- Solid dispersions enhance solubility, dissolution and permeability of thalidomide. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Dec 05; :1-28
- Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chem...
Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire® 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor® TPGS),in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggestthat the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several in vitro techniques. The developed SDs wereable toincrease the apparent solubility of the drug (up to 2-3x the equilibrium solubility) for a least 4h. Dissolution experiments (paddle method, 75 rpm) in different pHs showed that around 80% of drug dissolved after 120 min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drughave yet to be reported.
- SN-38 loading capacity of hydrophobic polymer blend nanoparticles: formulation, optimization and efficacy evaluation. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Dec 02; :1-33
- One of the most important problems in nanoencapsulation of extremely hydrophobic drugs is poor drug loading due to rapid drug crystallization outside the polymer core. The effort to use nanoprecipita...
One of the most important problems in nanoencapsulation of extremely hydrophobic drugs is poor drug loading due to rapid drug crystallization outside the polymer core. The effort to use nanoprecipitation, as a simple one-step procedure with good reproducibility and FDA approved polymers like Poly(lactic-co-glycolic acid) (PLGA) and Polycaprolactone (PCL), will only potentiate this issue. Considering that drug loading is one of the key defining characteristics, in this study we attempted to examine whether the nanoparticle core composed of two hydrophobic polymers will provide increased drug loading for 7-Ethyl-10-hydroxy-camptothecin (SN-38), relative to nanoparticles prepared using individual polymers. D-optimal design was applied to optimize PLGA/PCL ratio in the polymer blend and the mode of addition of the amphiphilic copolymer Lutrol®F127 in order to maximize SN-38 loading and obtain nanoparticles with acceptable size for passive tumor targeting. Drug/polymer and polymer/polymer interaction analysis pointed to high degree of compatibility and miscibility among both hydrophobic polymers, providing core configuration with higher drug loading capacity. Toxicity studies outlined the biocompatibility of the blank nanoparticles. Increased in vitro efficacy of drug-loaded nanoparticles compared to the free drug was confirmed by growth inhibition studies using SW-480 cell line. Additionally, the optimized NP formulation showed very promising blood circulation profile with elimination half-time of 7.4h.
- Development of a Nanogel Formulation for Transdermal Delivery of Tenoxicam: A Pharmacokinetic-Pharmacodynamic Modeling Approach for Quantitative Prediction of Skin Absorption. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Dec 02; :1-50
- This study investigates potentials of solid lipid nanoparticles (SLN) based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetics-pharmacodynamics (PK-PD) modeling approach...
This study investigates potentials of solid lipid nanoparticles (SLN) based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetics-pharmacodynamics (PK-PD) modeling approach for predicting concentration-time profile in skin. A 2(3) factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan induced rat paw edema test. A published Hill model for in-vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte-Carlo simulations. The optimized SLN was spherical vesicles (58.1±3.1 nm) with adequate entrapment efficiency (69.6±2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40±13.5, and 227±116%, respectively. Average Cmax and AUC0-24 predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in-vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in treatment of inflammatory disorders. PK-PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.
- Modification of gellan gum films by halloysite: Physicochemical evaluation and drug permeation properties. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Nov 30; :1-31
- The aims of this study were to determine the potential of gellan gum (GG) and halloysite (HS) dispersions at different mixing ratios and investigate the potential of GG-HS dispersions in film formati...
The aims of this study were to determine the potential of gellan gum (GG) and halloysite (HS) dispersions at different mixing ratios and investigate the potential of GG-HS dispersions in film formation. To this end, the dispersions and films were characterized. The dispersions formed films with large particles ranging from 3-4 µm in size, with a zeta potential of approximately -35 mV. The GG-HS films were fabricated using a solvent-casting technique, which generated films with a white opaque appearance and rough surface. The GG-HS films were formed via hydrogen bonding and electrostatic interactions at the inner cavity and outer surface, as confirmed by ATR-FTIR spectroscopy and X-ray diffractometry. The %water uptake and erosion of the GG-HS film decreased with increasing HS content, whereas both puncture strength and elongation was increased in the GG-HS ratios of 1:0.4 and 1:1.2. Moreover, addition of HS into the GG films could possibly decrease drug permeability coefficient when using higher HS ratio in acidic and neutral media. These results suggested that HS modifies the characteristics of the GG used to coat modified-release tablets.
- Efficacy, safety and mechanism of HP-β-CD-PEI polymers as absorption enhancers on the intestinal absorption of poorly absorbable drugs in rats. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Dec 05; :1-9
- CONCLUSIONS: HP-β-CD-PEI polymers might be potential and safe absorption enhancers for improving oral delivery of poorly absorbable macromolecules including peptides and proteins.
- Conveying a newly designed hydrophilic anti-human thymidylate synthase peptide to cisplatin resistant cancer cells: are pH-sensitive liposomes more effective than conventional ones? [Journal Article]
- DDDrug Dev Ind Pharm 2016 Nov 25; :1-28
- Context LR-peptide, a novel hydrophilic peptide synthetized and characterized in previous work, is able to reduce the multi-drug resistance response in cisplatin (cDPP) resistant cancer cells by inhi...
Context LR-peptide, a novel hydrophilic peptide synthetized and characterized in previous work, is able to reduce the multi-drug resistance response in cisplatin (cDPP) resistant cancer cells by inhibiting human thymidylate synthase overexpressed in several tumors, including ovarian and colon-rectal cancers, but it is unable to enter the cells spontaneously. Objective The aim of this work was to design and characterize liposomal vesicles as drug delivery systems for the LR peptide, evaluating the possible benefits of the pH-responsive feature in improving intracellular delivery. Materials and methods For this purpose, conventional and pH-sensitive liposomes were formulated, compared regarding their physical-chemical properties (size, PDI, morphology, in vitro stability and drug release) and studied for in vitro cytotoxicity against a cDDP-resistant cancer cells. Results and discussion Results indicated that LR peptide was successfully encapsulated in both liposomal formulations but at short incubation time only LR loaded pH-sensitive liposomes showed cell inhibition activity while for long incubation time the two kinds of liposomes demonstrated the same efficacy. Conclusions Data provide evidence that acidic pH-triggered liposomal delivery is able to significantly reduce the time required by the systems to deliver the drug to the cells without inducing an enhancement of the efficacy of the drug.
- Improved stability of solid dispersions of manidipine with polyethylene glycol 4000/copovidone blends: application of ternary phase diagram. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Dec 07; :1-9
- CONCLUSIONS: The results showed that MDP was molecularly dispersed in PEG4000 and copovidone when the tSD was created from homogeneous region of solid ternary phase diagram. FTIR results confirmed that strong hydrogen bonding was presented between MDP and copovidone, leading to a significant increase in the solubility and dissolution of MDP. After storage at accelerated condition (40 °C/75%RH) for 6 months, the tSD still showed a good appearance and high solubility.The results of this study suggest that tSD prepared by melting has promising potential for oral administration and may be an efficacious approach for improving the therapeutic potential of MDP.
- Preparation and physicochemical characterization of matrix pellets containing APIs with different solubility via extrusion process. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Nov 28; :1-7
- In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points...
In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process.
- Comparative in vitro release and clinical pharmacokinetics of leuprolide from Luphere 3M Depot, a 3-month release formulation of leuprolide acetate. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Nov 22; :1-7
- A 3-month depot formulation of leuprolide acetate (Luphere 3M Depot) with a mean microsphere diameter of 22.3 μm was prepared aseptically by spray-drying glacial acetic acid solution of the drug and ...
A 3-month depot formulation of leuprolide acetate (Luphere 3M Depot) with a mean microsphere diameter of 22.3 μm was prepared aseptically by spray-drying glacial acetic acid solution of the drug and polylactic acid, and lyophilization in a d-mannitol solution. The encapsulation efficiency and loading content of the drug in the Luphere 3M Depot were 94.7% and 9.92% (w/w), respectively. The in vitro release of leuprolide from the depot was substantially delayed and the release profile was similar to that of Lucrin Depot (Abbott Korea, Korea). The safety and pharmacokinetics of leuprolide were investigated over a period of 42 days in 20 prostate cancer patients following a subcutaneous injection of Luphere 3M or Lucrin Depot suspensions (leuprolide acetate dose of 11.25 mg) in a multi-center, randomized, single dose, parallel study. Both formulations were well tolerated by the patients and no serious adverse effects were observed during and after the study. No significant differences were observed in the maximum serum concentration (Cmax) and area under the curve (AUClast) of leuprolide between the two formulations. The results suggest comparable safety and efficacy profiles of Luphere 3M Depot and Lucrin Depot in clinical situations.
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- Improvement of side-effects and treatment on the experimental colitis in mice of a resin microcapsule-loading hydrocortisone sodium succinate. [Journal Article]
- DDDrug Dev Ind Pharm 2016 Nov 21; :1-10
- CONCLUSIONS: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeting preparations.