the L area, which moved towards the aqueous corner of the phase diagrams. The LC phase was detected only in the presence of the hexadecanoyl derivative for the systems containing MCT, and it was not detected only in the presence of the butanoyl derivative for the systems containing IPM. The use of a second hydrophilic surfactant to adjust the packing properties of the lecithin-alcohol systems, and/or to increase the fluidity of the surfactant film, increased the region of existence of the isotropic systems. This may be of importance in the formulation of drug delivery systems, especially those which are diluted by biological fluids upon administration.
The objective of the present investigation was to evaluate gastro-retentive performance and pharmacokinetic parameters of optimized floating microspheres (RgFMCS4) consisting of (i) calcium silicate (CS) as porous carrier; (ii) repaglinide (Rg), an oral hypoglycemic agent; and (iii) Eudragit S (ES) as polymer. The optimized formulation demonstrated favorable in-vitro-floating and drug release characteristics. The gastro-retentive behavior of this optimized formulation was compared with non-floating microspheres (RgNFM) prepared from the identical polymer. Stability test of (99m)Tc-labeled formulations were carried out using appropriate standard buffer solutions of pH 2.0, 6.8 and 7.4. The organ distribution study was performed in albino rats in order to measure labeling efficiency of the formulation with (99m)Tc. The gamma scintigraphy of the formulations was carried out in albino rabbits to monitor the transit of RgFMCS4 and RgNFM in the gastrointestinal (GI) tract. Prolonged gastric residence time (GRT) of over 6 h was achieved in all animals for calcium silicate based floating microspheres of Rg. Rg loaded optimized formulation was orally administered to albino rabbits and blood samples were used to determine pharmacokinetic parameters of Rg from floating microspheres, which were compared with pharmacokinetic parameters of the marketed tablet formulation. The relative bioavailability of Rg loaded floating microspheres was found to be increased about 3.17 times in comparison to that of the marketed tablet. The enhanced bioavailability and eliminated half-lives of Rg formulation observed in the present study are attributed to the floating nature of the designed formulations.
The purpose of this study was to use Artificial Neural Networks (ANNs) in identifying factors, in addition to surfactant and internal phase content, that influence the particle size of nanoemulsions. The phase diagram and rheometric characteristics of a nanoemulsion system containing polysorbate 80, ethanol, medium chain triglycerides and normal saline loaded with budesonide were investigated. The particle size of samples of various compositions prepared using different rates and amounts of applied energy was measured. Data, divided into training, test and validation sets, were modelled by ANNs. The developed model was assessed and found to be of high quality. The model was then used to explore the effect of composition and processing factors on particle size of the nanoemulsion preparation. The study demonstrates the potential of ANNs in identifying critical parameters controlling preparation for this system, with the total amount of applied energy during preparation found to be the dominant factor in controlling the final particle size.