- Temperature-dependent in Situ Gel of Clotrimazole: an Experimental Study. [Journal Article]
- FMFolia Med (Plovdiv) 2019 Jun 01; 61(2):266-276
- CONCLUSIONS: It was possible to formulate effective in situ vaginal gel for control release action of clotrimazole.
- Curcumin-Loaded Nanostructured Lipid Carrier Modified with Partially Hydrolyzed Ginsenoside. [Journal Article]
- APAAPS PharmSciTech 2019 Jul 12; 20(6):252
- The objective of the present study was to investigate the effect of partially hydrolyzed ginsenoside on the physicochemical properties and in vitro release of curcumin from phospholipid-based nanostr…
The objective of the present study was to investigate the effect of partially hydrolyzed ginsenoside on the physicochemical properties and in vitro release of curcumin from phospholipid-based nanostructured lipid carrier (NLC). NLC formulas modified with partially hydrolyzed ginsenoside (NLC-PG) were prepared with different amounts of ginsenoside using the conventional hot-melt method. The average particle size of curcumin-loaded NLC-PG ranged from 150 to 200 nm, and polydispersity index was in the range of 0.101-0.177, indicating monodispersed particle size distribution. Optical microscopy showed no sedimentation or recrystallization of curcumin even at 10,000 μg/ml concentration as NLC-PG in distilled water, indicating significantly enhanced solubility. TEM image showed that the nanoparticles were monodispersed with a multilayered core/shell structure. X-ray diffraction and FTIR spectroscopy showed that curcumin was amorphous in the NLC-PG, and there was no interaction between curcumin and the excipients. In vitro release study using simulated gastric/intestinal fluid media revealed that the release rate (Jss) of curcumin from the NLC-PG increased as a function of the ginsenoside content in the lipid carrier. Moreover, the Jss of curcumin kept gradually increasing in the presence of lipase, whereas in the presence of viscozyme, it sharply increased until the ginsenoside content reached 9.09% and subsequently plateaued. Partially hydrolyzed ginsenoside increased the Jss of curcumin from curcumin-loaded NLC-PG and therefore may be useful for improving the bioavailability of curcumin.
- Curcumin-loaded self-emulsifying drug delivery system (cu-SEDDS): a promising approach for the control of primary pathogen and secondary bacterial infections in cutaneous leishmaniasis. [Journal Article]
- AMAppl Microbiol Biotechnol 2019 Jul 12
- Cutaneous leishmaniasis being a neglected tropical disease (NTD) faces several challenges in chemotherapy. If infected with secondary bacterial infections, the treatment regime of cutaneous ulcers in…
Cutaneous leishmaniasis being a neglected tropical disease (NTD) faces several challenges in chemotherapy. If infected with secondary bacterial infections, the treatment regime of cutaneous ulcers in cutaneous leishmaniasis is further complicated which usually require two or more than two chemotherapeutic agents for healing. In the current study, seven curcumin-loaded self-emulsifying drug delivery system (cu-SEDDS) formulations (namely F1-F7) were prepared by mixing different excipients (oils, surfactants, and co-solvents) through stirring (vortex) and sonication. The formulations were characterized regarding their droplet size, polydispersity index (PDI), and zeta potential by zeta sizer. The cu-SEDDS formulations displayed different sizes ranging from 32.4 up to 80.0 nm. The zeta potential of the formulations ranged from - 1.56 up to - 4.8. The antileishmanial activities of the cu-SEDDS formulations in terms of IC50 against Leishmania tropica ranged from 0.19 up to 0.37 μg/ml. The minimum inhibitory concentrations (MICs) of these formulations against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae were in the range of 48-62 μg/ml. The hemolysis caused by formulations was 1-2%. The spreading potential of the formulations (F1 and F5) over damaged skin model was remarkable. These results suggest that cu-SEDDS further enhanced the broad spectrum antileishmanial and antibacterial profile of curcumin and could be used for the treatment of cutaneous leishmaniasis and its associated secondary infections.
- Compensated Hydroxyl Radical Protein Footprinting Measures Buffer and Excipient Effects on Conformation and Aggregation in an Adalimumab Biosimilar. [Journal Article]
- AJAAPS J 2019 Jul 11; 21(5):87
- Unlike small molecule drugs, therapeutic proteins must maintain the proper higher-order structure (HOS) in order to maintain safety and efficacy. Due to the sensitivity of many protein systems, even …
Unlike small molecule drugs, therapeutic proteins must maintain the proper higher-order structure (HOS) in order to maintain safety and efficacy. Due to the sensitivity of many protein systems, even small changes due to differences in protein expression or formulation can alter HOS. Previous work has demonstrated how hydroxyl radical protein footprinting (HRPF) can sensitively detect changes in protein HOS by measuring the average topography of the protein monomers, as well as identify specific regions of the therapeutic protein impacted by the conformational changes. However, HRPF is very sensitive to the radical scavenging capacity of the buffer; addition of organic buffers and/or excipients can dramatically alter the HRPF footprint without affecting protein HOS. By compensating for the radical scavenging effects of different adalimumab biosimilar formulations using real-time adenine dosimetry, we identify that sodium citrate buffer causes a modest decrease in average solvent accessibility compared to sodium phosphate buffer at the same pH. We find that the addition of polysorbate 80 does not alter the conformation of the biosimilar in either buffer, but it does provide substantial protection from protein conformational perturbation during short periods of exposure to high temperature. Compensated HRPF measurements are validated and contextualized by dynamic light scattering (DLS), which suggests that changes in adalimumab biosimilar aggregation are major drivers in measured changes in protein topography. Overall, compensated HRPF accurately measured conformational changes in adalimumab biosimilar that occurred during formulation changes and identified the effect of formulation changes on protection of HOS from temperature extremes.
- Efficient anti-tumor nano-lipoplexes with unsaturated or saturated lipid induce differential genotoxic effects in mice. [Journal Article]
- NNanotoxicology 2019 Jul 11; :1-24
- Cationic lipids are well known excipients for nanometric liposomal gene delivery systems. However, because of the suspected, collateral toxicity in normal cells, the use of cationic lipids for the tr…
Cationic lipids are well known excipients for nanometric liposomal gene delivery systems. However, because of the suspected, collateral toxicity in normal cells, the use of cationic lipids for the treatment of human tumor is largely limited. Recently, using a glucocorticoid receptor (GR)-targeted liposomal, anticancer delivery system (DXE nano-lipoplex), which carried cationic lipid of saturated twin aliphatic chains, we accomplished efficient anti-tumor effect in aggressive and drug-resistant tumor models of breast cancer stem cells, melanoma and pancreatic cancer. However, to explore its human clinical use, a complete in vivo genotoxicological profile-based safety assessment was due. In addition, in this study we incorporated another nano-lipoplex (D1XE) that carried cationic lipid with one unsaturated aliphatic chain. The study was to compare the genotoxic and anti-tumor profile of both the lipoplexes, which differ by the chemical identity of only one constituent cationic lipid, i.e., lipid either carrying both the saturated aliphatic chains or carrying one saturated and one unsaturated aliphatic chains. It is well-known that unsaturated aliphatic chains in lipid impart efficient cell surface fusogenic property in lipid formulations. Herein, we report that nanoplex with unsaturated cationic lipid (D1XE) exhibited better physical appearance with less flocculent behavior than nanoplex with saturated lipid (DXE). Upon multiple injections, D1XE nanoplex imparted better tumor regression but most importantly, exhibited much lower overall toxicity (e.g., genotoxicity, weight loss etc.) than DXE nanoplex. With higher antitumor effect but lower genotoxic effect, D1XE is proved to be a better nanoplex than DXE for potential clinical trial. Thus, this study clearly delineates the importance of incorporating a constituent lipid that carries single unsaturated aliphatic chain towards developing efficient anti-tumor nano-lipoplexes with reduced genotoxicity.
- Pharmacokinetic Modeling of the Blood-Stable Camptothecin Analogue AR-67 in Two Different Formulations. [Journal Article]
- BDBiopharm Drug Dispos 2019 Jul 10
- AR-67 is a lipophilic camptothecin analogue currently under clinical investigation using a Cremophor EL based formulation. However, as potential toxicity limitations exist in the clinical use of Crem…
AR-67 is a lipophilic camptothecin analogue currently under clinical investigation using a Cremophor EL based formulation. However, as potential toxicity limitations exist in the clinical use of Cremophor, an alternative cyclodextrin (SBE-β-CD) based formulation has been proposed. Here we conducted pharmacokinetic (PK) studies in mice and compared the SBE-β-CD based formulation to the Cremophor EL formulation. PK studies were conducted following intravenous or oral administration of AR-67 in either Cremophor or SBE-β-CD formulation in mice. Noncompartmental analysis was used to determine the plasma and tissue drug distribution. A non-linear mixed effects (population) PK model was developed to fit both the oral and intravenous data and estimate key PK parameters. The effect of formulation was explored as a covariate in the PK model. AR-67 in SBE-β-CD formulation had similar plasma PK and biodistribution as that in the Cremophor EL formulation. The proposed 2-compartment model described the plasma PK of AR-67 in both formulations adequately. AR-67 in the SBE-β-CD formulation exhibited dose linearity following both oral and intravenous administration. Our studies indicate the SBE-β-CD is a viable alternative to Cremophor EL as a pharmaceutical excipient for formulating AR-67.
- Thermophysical Fingerprinting of Probiotic-Based Products. [Journal Article]
- SRSci Rep 2019 Jul 10; 9(1):10011
- Variability in efficacy and safety is a worldwide concern with commercial probiotics for their growing and inevitable use in food and health sectors. Here, we introduce a probiotic thermophysical fin…
Variability in efficacy and safety is a worldwide concern with commercial probiotics for their growing and inevitable use in food and health sectors. Here, we introduce a probiotic thermophysical fingerprinting methodology using a coupling thermogravimetry and differential scanning calorimetry. Qualitative and quantitative information on the material decomposition and transition phases is provided under heating conditions. By monitoring the changes in both mass and internal energy over temperature and time, a couple of thermal data at the maximum decomposition steps allow the creation of a unique and global product identity, depending on both strain and excipient components. We demonstrate that each powder formulation of monostrain and multistrain from different lots and origins have a unique thermophysical profile. Our approach also provides information on the formulation thermostability and additive/excipient composition. An original fingerprint form is proposed by converting the generated thermal data sequence into a star-like pattern for a perspective library construction.
- Glass Transition Dynamics and Physical Stability of Amorphous Griseofulvin in Binary Mixtures with Low Tg excipients. [Journal Article]
- MPMol Pharm 2019 Jul 09
- Amorphization of drug formulations containing active pharmaceutical ingredients (APIs) and excipients has been proven to be an effective strategy to improve their poor aqueous solubility. The excipie…
Amorphization of drug formulations containing active pharmaceutical ingredients (APIs) and excipients has been proven to be an effective strategy to improve their poor aqueous solubility. The excipients can also impact on the physical stability of the prepared amorphous forms. Generally, researchers are more apt to select excipients that have high value of the glass transition temperature Tg because of the antiplasticization effect of the additives on APIs. In this article, we studied the glass transition dynamics as well as crystallization behavior in binary blends composed of griseofulvin (GSF) and two low - Tg additives, octaacetylmaltose (acMAL) and polyvinyl acetate (PVAc), with particular focus on the plasticization effect. Effectively suppressed crystallization of GSF is observed in both systems when higher excipient contents are used. Our finding aims to encourage the use of specifically developed protocols, in which suitable plasticizers are used as excipients for stabilizing the amorphous state of a drug.
- Importance of intact secondary protein structures of cell envelopes and glass transition temperature of the stabilization matrix on the storage stability of probiotics. [Journal Article]
- FRFood Res Int 2019; 123:198-207
- Lactobacillus reuteri LR6 cells were stabilized using a novel combination of wet granulation and fluidized-bed-drying techniques. The stabilized cells were stored at 37 °C and at two water activity (…
Lactobacillus reuteri LR6 cells were stabilized using a novel combination of wet granulation and fluidized-bed-drying techniques. The stabilized cells were stored at 37 °C and at two water activity (aw) levels (0.11 & 0.30). Superior storage stability was recorded in the lower aw environment, supported by a stronger glassy matrix when skim milk powder was used as the excipient. The initial viable cell populations of the samples stabilized in different matrices ranged from 8.3 to 9.1 log CFU/g. At the end of the storage period, the viable cell populations were reduced to 6.7 to 7.3 log CFU/g at aw 0.11 and to 6.1 to 6.6 CFU/g when the aw was maintained at 0.30. Fourier transform infrared spectroscopic examination of the cell envelopes revealed substantial dissimilarities between samples at the beginning and at the end of the storage period, which indicated alteration in the secondary protein structures of the cell envelope and also correlated well with the loss in cell viability. In milk-powder-based matrices, adjusting the aw to 0.30 resulted in a weaker or no glassy state whereas the same matrices had a high glass transition temperature at aw 0.11. This strong glassy matrix and low aw combination was found to enhance the bacterial stability at the storage temperature of 37 °C. Scanning electron microscopy revealed the formation of corrugated surfaces and blister-type deformations on the cell envelopes during the stabilization process.
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- Novel spectral manipulations for determinations of Tolnaftate along with related toxic compounds: Drug profiling and a comparative study. [Journal Article]
- SASpectrochim Acta A Mol Biomol Spectrosc 2019 Jun 19; 223:117290
- A comparative study using novel quadruple divisor and mean centering of ratio spectra spectrophotometric methods was developed for resolution of five- component mixture of Tolnaftate, β-naphthol (Tol…
A comparative study using novel quadruple divisor and mean centering of ratio spectra spectrophotometric methods was developed for resolution of five- component mixture of Tolnaftate, β-naphthol (Tolnaftate alkaline degradation product and its toxic impurity), methyl(m-tolyl)carbamic acid (Tolnaftate alkaline degradation product), N-methyl-m-toluidine (Tolnaftate toxic impurity) and methyl paraben (as a preservative). For the novel quadruple divisor method, each component in the quinary mixture was determined by dividing the quinary mixture spectrum by a sum of standard spectrum of equal concentration of the other four components as a quadruple divisor. First derivative of each ratio spectra was then obtained which allowed selective determination of each component without interference from other components in the mixture. The second method was mean centering of ratio spectra that depended on utilizing the mean centered ratio spectra in four successive steps leading to enhancement of the signal to noise ratio. The absorption spectra of the five studied components were recorded in the wavelength range of 210-350 nm. The mean centered fourth ratio spectra amplitudes for each component were used for its determination. The developed methods were successfully applied for determination of laboratory prepared quinary mixtures to ensure method's specificity, then, were further applied on Tinea Cure® cream where no interference from excipients. For the first time, Tolnaftate was determined along with its toxic impurity; β-naphthol, that could be absorbed by the skin, causing systemic toxic effects, unlike Tolnaftate that poorly absorbed, indicating the significance of this work. The proposed methods were statistically compared with each other and with the reference method. Furthermore, ICH guidelines were followed for their validation.