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1.
Pharm Dev Technol ; 26(9): 1021-1033, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34435939

ABSTRACT

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.


Subject(s)
Emulsifying Agents/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Prasugrel Hydrochloride/pharmacokinetics , Animals , Biological Availability , Dose-Response Relationship, Drug , Emulsifying Agents/blood , Male , Platelet Aggregation Inhibitors/blood , Prasugrel Hydrochloride/blood , Rats , Rats, Sprague-Dawley , Solubility , X-Ray Diffraction/methods
2.
Pharm Nanotechnol ; 8(3): 207-224, 2020.
Article in English | MEDLINE | ID: mdl-32416685

ABSTRACT

BACKGROUND: Carvedilol (CD), a non-selective beta-blocker, is indicated for the management of mild to moderate congestive heart failure. After oral administration, CD is rapidly absorbed with an absolute bioavailability of 18-25% because of low solubility and extensive first-pass metabolism. OBJECTIVE: The present investigation focused on enhanced oral delivery of CD using supersaturated self-emulsifying drug delivery (SEDDS) system. METHODS: Optimized SEDDS consisted of a blend of Oleic acid and Labrafil-M2125 as an oil-phase, Cremophor-RH40, polyethylene glycol-400 and HPMC-E5 as a surfactant, co-surfactant and supersaturation promoter respectively. Formulations were characterized for physical characteristics, invitro release in simulated and biorelevant dissolution media, intestinal permeability and bioavailability studies in Wistar rats. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized formulation. RESULTS: DSC and XRD, SEM studies showed that the drug was in amorphous form, and droplets were spherical in shape. Dissolution studies clearly showed distinct CD release in compendial and biorelevant dissolution media. The results from permeability and in-vivo studies depicted 2.2-folds and 3.2-folds increase in permeability and bioavailability, respectively from supersaturated SEDDS in comparison with control. CONCLUSION: The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral supply of CD. Lay Summary: Carvedilol (CD) is a non-selective antihypertensive drug with poor oral bioavailability. Previously, various lipid delivery systems were reported with enhanced oral delivery. We developed suprsaturable SEDDS formulation with immediate onset of action. SEDDS formulation was developed and optimized as per the established protocols. The optimized SEDDS formulation was stable over three months and converted to solid and supersaturated SEDDS. The results from permeability and in-vivo studies demonstrated an enhancement in permeability and bioavailability from supersaturated SEDDS in comparison with control. The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral administration of CD.


Subject(s)
Adrenergic beta-Antagonists/pharmacokinetics , Carvedilol/pharmacokinetics , Drug Delivery Systems/methods , Emulsifying Agents/pharmacokinetics , Intestinal Absorption/drug effects , Administration, Oral , Adrenergic beta-Antagonists/administration & dosage , Animals , Carvedilol/administration & dosage , Emulsifying Agents/administration & dosage , Intestinal Absorption/physiology , Male , Organ Culture Techniques , Rats , Rats, Wistar , Solubility
3.
AAPS PharmSciTech ; 21(4): 118, 2020 Apr 21.
Article in English | MEDLINE | ID: mdl-32318890

ABSTRACT

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.


Subject(s)
Caprylates/pharmacokinetics , Drug Delivery Systems/methods , Emulsifying Agents/pharmacokinetics , Glycerides/pharmacokinetics , Nanoparticles/metabolism , Palm Oil/pharmacokinetics , Pentoxifylline/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Caprylates/administration & dosage , Drug Liberation , Emulsifying Agents/administration & dosage , Glycerides/administration & dosage , Male , Nanoparticles/administration & dosage , Palm Oil/administration & dosage , Particle Size , Pentoxifylline/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacokinetics , Rats , Rats, Wistar
4.
Int J Pharm ; 580: 119180, 2020 Apr 30.
Article in English | MEDLINE | ID: mdl-32135227

ABSTRACT

Senicapoc (SEN), a potent antisickling agent, shows poor water solubility and poor oral bioavailability. To improve the solubility and cell permeation of SEN, self-nanoemulsifying drug delivery systems (SNEDDSs) were developed. Capryol PGMC®, which showed the highest solubilization capacity, was selected as the oil. The self-emulsification ability of two surfactants, viz., Cremophor-EL® and Tween® 80, was compared. Based on a solubility study and ternary phase diagrams, three optimized nanoemulsions with droplet sizes less than 200 nm were prepared. An in vitro dissolution study demonstrated the superior performance of the SNEDDS over the free drug. During in vitro lipolysis, 80% of SEN loaded in the SNEDDS remained solubilized. An in vitro cytotoxicity study using the Caco-2 cell line indicated the safety of the formulations at 1 mg/mL. The transport of SEN-SNEDDSs across Caco-2 monolayers was enhanced 115-fold (p < 0.01) compared to that of the free drug. According to these results, SNEDDS formulations could be promising tools for the oral delivery of SEN.


Subject(s)
Acetamides/chemical synthesis , Drug Delivery Systems/methods , Drug Design , Emulsifying Agents/chemical synthesis , Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Trityl Compounds/chemical synthesis , Acetamides/pharmacokinetics , Caco-2 Cells , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Emulsifying Agents/pharmacokinetics , Humans , Intermediate-Conductance Calcium-Activated Potassium Channels/physiology , Solubility , Trityl Compounds/pharmacokinetics
5.
Food Chem ; 299: 125164, 2019 Nov 30.
Article in English | MEDLINE | ID: mdl-31319345

ABSTRACT

Control of lipid digestibility by various food components has received great attention in recent decades. However, there is limited literature on investigating the synergistic effect of exogenous emulsifiers and endogenous sodium cholate (SC) on lipid digestion in a simulated physiological crowded medium. In this work, the synergistic interaction of Tween80 and SC according to the regular solution theory, and the hydrolysis of lipid emulsions containing tricaprylin, glyceryltrioleate or soybean oil in crowding medium was studied. The results show that emulsions stabilized by a combination of Tween80 and SC showed higher digestion rate and transformation than those with Tween80 or SC. The digestion rate could be increased by polyethylene glycols (PEGn) with varying crowding degree. The denaturation temperature of the lipase was increased in macromolecular crowded medium. This work allows for better understanding of the interaction between the amphiphiles and the macromolecular crowding effect on lipase digestion in the physiological environment.


Subject(s)
Emulsifying Agents/pharmacokinetics , Lipids/pharmacokinetics , Polysorbates/pharmacokinetics , Sodium Cholate/pharmacokinetics , Caprylates/metabolism , Digestion , Emulsions/chemistry , Emulsions/pharmacokinetics , Hydrolysis , Lipase/chemistry , Lipase/metabolism , Lipids/chemistry , Polyethylene Glycols , Polysorbates/chemistry , Sodium Cholate/chemistry , Soybean Oil/metabolism , Temperature , Triglycerides/metabolism
6.
AAPS PharmSciTech ; 20(3): 101, 2019 Feb 05.
Article in English | MEDLINE | ID: mdl-30721444

ABSTRACT

Ziyuglycoside I (ZgI), a major effective ingredient of Sanguisorba officinalis L, has shown good activity in increasing leukocyte of myelosuppression mice. However, oral ZgI therapy has been deterred by poor bioavailability because of its low aqueous solubility and permeability. Our study was to develop ZgI-loaded self-microemulsifying drug delivery system (SMEDDS) and evaluate its intestinal absorption, and pharmacokinetic and pharmacodynamic activity for increasing leukocyte. The formulation was designed and optimized by measuring the equilibrium solubility of ZgI in different vehicles and the pseudoternary phase diagram. Further, morphology, particle size, stability, in vitro release, in situ single-pass intestinal perfusion (SPIP), in vivo activity, and in vivo pharmacokinetic (PK) of ZgI-SMEDDS were charactered or studied. Optimized formulations for in vitro dissolution were Obleique CC497, Tween-20, and Transcutol HP with a proportion of 0.25/0.45/0.30 via D-optimal mixture design. Results showed that the solubility of ZgI was enhanced up to 23.93 mg/g and its average particle size was 207.92 ± 2.13 nm. The release of ZgI had been greatly improved by the SMEDDS. In SPIP, the intestinal absorption of SMEDDS was much better than plain ZgI. In PK, we found the oral bioavailability of ZgI-SMEDDS was 6.94-fold higher absolute bioavailability (21.94 ± 4.67) % than ZgI (3.16 ± 0.89) %. The most important was that the mice WBC of ZgI-SMEDDS group was significantly higher than that of the ZgI group. Our study suggested that SMEDDS could increase the solubility of ZgI, which was beneficial to improve oral bioavailability and enhance biological activity.


Subject(s)
Drug Development/methods , Emulsifying Agents/chemistry , Emulsifying Agents/pharmacokinetics , Leukocytes/metabolism , Saponins/chemistry , Saponins/pharmacokinetics , Animals , Biological Availability , Drug Delivery Systems/methods , Drug Evaluation, Preclinical/methods , Female , Intestinal Absorption/drug effects , Intestinal Absorption/physiology , Leukocytes/drug effects , Male , Mice , Particle Size , Random Allocation , Rats , Solubility
7.
Eur J Pharm Sci ; 130: 215-224, 2019 Mar 15.
Article in English | MEDLINE | ID: mdl-30716381

ABSTRACT

The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.


Subject(s)
Captopril/pharmacokinetics , Drug Delivery Systems/methods , Emulsifying Agents/pharmacokinetics , Mouth Mucosa/drug effects , Oral Mucosal Absorption/drug effects , Administration, Oral , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Animals , Captopril/administration & dosage , Drug Evaluation, Preclinical/methods , Emulsifying Agents/administration & dosage , Mouth Mucosa/metabolism , Multivariate Analysis , Oral Mucosal Absorption/physiology , Swine
8.
AAPS PharmSciTech ; 20(1): 26, 2019 Jan 02.
Article in English | MEDLINE | ID: mdl-30604333

ABSTRACT

Rebamipide has low oral bioavailability (10%) due to its low solubility and permeability. Lipid nanoemulsions (LNEs) were prepared in order to improve its oral bioavailability. Rebamipide-loaded lipid nanoemulsions were formulated by hot homogenization and ultrasonication method. Olive oil and egg lecithin in various concentrations as emulsifier were used in the preparation of LNEs. The lipid nanoemulsions were evaluated for various parameters. The globule size, polydispersity index (PDI), and zeta potential (ZP) of the formulations ranged from 230.3 ± 3.88 to 279.8 ± 5.76 nm, 0.204 ± 0.008 to 0.246 ± 0.029, and - 27.7 ± 2.05 to - 31.0 ± 1.87 mV, respectively. Entrapment efficiency and assay values ranged from 99.90 ± 0.006 to 99.92 ± 0.002% and 99.3 ± 0.808 to 99.6 ± 0.360, respectively. Physical stability test results revealed that the optimized LNEs were stable for 2 months at both room (25°C) and refrigerated temperature (4°C). The optimized LNE showed 4.32-fold improvement in the oral bioavailability in comparison to a marketed tablet suspension. In vivo anti ulcer activity of rebamipide LNE was studied by testing the prophylactic effect in preventing the mucosal damage in stomach region. The mucosa of stomach in animals was damaged by per oral administration of 80% alcohol. Maximum prophylactic antiulcer activity was observed by per oral delivery of rebamipide as LNE. Our results indicated that LNEs were a promising approach for the oral delivery of rebamipide for systemic effects along with local effects in protecting gastric region, which gets damaged during peptic ulcers.


Subject(s)
Alanine/analogs & derivatives , Anti-Ulcer Agents/pharmacokinetics , Emulsifying Agents/pharmacokinetics , Nanoparticles/metabolism , Quinolones/pharmacokinetics , Administration, Oral , Alanine/chemical synthesis , Alanine/pharmacokinetics , Animals , Anti-Ulcer Agents/chemical synthesis , Drug Evaluation, Preclinical/methods , Emulsifying Agents/chemical synthesis , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Lipids , Male , Nanoparticles/chemistry , Particle Size , Quinolones/chemical synthesis , Rats , Rats, Wistar
9.
AAPS PharmSciTech ; 20(2): 44, 2019 Jan 07.
Article in English | MEDLINE | ID: mdl-30617712

ABSTRACT

Asenapine maleate (AM)-loaded self-microemulsifying drug delivery system (AM-SMEDDS) was prepared to increase its oral bioavailability. AM-SMEDDS was developed using Capryol 90, Cremophor EL, and Transcutol HP as oil, surfactant, and cosurfactant, respectively, by spontaneous emulsification method. Pseudoternary diagram showed maximum region at 3:1 ratio of Cremophor EL/Transcutol HP. The AM-SMEDDS showed globule size and zeta potential of 21.1 ± 1.2 nm and - 19.3 ± 1.8 mV, respectively. Globules were found to be of spherical shape and uniformly distributed by transmission electron microscopy. In vitro drug release study showed 99.2 ± 3.3% of drug release at the end of 8 h in phosphate buffer pH 6.8. Ex vivo drug release study showed only 15% of drug diffusion through stomach and ~ 85% drug was diffused through intestinal membrane. Confocal and flow cytometry study showed that cellular uptake of coumarin-6 loaded SMEDDS was significantly enhanced by Caco-2 cells as that of coumarin-6 solution. The relative bioavailability of AM-SMEDDS was found to be 23.53 times greater than AM suspension. Intestinal lymphatic transport study using Cycloheximide (CHX) showed that the AUCtotal of AM-SMEDDS reduced about 35.67% compared with that without the treatment of CHX indicating involvement of lymphatic system in intestinal absorption of AM-loaded SMEDDS. These findings demonstrated the potential of SMEDDS for oral bioavailability improvement of AM via lymphatic uptake. Graphical Abstract.


Subject(s)
Drug Delivery Systems/methods , Emulsifying Agents/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Intestinal Absorption/drug effects , Administration, Oral , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , Biological Availability , Caco-2 Cells , Cell Survival/drug effects , Cell Survival/physiology , Dibenzocycloheptenes , Dose-Response Relationship, Drug , Emulsifying Agents/administration & dosage , Emulsifying Agents/chemistry , Female , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Intestinal Absorption/physiology , Rats , Rats, Sprague-Dawley , Solubility
10.
Eur J Pharm Biopharm ; 136: 138-146, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30660694

ABSTRACT

An ideal cancer therapy targets the tumor cells selectively without damaging healthy tissues. Even though the tumor-specific markers are limited, these molecules can be used for the delivery of anti-cancer drugs as an active targeting strategy. Since the lymphatic system plays a critical role in the dissemination of cancer cells, the drugs directed through lymphatics can feasibly reach to the sites of metastasis. LyP-1 is a peptide that binds to the p32 receptor which is highly expressed not only on the lymphatic endothelium but also on the malignant cells; thus, making this peptide ligand a preferable candidate to mediate active targeting of lymphatics and cancer cells. In this study, different formulations of LyP-1 containing lipid-based nanopharmaceutics so-called self-microemulsifying drug delivery systems (SMEDDS) were developed and tested for their efficacy in targeting breast cancer. Following the selection of non-toxic formulation, doxorubicin hydrochloride and LyP-1 were co-administered in the SMEDDS, which resulted in a significant increase in in vitro cytotoxicity in p32-expressing breast cancer cells, 4T1 and MDA-MB-231. Accordingly, the uptake of LyP-1 in the SMEDDS by the cancer cells was demonstrated. The expression of p32 was detected in the 4T1 tumor tissues which were efficiently targeted with LyP-1 in the SMEDDS. When doxorubicin was co-administrated with LyP-1 in SMEDDS via intraperitonial administration, tumor growth and metastasis were significantly reduced. In conclusion, a novel and efficacious SMEDDS formulation containing LyP-1 with a droplet size less than 100 nm was developed for the lymphatic targeting of breast cancer.


Subject(s)
Breast Neoplasms/metabolism , Drug Delivery Systems/methods , Emulsifying Agents/pharmacokinetics , Microspheres , Peptides, Cyclic/pharmacokinetics , Animals , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Emulsifying Agents/administration & dosage , Female , Humans , Mice , Mice, Inbred BALB C , Peptides, Cyclic/administration & dosage
11.
Biomed Pharmacother ; 109: 2427-2433, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30551502

ABSTRACT

A self-nanoemulsifying drug delivery system (SNEDDS) was developed as a novel route to enhance the efficacy of docetaxel lipophilic drug. SNEDDS comprised ethyl oleate, Tween 80 and poly(ethylene glycol) 600, as oil, surfactant and co-surfactant, and formed stabilized monodispersed oil nanodroplets upon dilution in water. SNEDDS represented encapsulation efficiency and loading capacity of 21.4 and 52.7%, respectively. The docetaxel release profile from the drug-loaded SNEDDS was recorded, its effectiveness against MCF-7 cell line was investigated, and an IC50 value of 0.98 ± 0.05 µg mL-1 was attained. The drug-loaded SNEDDS was administrated in rats, and the pharmacokinetic parameters of maximum concentration of 22.2 ± 0.8 µg mL-1, time to attain this maximum concentration of 230 min, and area under the curve of 1.71 ± 0.18 µg min mL-1 were obtained. The developed SNEDDS formulation can be represented as an alternative to docetaxel administration.


Subject(s)
Antineoplastic Agents/administration & dosage , Cell Survival/drug effects , Docetaxel/administration & dosage , Drug Delivery Systems/methods , Emulsifying Agents/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Cell Survival/physiology , Docetaxel/pharmacokinetics , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Emulsifying Agents/pharmacokinetics , Female , Humans , MCF-7 Cells , Rats , Rats, Sprague-Dawley
12.
Curr Drug Deliv ; 16(4): 325-330, 2019.
Article in English | MEDLINE | ID: mdl-30588885

ABSTRACT

BACKGROUND: Self-Emulsifying Drug Delivery System (SEDDS), if taken orally, is expected to self-emulsify in GIT and improve the absorption and bioavailability. Probucol (PB) is a highly lipophilic compound with very low and variable bioavailability. OBJECTIVE: The objectives of this study were to examine the stability and conduct bioavailability of the prepared Probucol Self-Emulsified Drug Delivery System (PBSEDDS) in human volunteers. METHODS: The methods included preparation of different PBSEDDS using soybean oil (solvent), Labrafil M1944CS (surfactant) and Capmul MCM-C8 (co-surfactant). The formulations were characterized in vitro for spontaneity of emulsification, droplet size, turbidity and dissolution in water after packing in HPMC capsules. The optimized formulations were evaluated for stability at different storage temperatures and human bioavailability compared with the drug dissolved in soybean oil (reference). RESULTS: The results showed that formulations (F1-F4) were stable if stored at 20 °C. The mean (n=3) pharmacokinetic parameters for stable formulations were: The Cmax, 1070.76, 883.16, 2876.43, 3513.46 and 1047.37 ng/ml; the Tmax, 7.93, 7.33, 3.96, 3.67 and 4.67 hr.; the AUC (0-t), 41043.41, 37763.23, 75006.26, 46731.36 and 26966.43 ng.hr/ml for F1, F2, F3, F4 and reference, respectively. The percentage relative bioavailability was in this order: F3> F4> F1> F2>. CONCLUSION: In conclusion, the PBSEDDS formulations were stable at room temperature. F4 showed the highest Cmax and the shortest Tmax. All the formulations showed significant enhancement of bioavailability compared with the reference. The results illustrated the potential use of SEDDS for the delivery of probucol hydrophobic compound.


Subject(s)
Drug Delivery Systems , Emulsifying Agents/chemistry , Emulsifying Agents/pharmacokinetics , Probucol/chemistry , Probucol/pharmacokinetics , Adult , Biological Availability , Drug Compounding , Drug Stability , Emulsifying Agents/administration & dosage , Female , Healthy Volunteers , Humans , Male , Middle Aged , Particle Size , Probucol/administration & dosage , Surface Properties , Young Adult
13.
Food Chem ; 278: 811-819, 2019 Apr 25.
Article in English | MEDLINE | ID: mdl-30583447

ABSTRACT

The impact of the type of emulsifier used to formulate excipient emulsions on the degradation (D*) and bioaccessibility (B*) of ß-carotene in spinach was investigated using a simulated gastrointestinal tract (GIT). Emulsions stabilized by sodium caseinate (SC) were more prone to droplet aggregation than those stabilized by either Tween 20 or octenyl succinic anhydride (OSA)-modified starch. The fraction of ß-carotene available for absorption (D* × B*) was also affected by emulsifier type: SC (12.0%) > Tween 20 (5.0%) ≈ OSA stabilized (2.6%) (p < 0.05). This effect was mainly attributed to differences in the digestive characteristics of the emulsifiers, which affected the transfer efficiency of ß-carotene from the plant tissues to the lipid phase, lipid digestion, and mixed micelle formation. These results show the importance of selecting an appropriate emulsifier when designing excipient emulsions to enhance the bioavailability of nutraceuticals in fruits and vegetables.


Subject(s)
Emulsifying Agents/pharmacokinetics , Emulsions/pharmacokinetics , Excipients/chemistry , Spinacia oleracea/chemistry , beta Carotene/pharmacokinetics , Animals , Biological Availability , Caseins/chemistry , Digestion , Emulsifying Agents/chemistry , Emulsions/chemistry , Excipients/pharmacokinetics , Gastrointestinal Tract/metabolism , Lipid Metabolism , Mice , Micelles , Polysorbates/chemistry , Starch/analogs & derivatives , Starch/chemistry
14.
J Colloid Interface Sci ; 531: 253-260, 2018 Dec 01.
Article in English | MEDLINE | ID: mdl-30036849

ABSTRACT

It was the aim of this study to prepare trypsin decorated mucus permeating self-emulsifying drug delivery systems (SEDDS). Lipophilicity of enzyme was increased by hydrophobic ion pairing (HIP) with the anionic surfactants sodium dodecyl sulfate (SDS), sodium taurocholate (ST) and sodium deoxycholate (SDO) to facilitate its incorporation in SEDDS. Blank SEDDS and trypsin decorated SEDDS were characterized regarding droplet size, polydispersity index (PI), zeta potential and proteolytic activity using Nα-benzoyl-l-arginine ethyl ester (BAEE) assay. Log DSEDDS/release medium of each complex was determined to assess its affinity towards SEDDS oily droplet upon emulsification. Ability of trypsin decorated SEDDS to enhance mucus permeation was studied on mucus gel from porcine small intestine for the period of 4 h at 37 °C. Degree of enzyme precipitation via HIP was 94.5%, 85.7% and 48.2% for SDS, ST and SDO complex, respectively. SEDDS composed of 50% (w/w) cremophor EL, 20% (w/w) captex 300, and 30% (w/w) propylene glycol with a complex payload of 1% (w/w) exhibited a droplet size in the range of 29.92 ±â€¯0.09 nm to 39.15 ±â€¯0.37 nm, a polydispersity index of 0.116-0.265 and zeta potential in the range of -2.36 mv to -4.25 mv. The enzymatic activity of trypsin complexed with SDO, SDS and ST in SEDDS was 51.9%, 44.8%, and 40.7% respectively, of the corresponding activity of free trypsin. Log D values of trypsin, SDS, ST and SDO complex were -2.73, 1.97, 1.89 and 1.68, respectively, suggesting higher lipophilicity of trypsin complexes as compare to free trypsin and ability to reside on SEDDS droplets. Enzyme decorated SEDDS improved mucus permeation 1.6- to 2.6-fold in comparison to blank SEDDS. Results demonstrated that decorating SEDDS with trypsin can be a promising technique to improve their mucus permeating properties.


Subject(s)
Drug Carriers/pharmacokinetics , Emulsifying Agents/pharmacokinetics , Intestine, Small/metabolism , Mucus/metabolism , Trypsin/pharmacokinetics , Animals , Deoxycholic Acid/chemistry , Deoxycholic Acid/metabolism , Deoxycholic Acid/pharmacokinetics , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Delivery Systems , Emulsifying Agents/chemistry , Emulsifying Agents/metabolism , Emulsions/chemistry , Emulsions/metabolism , Emulsions/pharmacokinetics , Permeability , Proteolysis , Sodium Dodecyl Sulfate/chemistry , Sodium Dodecyl Sulfate/metabolism , Sodium Dodecyl Sulfate/pharmacokinetics , Swine , Taurocholic Acid/chemistry , Taurocholic Acid/metabolism , Taurocholic Acid/pharmacokinetics , Trypsin/chemistry , Trypsin/metabolism
15.
Pharm Dev Technol ; 23(9): 900-910, 2018 Nov.
Article in English | MEDLINE | ID: mdl-28540754

ABSTRACT

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5 mg VNP composed of Maisine™ 35-1, Transcutol® HP, and Cremophor® EL was adsorbed on the solid carrier Aeroperl®. S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel®, HPMC-K4M, PVP-K30, and Lubripharm®), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 32*21 full factorial design was adopted. The independent variables were: type of coating material (X1), concentration of coating solution (X2), and number of drills (X3). The dependent variables included % release at 2 h (Y1), at 4 h (Y2), and at 8 h (Y3). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.


Subject(s)
Emulsifying Agents/pharmacokinetics , Infusion Pumps, Implantable , Osmosis/physiology , Vinca Alkaloids/pharmacokinetics , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacokinetics , Biological Availability , Emulsifying Agents/chemistry , Male , Rabbits , Solubility , Tablets , Vinca Alkaloids/chemistry
16.
Colloids Surf B Biointerfaces ; 161: 228-235, 2018 Jan 01.
Article in English | MEDLINE | ID: mdl-29080507

ABSTRACT

This study aimed to improve the mucus permeating properties of self-emulsifying drug delivery systems (SEDDS) by anchoring lipidized bromelain, papain and trypsin using palmitoyl chloride. SEDDS containing enzyme-palmitate conjugates were characterized regarding droplet size and zeta potential. Their mucus permeating properties were evaluated by Transwell diffusion and rotating tube method using fluorescein diacetate (FDA) as marker. Degree of substitution of modified enzymes was 35.3%, 47.8% and 38.5% for bromelain-palmitate, papain-palmitate and trypsin-palmitate, respectively. SEDDS as control and SEDDS containing enzyme-palmitate conjugates displayed a droplet size less than 50nm and 180-312nm as well as a zeta potential of -3 to -4 and -4 to -5mV, respectively. The highest percentage of permeation was achieved by introducing 5% papain-palmitate into SEDDS. It could enhance the mucus permeation of SEDDS in porcine intestinal mucus 4.6-fold and 2-fold as evaluated by Transwell diffusion and rotating tube method, respectively. It is concluded that mucus permeation of SEDDS can be strongly improved by incorporation of enzyme-palmitate conjugates.


Subject(s)
Drug Delivery Systems/methods , Emulsifying Agents/administration & dosage , Expectorants/metabolism , Mucus/metabolism , Animals , Bromelains/chemistry , Bromelains/metabolism , Emulsifying Agents/chemistry , Emulsifying Agents/pharmacokinetics , Expectorants/chemistry , Intestinal Mucosa/metabolism , Lipids/chemistry , Palmitates/metabolism , Papain/chemistry , Papain/metabolism , Particle Size , Permeability , Swine , Trypsin/chemistry , Trypsin/metabolism
17.
Int J Toxicol ; 35(1 Suppl): 60S-89S, 2016 07.
Article in English | MEDLINE | ID: mdl-27383199

ABSTRACT

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety.


Subject(s)
Consumer Product Safety , Cosmetics , Ethers/toxicity , Polyethylene Glycols/toxicity , Propylene Glycols/toxicity , Alkylation , Animals , Dermatologic Agents/chemistry , Dermatologic Agents/pharmacokinetics , Dermatologic Agents/toxicity , Emulsifying Agents/chemistry , Emulsifying Agents/pharmacokinetics , Emulsifying Agents/toxicity , Ethers/chemistry , Ethers/pharmacokinetics , Humans , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Propylene Glycols/chemistry , Propylene Glycols/pharmacokinetics , Surface-Active Agents/chemistry , Surface-Active Agents/pharmacokinetics , Surface-Active Agents/toxicity , Toxicity Tests
18.
Pharm Res ; 33(8): 1972-87, 2016 08.
Article in English | MEDLINE | ID: mdl-27245466

ABSTRACT

PURPOSE: The aim of our study was development of advanced third generation Curcumin self microemulsifying composition solid dispersion (Cur SMEC-SD) with high drug loading, improved stability, rapid in-vitro dissolution and enhanced bioavailability for improved therapy of rheumatoid arthritis. METHOD: The Cur SMEC-SD comprising polymers (KollidonVA64[KVA], Eudragits, HPMC and Soluplus) and self microemulsifying composition of surfactant:co-surfactant:oil were coated onto rapidly disintegrating inert tablet core. SDs evaluated for stability, in-vitro release and bioenhancement. RESULTS: Cur SMEC-SDs exhibited high Cur loading of 45% w/w and microemulsion formation with globule size (~100 nm) irrespective of polymers. Among the polymers, SD with KVA revealed exceptionally low contact angle (7°C) and rapid in-vitro release (t50%-6.45 min). No crystallization was evident as confirmed by SEM, DSC and XRD and is attributed to SMEC aided solubilization/amorphisation, and interaction of KVA with Cur seen in the FTIR spectra. Stability was confirmed as per ICH guidelines. Remarkable bioenhancement with Cur SMEC-SD was confirmed by the > four fold and a two fold compared to Cur and Cur-SD without SMEC respectively. High efficacy ~ 80% compared to Indomethacin, seen with rheumatoid arthritis (RA) induced rats coupled with no adverse toxicity. CONCLUSION: The advanced third generation Cur SMEC-SD presents a practical technological advancement and suggests Cur SMEC-SD as promising alternative for RA therapy.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Curcumin/administration & dosage , Drug Carriers/administration & dosage , Emulsifying Agents/administration & dosage , Polymers/administration & dosage , Animals , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/metabolism , Biological Availability , Curcumin/pharmacokinetics , Drug Carriers/pharmacokinetics , Emulsifying Agents/pharmacokinetics , Male , Polymers/pharmacokinetics , Rats , Rats, Wistar , X-Ray Diffraction
19.
Drug Deliv ; 23(6): 2074-83, 2016 Jul.
Article in English | MEDLINE | ID: mdl-26923905

ABSTRACT

CONTEXT: Self-emulsifying drug delivery systems (SEDDS) are among most promising tools for improving oral peptide bioavailability. OBJECTIVE: In this study, in vitro protective effect of SEDDS containing desmopressin against presystemic inactivation by glutathione and α-chymotrypsin was evaluated. MATERIALS AND METHODS: The partitioning coefficient (log P) of desmopressin was increased via hydrophobic ion pairing using anionic surfactants. Solubility studies were performed to select the appropriate solvents for SEDDS preparation. Subsequently, droplet size and emulsification properties of 22 SEDDS formulations were evaluated. Moreover, the peptide-surfactant complex was dissolved in two chosen SEDDS formulations. Finally, SEDDS containing desmopressin were characterized regarding lipase stability, toxicity, and in vitro protective effect toward glutathione and α-chymotrypsin. RESULTS: Desmopressin log P was increased from initial -6.13 to 0.33 using sodium docusate. The resulting desmopressin docusate complex (DES/AOT) was incorporated in two different SEDDS formulations, containing Capmul 907 P as main solvent. DES/AOT-SEDDS-F4 (containing 0.07% w/w DES/AOT) was composed of 50% Capmul 907P, 40% Cremophor RH40, and 10% Transcutol. The comparatively more hydrophilic formulation DES/AOT-SEDDS-F15 (containing 0.25% w/w DES/AOT) consisted of 20% Capmul 907P, 40% Acconon MC8-2, and 40% Tween 20. Both formulations were stable toward digestion by lipase and protected desmopressin toward α-chymotrypsin degradation. Moreover, DES/AOT-SEDDS-F4 also protected the peptide from thiol/disulfide exchange reactions with glutathione and was not cytotoxic at a concentration of 0.375% (w/w). CONCLUSION: DES/AOT-SEDDS-F4 protected desmopressin from in vitro glutathione and α-chymotrypsin degradation. DES/AOT-SEDDS-F4 was metabolically stable and nontoxic. Therefore, it could be considered as a potential delivery system for oral desmopressin administration.


Subject(s)
Chymotrypsin/chemistry , Emulsifying Agents/chemistry , Glutathione/chemistry , Polyethylene Glycols/chemistry , Polysorbates/chemistry , Administration, Oral , Biological Availability , Chemistry, Pharmaceutical , Chymotrypsin/metabolism , Drug Delivery Systems , Emulsifying Agents/metabolism , Emulsifying Agents/pharmacokinetics , Glutathione/metabolism , Humans , Solubility , Solvents/chemistry
20.
Drug Dev Ind Pharm ; 42(3): 506-12, 2016.
Article in English | MEDLINE | ID: mdl-26177197

ABSTRACT

The novel self-microemulsifying (SME) tablets were developed to enhance the oral bioavailability of a poor water-soluble drug felodipine (FDP). Firstly, FDP was dissolved in the optimized liquid self-microemusifying drug delivery systems (SMEDDS) containing Miglyol® 812, Cremophor® RH 40, Tween 80 and Transcutol® P, and the mixture was solidified with porous silicon dioxide and crospovidone as adsorbents. Then after combining the solidified powders with other excipients, the solid SME tablets were prepared by wet granulation-compression method. The prepared tablets possessed satisfactory characterization; the droplet size of the SME tablets following self-emulsification in water was nearly equivalent to the liquid SMEDDS (68.4 ± 14.0 and 64.4 ± 12.0 nm); differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) analysis demonstrated that FDP in SME tablets had undergone a polymorphism transition from a crystal form to an amorphous state, which was further confirmed by transmission electron microscopy (TEM). A similar dissolution performance of SME tablets and liquid SMEDDS was also obtained under the sink condition (85% within 10 min), both significantly higher than commercial tablets. The oral bioavailability was evaluated for the SME tablets, liquid SMEDDS and commercial conventional tablets in the fasted beagle dogs. The AUC of FDP from the SME tablets was about 2-fold greater than that of conventional tablets, but no significant difference was found when compared with the liquid SMEDDS. Accordingly, these preliminary results suggest that this formulation approach offers a useful large-scale producing method to prepare the solid SME tablets from the liquid SMEDDS for oral bioavailability equivalent enhancement of poorly soluble FDP.


Subject(s)
Emulsifying Agents/administration & dosage , Emulsifying Agents/pharmacokinetics , Felodipine/administration & dosage , Felodipine/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Dogs , Dose-Response Relationship, Drug , Emulsifying Agents/chemistry , Felodipine/chemistry , Male , Pilot Projects , Tablets
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