Solid self nano-emulsifying system for the enhancement of dissolution and bioavailability of Prasugrel HCl: in vitro and in vivo studies.

Prasugrel Hydrochloride (PHCl) is an antiplatelet drug. It is a class II drug with variable bioavailability. The objective of this work was to enhance the solubility and hence the bioavailability and efficacy of PHCl. A Self Nano-Emulsifying Drug Delivery System (SNEDDS) was prepared using Kolliphor El, Maisine 35-1, and Transcutol P as surfactant, oil, and co-surfactant, respectively in a ratio 10:72:18 v/v%. The SNEDDS was converted into solid by adsorption onto Neusilin. In vitro release of the drug from SNEDDS in (pH = 4) at 37 °C and 75 rpm for 45 min was studied. The results were compared to those from the unprocessed PHCl and Lexar® (the commercial drug). In-vivo studies (platelet Aggregation and bleeding time) were conducted using rats as animal models. It was found that the particle size of the SNEDDS ranged between 80 and 155 nm and EE% was in the range of 90.2% ± 0.4. The release from SNEDDS was about 84% compared to around 25% from unprocessed PHCl and 65% from Lexar® after 15 min. The platelet aggregation of the formula was lower than the PHCl, and Lexar® indicating higher bioavailability. In conclusion, SNEDDS with high EE% was prepared and was successful in enhancing the solubility, dissolution rate, and the bioavailability.

Supersaturable self-microemulsifying drug delivery system enhances dissolution and bioavailability of telmisartan.

To enhance the dissolution and oral bioavailability of telmisartan (TMS), a poorly water-soluble anti-hypertensive drug, a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) was developed. Amorphous alkalinized TMS (AAT) was formulated into a SMEDDS, composed of Capmul® MCM (oil), Cremophor® RH40 (surfactant), and tetraglycol (co-surfactant). Although the SMEDDS was rapidly dissolved (>80% within 5 min) in a limited condition (500 mL, pH 6.8), drug precipitation was observed over time, resulting in a decrease in dissolution levels. The precipitation was due to drug recrystallization, as determined by differential scanning calorimetry and powder X-ray diffraction analyses. Several polymers, including Soluplus® (SOL), were screened as precipitation inhibitors; ultimately, SuSMEDDS-SOL was prepared by admixing SOL and the SMEDDS at a 5:100 (w/w) ratio. SuSMEDDS-SOL was superior in terms of dissolution efficiency (>90% over 2 h) and dissolution-retaining time (no precipitation over 2 h). An in vivo pharmacokinetic study in rats revealed that the oral bioavailability of SuSMEDDS-SOL was 4.8-, 1.3-, and 1.2-fold greater than those of the TMS suspension, AAT solution, and SMEDDS, respectively. Therefore, SuSMEDDS-SOL is a promising candidate to enhance the dissolution and oral bioavailability of TMS.

Emulsifiers Impact Colonic Length in Mice and Emulsifier Restriction is Feasible in People with Crohn's Disease.

There is an association between food additive emulsifiers and the prevalence of Crohn's disease. This study aimed to investigate: (i) the effect of different classes of emulsifiers on markers of intestinal inflammation in mice and (ii) the feasibility, nutritional adequacy and symptom impact of restricting all emulsifier classes in Crohn's disease. Mice were exposed to different classes of emulsifiers (carboxymethycellose, polysorbate-80, soy lecithin, gum arabic) in drinking water for 12-weeks, after which markers of inflammation and metabolism were measured. A low emulsifier diet was developed to restrict all classes of emulsifiers and its feasibility measured over 14-days in 20 participants with stable Crohn's disease. Crohn's disease-related symptoms, disease control, body weight and composition, nutrient intake and food-related quality of life (QoL) were measured. All emulsifiers resulted in lower murine colonic length compared with control (mean 9.5 cm (SEM 0.20)), but this only reached significance for polysorbate-80 (8.2 cm (0.34), p = 0.024) and carboxymethylcellulose (8.0 cm (0.35), p = 0.013). All 20 participants completed the feasibility study. The frequency of consuming emulsifier-containing foods decreased by 94.6% (SD 10.3%). Food-related QoL improved between habitual (median 81.5 (IQR 25.0)) and low emulsifier diet (90.0 (24.0), p = 0.028). Crohn's disease-related symptoms reduced (median 3.0 (IQR 5.3) vs. 1.4 (3.9), p = 0.006), and disease control scores improved (13.5 (IQR 6.0) vs. 15.5 (IQR 3.0), p = 0.026). A range of emulsifiers may influence intestinal inflammation in mice, and dietary restriction of emulsifiers is feasible. Trials investigating the efficacy of a low emulsifier diet in Crohn's disease are warranted.

Lipophilic salts of poorly soluble compounds to enable high-dose lipidic SEDDS formulations in drug discovery.

Self-emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water-soluble drugs to improve exposure in high-dose pharmacokinetic (PK) and toxicokinetic (TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophilic counterions to prepare lipophilic salts of drugs. SEDDS formulations of two lipophilic salts-atazanavir-2-naphthalene sulfonic acid (ATV-2-NSA) and atazanavir-dioctyl sulfosuccinic acid (ATV-Doc)-were characterized and their performance compared to atazanavir (ATV) free base formulated as an aqueous crystalline suspension, an organic solution, and a SEDDS suspension, using in vitro, in vivo, and in silico methods. ATV-2-NSA exhibited ∼6-fold increased solubility in a SEDDS vehicle, allowing emulsion dosing at 12mg/mL. In rat PK studies at 60mg/kg, the ATV-2-NSA SEDDS emulsion had comparable exposure to the free-base solution, but with less variability, and had better exposure at high dose than aqueous suspensions of ATV free base. Trends in dose-dependent exposure for various formulations were consistent with GastroPlus™ modeling. Results suggest use of lipophilic salts is a valuable approach for delivering poorly soluble compounds at high doses in Discovery.

A cremophor-free self-microemulsified delivery system for intravenous injection of teniposide: evaluation in vitro and in vivo.

In order to tackle the problems on low water solubility of teniposide, involvement of toxic surfactant in its injection, and the poor stability during infusion, a Cremophor-free teniposide self-microemulsified drug delivery system (TEN-SMEDDS) was prepared for the first time, characterized, and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. The optimized formulation contained N, N-dimethylacetamide, medium-chain triglyceride, lecithin, and dehydrated alcohol besides teniposide. The TEN-SMEDDS could form fine droplets with mean diameter of 282 ± 21 nm and zeta potential of -7.5 ± 1.7 mV after dilution with 5% glucose, which were stable within 4 h. The release of teniposide from TEN-SMEDDS and VUMON was similar. However, the pharmacokinetic behavior of TEN-SMEDDS in rats was different from that of VUMON, evidenced by the lower area under the concentration-time curve and larger volume of distribution in emulsion group. Finally, TEN-SMEDDS was found to distribute more teniposide in most tissues, especially in reticuloendothelial system, after intravenous administration to rats. Importantly, brain drug level in TEN-SMEDDS group was higher than or similar to that in control group, although the emulsion system had a lower plasma drug concentration. In conclusion, the novel SMEDDS prepared here, without toxic surfactant and as an oil solution before use, may be potential for clinical use due to its low toxicity and high store stability. It may be favorable for the treatment of some tumors like cerebroma, since it may achieve the relatively higher drug level in brain but lower blood concentration.

In vitro and in vivo evaluation of self-microemulsifying drug delivery system of buparvaquone.

AIM: The aim of this study was to prepare a lipid-based self-microemulsifying drug delivery system (SMEDDS) to increase the solubility and oral bioavailability of a poorly water-soluble compound, buparvaquone (BPQ). METHODS: The solubility of BPQ was determined in various vehicles, and pseudo-ternary phase diagrams were constructed to determine the microemulsion region. A series of formulations with different compositions were selected in the microemulsion region for assessment of self-emulsification time and droplet size. The optimized SMEDDS formulation was used for in vitro dissolution and pharmacokinetic studies in rabbits. RESULTS: The optimum formulation of SMEDDS consisted of Capryol 90 (9.82%), Cremophor EL (70.72%), Labrasol (17.68%), and BPQ (1.78%). Emulsification time and the mean droplet size were found to be 1 minute and 18.0 +/- 0.25 nm, respectively, for the optimum formulation. The cumulative percentage of drug released in 90 minutes was 100% in both SGF and SIF. The calculated absolute oral bioavailability for BPQ was found to be 40.10%. CONCLUSIONS: The optimum SMEDDS formulation was increased the rate and extent of absorption of BPQ. The formulation is suitable for oral administration of BPQ. It would be useful to conduct efficacy studies of BPQ in diseased animal models and subsequently for toxicokinetics studies.

Solid self-emulsifying nitrendipine pellets: preparation and in vitro/in vivo evaluation.

Objective of this study is to develop and evaluate the new solid self-emulsifying (SE) pellets of poorly soluble nitrendipine (NTD). These pellets were prepared via extrusion/spheronization technique, using liquid SEDDS (NTD, Miglyol 812, Cremophor RH 40, Tween 80, and Transcutol P), adsorbents (silicon dioxide and crospovidone), microcrystalline cellulose and lactose. The resulting SE pellets with 30% liquid SEDDS exhibited uniform size (800-1000 microm) and round shape, droplet size distribution following self-emulsification was nearly same to the liquid SEDDS (72+/-16 nm and 64+/-12 nm). The in vitro release was similar for the two SE formulations (over 80% within 30 min), both significantly higher than the conventional tablets (only 35% within 30 min). The oral bioavailability was evaluated for the SE pellets, liquid SEDDS and conventional tablets in fasted beagle dogs. AUC of NTD from the SE pellets showed 1.6-fold greater than the conventional tablets and no significant difference compared with the liquid SEDDS. In conclusion, our studies illustrated that extrusion/spheronization technique could be a useful large-scale producing method to prepare the solid SE pellets from liquid SEDDS, which can improve oral absorption of NTD, nearly equivalent to the liquid SEDDS, but better in the formulation stability, drugs leakage and precipitation, etc.

Preparation and in vitro-in vivo evaluation of Witepsol H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q(10).

Coenzyme Q(10) (CoQ(10)) was formulated into self-nanoemulsifying drug delivery systems (SNEDDS) to overcome low bioavailability attributed to hydrophobic nature of the drug. Screening of oil phase, surfactants and co-surfactants were performed to select Witepsol H35, Solutol HS15 and Lauroglycol FCC, respectively. Ternary phase diagrams were drawn to identify nanoemulsifying region followed by optimization of SNEDDS formulation. The optimized formulation, CoQ(10), Witepsol H35, Solutol HS15 and Lauroglycol FCC in the weight ratio of 1:0.7:4:2, respectively, emulsified readily at 37 degrees C with mean emulsion droplet size of 32.4 nm. The stability test of the optimized formulation in pH 1.2 and 6.8 buffers confirmed no pH effect on emulsion droplet size. In vitro dissolution (emulsification) test and in vivo animal study of the formulation elucidated the complete emulsification of drug and improved oral bioavailability of poorly soluble CoQ(10).

Self-microemulsifying drug delivery systems (SMEDDS) for improving in vitro dissolution and oral absorption of Pueraria lobata isoflavone.

The aim of our investigation was to develop and characterize self-microemulsifying drug delivery systems (SMEDDS) of Pueraria lobata isoflavone to improve its in vitro dissolution and oral absorption in beagle dogs. SMEDDS consisted of oil (ethyl oleate), a surfactant (Tween 80), and a cosurfactant (Transcutol P). In all the SMEDDS, the level of Pueraria lobata isoflavone was fixed at 20% w/w of the vehicle. The in vitro self-microemulsification properties and droplet size analysis of SMEDDS were studied following their addition to water under mild agitation. A pseudoternary phase diagram was constructed identifying the efficient self-microemulsification region. From these investigations, an optimized formulation was selected and its dissolution and bioavailability were compared with a tablet formulation in beagle dogs. The in vitro dissolution rate of puerarin from SMEDDS was more than threefold faster than that from Yufengningxin tablets (Pueraria lobata isoflavone tablets). A 2.5-fold increase in the relative bioavailability was observed for the SMEDDS compared with Yufengningxin tablets. The absolute bioavailability of the SMEDDS was 82.32 +/- 15.51%, which was significantly improved compared with that of Yufengningxin tablets. These results demonstrate the potential of SMEDDS as an efficient way of improving the oral absorption of Pueraria lobata isoflavone.

Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib.

Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. Dissolution efficiency, t(85%), absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted formulation were chosen as response variables. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The present study demonstrated the suitability of mixture design to optimize the compositions for SMEDDS. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.

Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs.

The main purpose of this work is to prepare self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, simvastatin. Solubility of simvastatin was determined in various vehicles. SMEDDS is mixture of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region and particle size distributions of the resultant microemulsions were determined using a laser diffraction sizer. Optimized formulations for in vitro dissolution and bioavailability assessment were Carpryol 90 (37%), Cremophor EL (28%), and Carbitol (28%). The release rate of simvastatin from SMEDDS was significantly higher than the conventional tablet. The prepared SMEDDS was compared with the conventional tablet (Zocor) by administering the prefilled hard capsules to fasted beagle dogs. The absorption of simvastatin acid from SMEDDS form resulted in about 1.5-fold increase in bioavailability compared with the conventional tablet. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as simvastatin by the oral route.