Development of Pseudo-Ternary Phase Diagram Based Microemulsion for Enhancement of Oral Bioavailability of Azithromycin: <I>In-Vitro</I> and <I>In-Vivo</I> Study

PURPOSE: The purpose of this study was to investigate the ability of a self-nano-emulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of a BCS class IV drug, etoposide (VP-16). METHOD: A series of SNEDDS formulations with VP-16 were prepared consisting of medium chain triglycerides, polysorbate 80, diethylene glycol monoethyl ether and propylene glycol monolaurate type-1. Based on an obtained ternary phase diagram, an optimum formulation was selected and characterized in terms of size, zeta potential, loading, morphology and in vitro drug release. The pharmacokinetic parameters and oral bioavailability of VP-16 suspension and VP-16 in SNEDDS was assessed using 30 Male Sprague–Dawley rats and compared with the commercial product (VePesid®). RESULTS: Pharmacokinetic data showed that the mean values for AUC0-t of VP-16 in SNEDDS was 6.4 fold higher compared to a drug suspension and 2.4-folds higher than VePesid®. Similarly, the mean value for Cmax of VP-16 in SNEDDS (1.13± 0.07 µg/ml µg.h/mL) was higher than VePesid® (0.62± 0.09 µg/mL) and drug suspension (0.13± 0.07 µg/mL). CONCLUSION: The SNEDDS formulation was able to enhance the oral bioavailability of the BCS Class IV chemotherapeutic agent VP-16 by increasing the dissolution and absorption of the drug. A good in vitro in vivo correlation was found between the in vitro dissolution and in vivo absorption data of VP-16 SNEDDS preparation. Therefore, SNEDDS formulations might be a very promising approach for BCS Class IV drugs.

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Development of a self-microemulsifying drug delivery system of domperidone: In vitro and in vivo characterization

Acta Pharmaceutica ◽

10.2478/acph-2013-0013 ◽

2013 ◽

Vol 63 (2) ◽

pp. 241-251 ◽

Cited By ~ 9

Author(s):

Ramesh Jakki ◽

Muzammil Afzal Syed ◽

Prabhakar Kandadi ◽

Kishan Veerabrahma

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Oral Bioavailability ◽

Ternary Phase Diagram ◽

Water Soluble ◽

In Vitro Dissolution ◽

Size Analysis

The main objective of this work was to prepare a self-micro emulsifying drug delivery system (SMEDDS) for enhancement of oral bioavailability of domperidone, a poorly water soluble drug. The solubility of the drug was determined in various vehicles. A pseudo ternary phase diagram was constructed to identify the self-micro emulsification region. The in vitro self-micro emulsification properties and droplet size analysis of SMEDDS were studied following their addition to water under mild agitation. Further, the resultant formulations were investigated for clarity, phase separation, globule size, effect of pH and dilutions (1:100, 1:500, 1:1000) and freeze-thaw stability. The optimized formulation, SMEDDS-B used for in vitro dissolution and bioavailability assessment, contained oil (Labrafac CC, 25 %, m/m), surfactant (Tween 80, 55 %, m/m), and co-surfactant (Transcutol®, 20 %, m/m). The preliminary oral bioavailability of domperidone from SMEDDS was 1.92-fold higher compared to that of domperidone suspension in rats. The AUC0-24 and cmax values were 3.38 ± 0.81 μg h mL-1 and 0.44 ± 0.03 μg mL-1 for SMEDDS-B formulation in comparison with 1.74 ± 0.18 μg h mL-1 and 0.24 ± 0.02 μg mL-1 for domperidone suspension, suggesting a significant increase (p < 0.05) in oral bioavailability of domperidone from SMEDDSS.

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Formulation and In Vivo Evaluation of Ticagrelor Self- Nanoemulsifying Drug Delivery Systems.

Pharmaceutical Nanotechnology ◽

10.2174/2211738508666200708150151 ◽

2020 ◽

Vol 08 ◽

Author(s):

Adella Aparna ◽

Yamsani Shravan Kumar ◽

D.V.R.N. Bhikshapathi

Keyword(s):

Drug Release ◽

Oral Bioavailability ◽

Ternary Phase Diagram ◽

Evaluation Studies ◽

Antiplatelet Agent ◽

In Vivo Evaluation ◽

Release Analysis ◽

Pure Drug

Background: Ticagrelor (TGR) being antiplatelet agent belongs to BCS class IV drug with low solubility and permeability that undergoes first-pass metabolism leads to reduced bioavailability of 36%. Objective: The main goal of the present study was to develop TGR SNEDDS for improving solubility and oral bioavailability. Methods: An oil, surfactant and co-surfactant (miglyol 810, brij 35 and lauro glycol FCC) were chosen based on the maximum solubility of TGR. The chosen vehicles were mixed in varying ratios and agitated mildly and transmittance values more than 80 were noted and used for constructing pseudo ternary phase diagram. Formulations that passed stability testing were evaluated for % transmission, drug content and in vitro drug release analysis. In-vivo bioavailability studies of optimized SNEDDS were performed in wistar rats. Results: From evaluation studies of TGR, formulation F13 with maximum drug release of 98.99% in 60 minutes that is higher than 31.99 % of pure drug is considered the optimised formulation. The particle size, Z average and zeta potential of the optimized TGR formulation F13 was 289.6 nm, 185.1 nm and -18.3 mV respectively. The FTIR and SEM studies do not indicate any drug excipient interaction and confirm nanosize and stable for 3 months. From in vivo bioavailability studies in rats, the Cmax of optimized TGR SNEDDS (302.43±4.78ng/ml) was higher than pure TGR suspension (47.32±2.75ng/ml) and optimized SNEDDS exhibited 5 folds increased oral bioavailability than pure drug. Conclusion: Hence, the results revealed that application of SNEDDS formulation technique for TGR increased solubility and oral bioavailability.

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Formulation and Characterization of Solid Self- Microemulsifying Cefuroxime Axetil Products

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2014.7.3.9 ◽

2014 ◽

Vol 7 (3) ◽

pp. 2567-2573

Author(s):

Satish Puttachari ◽

Navanath V. Kalyane ◽

Sarbani Duttagupta ◽

Koushik Yetukuri

Keyword(s):

Phase Diagram ◽

Ternary Phase ◽

Ternary Phase Diagram ◽

Cefuroxime Axetil ◽

Oral Dosage ◽

In Vitro Dissolution ◽

Emulsification Property ◽

Wide Range

The Cefuroxime axetil has been used in treatment of wide range of infections but exhibits poor and variable bioavailability thus it is difficult to establish optimal oral dosage schedule. The purpose of this work was to prepare stable solid self-microemusifying drug delivery system (S-SMEDDS) of cefuroxime to improve the solubility and dissolution. The saturation solubility of drug in oils, solvents, surfactants and co-surfactants were determined and ternary phase diagram was drawn. Based on the results SMEDDS were prepared and characterized for self-emulsification properties and in-vitro dissolution. One of the best SMEDDS formulations was converted to S-SMEDDS by adsorption technique using maltodextrin as adsorbent. SEM of the S-SMEDDS revealed that particles were well separated and were free flowing, characterization by DSC, XRD revealed no interaction between drug and excipients. In-vitro dissolution was rapid and complete and no marked changes in physical and emulsification property were observed on stability.

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Study of Solubility of Atorvastatin using Ternary Phase Diagram for the Development of Self-Emulsifying Drug Delivery Systems (SEDDS)

Dhaka University Journal of Pharmaceutical Sciences ◽

10.3329/dujps.v11i2.14507 ◽

2013 ◽

Vol 11 (2) ◽

pp. 83-91

Author(s):

Fariba Khan ◽

Md Saiful Islam ◽

Reza-ul Jalil

Keyword(s):

Drug Delivery ◽

Phase Diagram ◽

Oleic Acid ◽

Oral Bioavailability ◽

Ternary Phase ◽

Ternary Phase Diagram ◽

Tween 80 ◽

Tween 20 ◽

Surfactant Mixture ◽

Cremophor El

Self-emulsifying drug delivery system (SEDDS) is successfully used to improve the aqueous solubility and oral bioavailability of the poorly aqueous soluble drugs. Atorvastatin calcium (ATV), a poorly aqueous soluble drug having low oral bioavailability, was the model drug for this study. The aim of this study was to find out the suitable lipid and surfactant which can be used in formulation of ATV-SEDDS and this was done using ternary phase diagram, an important tool used very essentially in optimizing SEDDS formulations. Ternary phase diagrams of lipid/surfactant/ATV mixture were constructed to generate the solubility data of ATV. Two lipids namely Capmul PG 8, Oleic acid and seven different surfactants namely Tween 20, Tween 80, Cremophor CO 40, Cremophor CO 60, Cremophor EL, Cremophor RH 40 and Cremophor RH 60 were used. For Capmul PG 8/surfactant mixture, solubilizing efficiency order was: Cremophor RH 40 > Tween 80 > Tween 20 > Cremophor CO 60 > Cremophor RH 60 > Cremophor EL > Cremophor CO 40. For Oleic acid/surfactant mixture, solubilizing efficiency order was: Cremophor RH 40 > Tween 80 > Tween 20 > Cremophor RH 60 > Cremophor CO 60 > Cremophor EL > Cremophor CO 40. Considering the solubility phase diagrams of the drug, both Oleic acid and Capmul PG 8 can be used as lipid in combination with any of the surfactants, Cremophor RH40 or Tween 80 or Tween 20 for the development of SEDDS formulations of ATV having enhanced solubility and dissolution property. DOI: http://dx.doi.org/10.3329/dujps.v11i2.14507 Dhaka Univ. J. Pharm. Sci. 11(2): 83-91, 2012 (December)

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Flurbiprofen-Loaded Solid SNEDDS Preconcentrate for the Enhanced Solubility, In-Vitro Dissolution and Bioavailability in Rats

Pharmaceutics ◽

10.3390/pharmaceutics10040247 ◽

2018 ◽

Vol 10 (4) ◽

pp. 247 ◽

Cited By ~ 9

Author(s):

Rae Kim ◽

Dong-Jin Jang ◽

Yu Kim ◽

Jin-Ha Yoon ◽

Kyoung Min ◽

...

Keyword(s):

Drug Delivery ◽

Phase Diagram ◽

Particle Size ◽

Drug Delivery System ◽

Delivery System ◽

Ternary Phase ◽

Ternary Phase Diagram ◽

In Vitro Dissolution ◽

Enhanced Solubility

The aim of this work was to prepare and optimize a solid self-nanoemulsifying drug delivery system pre-concentrate (SSP) containing water-insoluble flurbiprofen (FL) using a novel pseudo-ternary phase diagram. The pseudo-ternary phase diagram, composed of FL as the drug and dispersion core, Kollisolv MCT 70 as the oil phase, and TPGS (tocopherol polyethylene glycol 1000 succinate) as the surfactant, was constructed for the determination of the SSP region. SSP was investigated in terms of particle size, physical state by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), in vitro dissolution and oral pharmacokinetics in rats. The determined SSP (FL/Kollisolv MCT 70/TPGS = 10/10/80, weight %) in the pseudo-ternary phase diagram had the melting point of 32.37 °C and uniform mean particle size of below 30 nm without any precipitation of FL in the dispersion. In the dissolution test, the SSP exhibited 95.70 ± 3.40% of release at 15 min, whereas the raw FL showed poor dissolution (i.e., 6.75 ± 1.30%) at that time point. In addition, the SSP showed the enhanced oral absorption (i.e., 1.93-fold increase in AUCinfinite) as compared to the suspension group of raw FL. Therefore, the developed SSP would be a promising drug delivery system with excellent solubilization, dissolution, and bioavailability for FL.

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Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.7 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5102-5109

Author(s):

Venu Madhav K ◽

Somnath De ◽

Chandra Shekar Bonagiri ◽

Sridhar Babu Gummadi

Keyword(s):

Oral Bioavailability ◽

Oral Delivery ◽

Solid Dispersions ◽

In Vitro Release ◽

Aqueous Solubility ◽

Water Soluble ◽

Scanning Calorimetry ◽

In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension. From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

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Freeze-Dried Clopidogrel Loaded Lyotropic Liquid Crystal: Box-Behnken Optimization, In-Vitro and In-Vivo Evaluation

Current Drug Delivery ◽

10.2174/1567201817666200122161433 ◽

2020 ◽

Vol 17 (3) ◽

pp. 207-217

Author(s):

Eman A. Hakeem ◽

Galal M. El-Mahrouk ◽

Ghada Abdelbary ◽

Mahmoud H. Teaima

Keyword(s):

Statistical Analysis ◽

Oral Bioavailability ◽

Quadratic Model ◽

Lipid Phase ◽

Individual Response ◽

In Vivo Evaluation ◽

Freeze Dried ◽

Suggested Formula

Background: Clopidogrel (CLP) suffers from extensive first pass metabolism results in a negative impact on its oral systemic bioavailability. Cubosomes are Lyotropic Liquid Crystalline (LLC) nano-systems comprising monoolein, a steric stabilizer and an aqueous system, it considered a promising carrier for different pharmaceutical compounds. Box-Behnken Design (BBD) is an efficient tool for process analysis and optimization skipping forceful treatment combinations. Objective: The study was designed to develop freeze-dried clopidogrel loaded LLC (cubosomes) for enhancement of its oral bioavailability. Methods: A 33 BBD was adopted, the studied independent factors were glyceryl monooleate (GMO lipid phase), Pluronic F127 (PL F127steric stabilizer) and polyvinyl alcohol powder (stabilizer). Particle Size (PS), Polydispersity Index (PDI) and Zeta Potential (ZP) were set as independent response variables. Seventeen formulae were prepared in accordance with the bottom up approach and in-vitro evaluated regarding PS, PDI and ZP. Statistical analysis and optimization were achieved using design expert software®, then the optimum suggested formula was prepared, in-vitro revaluated, freeze-dried with 3% mannitol (cryoprotectant), solid state characterized and finally packed in hard gelatin capsule for comparative in-vitro release and in-vivo evaluation to Plavix®. Results: Results of statistical analysis of each individual response revealed a quadratic model for PS and PDI where a linear model for ZP. The optimum suggested formula with desirability factor equal 0.990 consisting of (200 mg GMO, 78.15 mg PL F127 and 2% PVA). LC/MS/MS study confirmed significant higher C>max, AUC>0-24h and AUC>0-∞ than that of Plavix®. Conclusion: The results confirm the capability of developed carrier to overcome the low oral bioavailability.

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1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.1082 ◽

1997 ◽

Vol 41 (5) ◽

pp. 1082-1093 ◽

Cited By ~ 276

Author(s):

S M Daluge ◽

S S Good ◽

M B Faletto ◽

W H Miller ◽

M H St Clair ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Oral Bioavailability ◽

Human Peripheral Blood ◽

Cross Resistance ◽

Immunodeficiency Virus ◽

Carbocyclic Nucleoside ◽

Hiv 1 ◽

In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

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