Effect of biocompatible polymers on the physicochemical and dissolution properties of fenofibrate in nanoparticle system

This study aimed to evaluate the effect of biocompatible polymers on the physicochemical and dissolution properties of poorly water-soluble drugs in nanoparticle systems. Four types of nanoparticles containing poorly water-soluble fenofibrate were prepared using solvent evaporation technique with different biocompatible polymers such as polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), carbopol and ethylcellulose. Their physicochemical properties were investigated using scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. The solubility and dissolution of nanoparticle-entrapped fenofibrate were compared with those of free drug powder. Biocompatible polymers affected the morphology and sizes of fenofibrate nanoparticles. PVP or carbopol-based nanoparticles showed spherical appearance, whereas HPMC or ethylcellulose-based nanoparticles formed aggregates with irregular shape. The particle sizes increased in the order of the nanoparticle prepared with carbopol ≤ PVP < HPMC < ethylcellulose. The size of PVP-based nanoparticles did not significantly differ from that of carbopol-based nanoparticles, showing the mean sizes of ca. 10 μm. As compared to free drug powder, the solubility and dissolution of the drug in nanoparticles increased in the order of PVP > HPMC > carbopol > ethylcellulose. The enhanced solubility and dissolution of poorly water-soluble fenofibrate via nanoparticle system did not depend on particle size but on crystallinity. In conclusion, in nanoparticle development of poorly water-soluble drugs such as fenofibrate, the nature of biocompatible polymers plays an important role in the physicochemical and dissolution of poorly water-soluble drugs in the nanoparticles.     

Increased bioavailability of a transdermal application of a nano-sized emulsion preparation

The aim of this study was to compare the transdermal application of a nano-sized emulsion versus a micron-sized emulsion preparation of delta tocopherol as it relates to particle size and bioavailability. Two separate experiments were performed using seven F1B Syrian Golden hamsters, 1 week apart. Each emulsion preparation consisted of canola oil, polysorbate 80, deionized water and delta tocopherol; the only difference between the two preparations was processing the nano-sized emulsion with the Microfluidizer Processor. Both were formulated into a cream and applied to the shaven dorsal area. The particle size of the micron-sized emulsion preparation was 2788 nm compared to 65 nm for the nano-sized emulsion formulation. Two hours post-application, hamsters that were applied the nano-sized emulsion had a 36-fold significant increase of plasma delta tocopherol, where as hamsters that were applied the micron-sized emulsion only had a 9-fold significant increase, compared to baseline, respectively. At 3h post-application, plasma delta tocopherol had significantly increased 68-fold for hamsters applied the nano-sized emulsion, whereas only an 11-fold significant increase was observed in hamsters applied the micron-sized emulsion, compared to baseline, respectively. Significant differences were also observed between the nano-sized and micron-sized emulsion at 2 and 3h post-application. This study suggests that nano-sized emulsions significantly increase the bioavailability of transdermally applied delta tocopherol.     

Properties of rapidly dissolving eutectic mixtures of poly(ethylene glycol) and fenofibrate: the eutectic microstructure

Poly(ethylene glycol) or PEG is an ideal inactive component for preparing simple binary eutectic mixtures because of its low entropy of fusion ( approximately 0.0076 J/mol-K), lower melting point (approximately 62 degrees C) compared to most pharmaceuticals, miscibility with drugs at elevated temperatures, and its covalent crystalline lattice. Implication of these physicochemical properties on eutectic crystallization and size reduction of the drug is discussed. Enhancement of the dissolution rate of a poorly soluble compound through the formation of PEG-drug eutectics was investigated using fenofibrate. Solid dispersions of PEG-fenofibrate when characterized, revealed that PEG and fenofibrate form a simple eutectic mixture containing 20-25%(w/w) fenofibrate at the eutectic point. Eutectic crystallization led to the formation of an irregular microstructure in which fenofibrate crystals were found to be less than 10 microm in size. Dissolution rate improvement of fenofibrate correlated with the phase diagram, and the amount of fenofibrate released from the dispersions that contained fenofibrate as a eutectic mixture was at least 10-fold higher compared to untreated fenofibrate. On aging, the dissolution rate of the dispersion containing 15%(w/w) fenofibrate in PEG remained unaltered. The results indicate that PEG-drug eutectic formation is a valuable option for particle size reduction and subsequent dissolution rate improvement.     

Budesonide Nanoparticle Agglomerates as Dry Powder Aerosols With Rapid Dissolution

: Nanoparticle technology represents an attractive approach for formulating poorly water-soluble pulmonary medicines. Unfortunately, nanoparticle suspensions used in nebulizers or metered dose inhalers often suffer from physical instability in the form of uncontrolled agglomeration or Ostwald ripening. In addition, processing such suspensions into dry powders can yield broad particle size distributions. To address these encumbrances, a controlled nanoparticle flocculation process has been developed. Nanosuspensions of the poorly water-soluble drug budesonide were prepared by dissolving the drug in organic solvent containing surfactants followed by rapid solvent extraction in water. Different surfactants were employed to control the size and surface charge of the precipitated nanoparticles. Nanosuspensions were flocculated using leucine and lyophilized. Selected budesonide nanoparticle suspensions exhibited an average particle size ranging from ~ 160 to 230 nm, high yield and high drug content. Flocculated nanosuspensions produced micron-sized agglomerates. Freeze-drying the nanoparticle agglomerates yielded dry powders with desirable aerodynamic properties for inhalation therapy. In addition, the dissolution rates of dried nanoparticle agglomerate formulations were significantly faster than that of stock budesonide. The results of this study suggest that nanoparticle agglomerates possess the microstructure desired for lung deposition and the nanostructure to facilitate rapid dissolution of poorly water-soluble drugs.     

Effect of powder processing on performance of fenofibrate formulations

In this study, the effect of the order in which powder blending and jet-milling were performed for the production of the bulk powders on the performance of 200-mg dose orally disintegrating tablets (ODTs) of fenofibrate was evaluated. Bulk powders composed of fenofibrate, mannitol, copovidone S630, and docusate sodium in a 10:10:2:1.2 ratio were prepared by the following three processes: process A: fenofibrate+excipients-->blending; process B: fenofibrate-->jet-milling-->blending with excipients; process C: fenofibrate+excipients-->blending-->jet-milling. The bulk powders were granulated followed by blending and tableting. The materials were tested for Differential Scanning Calorimetry (DSC), drug particle sizing post-reconstitution, dissolution, optical micrography, Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDS) and disintegration of the ODTs. It was found that the crystallinity of fenofibrate was not impacted by the blending and jet-milling processes. Process A produced materials having poorer fenofibrate reconstitution as compared to processes involving jet-milling. It was discovered that milling a blend of fenofibrate/excipient (process C) was advantageous over milling the raw drug alone (process B). Process C yielded bulk powder that showed rapid dissolution and ODTs which exhibited rapid disintegration.     

Development of Fully Redispersible Dried Nanocrystals by Using Sucrose Laurate as Stabilizer for Increasing Surface Area and Dissolution Rate of Poorly Water-Soluble Drugs

There is much interest in converting poorly water-soluble drugs into nanocrystals as they provide extremely high surface area that increases dissolution rate and oral bioavailability. However, nanocrystals are prepared as aqueous suspensions, and once the suspensions are dried for development of solid dosage forms, the nanocrystals agglomerate as large particles to reduce the excess surface energy. For successful development of drug products, it is essential that any agglomeration is reversible, and the dried nanocrystals regain original particle sizes after redispersion in aqueous media. We have established that sucrose laurate serves as a superb stabilizer to ensure complete redispersion of dried nanocrystals in aqueous media with mild agitation. Nanocrystals (150–300 nm) of three neutral drugs (fenofibrate, danazol and probucol) were produced with sucrose laurate by media milling, and suspensions were dried by tray drying under vacuum, spray drying, and lyophilization. Dried solids and their tablets redispersed into original particle sizes spontaneously. Preliminary studies showed that sucrose laurate can also redisperse acidic and basic drugs, indicating its versatile application. Fatty acid ester of another disaccharide, lactose laurate, also performed like sucrose laurate. Thus, we have developed a method of retaining high dissolution rate and, by implication, high bioavailability of nanocrystals from solid formulations.     

Investigation of preparation parameters of nanosuspension by top-down media milling to improve the dissolution of poorly water-soluble glyburide

The objective of this study was to identify and optimize formulation and process variables affecting characteristic and scale-up of nanosuspension manufacturing process on bead mill considering industrial perspective. Formulation factors evaluated were ratio of polymer to drug and ratio of surfactant to drug, whereas process parameters were milling time and milling speed. Responses measured in this study include zeta potential and mean particle size d(90). The test revealed that ratio of polymer to drug and milling speed have significant effect on zeta potential whereas milling time and milling speed have significant effect on the particle size distribution of nanosuspension. The X-ray powder diffraction pattern of drug milled at high and low speed reveals no form conversion when compared with unmilled drug. The formulated nanosuspension has shown a faster dissolution profile (98.97% in 10 min), relative to that of raw glyburide (18.17% in 10 min), mainly due to the formation of nanosized particles. The ANOVA test revealed that there was no significant difference in the dissolution profiles of fresh and aged nanosuspension. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate and thus possibly enhance fast onset of therapeutic drug effect.     

Increased dissolution and physical stability of micronized nifedipine particles encapsulated with a biocompatible polymer and surfactants in a wet ball milling process

Suspensions of nifedipine, a practically water-insoluble drug, were prepared in the presence of a biocompatible polymer, polyvinylpyrrolidone (PVP, K value 17), and three surfactants, sodium lauryl sulfate (SLS, anionic), cetyltrimethylammonium bromide (CETAB, cationic), polysorbate 80 (Tween 80, nonionic), by wet milling in ceramic ball mills. Nifedipine powders encapsulated with PVP and the surfactants were recovered from the suspensions after milling and evaluated for changes in particle size, morphology, sedimentation rate in aqueous suspensions, crystal form, and dissolution. Particle size analysis indicated that milling of suspensions in solutions of PVP and surfactants is an efficient method for reducing the particle size of nifedipine to below 10 microm. Furthermore, DSC and XPS analysis indicated that during milling the nifedipine crystals were coated with the PVP or surfactants and that milling with PVP stabilized the nifedipine crystal form during milling while nifedipine was gradually amorphisized when milled in a quaternary nifedipine/PVP/SLS/CETAB system. The decrease in particle size caused a significant decrease in sedimentation rate and increased the dissolution rate of nifedipine in simulated gastric fluid when compared to milled nifedipine and powder mixtures of the drug and the excipients.     

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

Nano-sized cosmetic formulations or solid nanoparticles in sunscreens: a risk to human health?

Personal care products (PCP) often contain micron- or nano-sized formulation components, such as nanoemulsions or microscopic vesicles. A large number of studies suggest that such vesicles do not penetrate human skin beyond the superficial layers of the stratum corneum. Nano-sized PCP formulations may enhance or reduce skin absorption of ingredients, albeit at a limited scale. Modern sunscreens contain insoluble titanium dioxide (TiO₂) or zinc oxide (ZnO) nanoparticles (NP), which are efficient filters of UV light. A large number of studies suggest that insoluble NP do not penetrate into or through human skin. A number of in vivo toxicity tests, including in vivo intravenous studies, showed that TiO₂ and ZnO NP are non-toxic and have an excellent skin tolerance. Cytotoxicity, genotoxicity, photo-genotoxicity, general toxicity and carcinogenicity studies on TiO₂ and ZnO NP found no difference in the safety profile of micro- or nano-sized materials, all of which were found to be non-toxic. Although some published in vitro studies on insoluble nano- or micron-sized particles suggested cell uptake, oxidative cell damage or genotoxicity, these data are consistent with those from micron-sized particles and should be interpreted with caution. Data on insoluble NP, such as surgical implant-derived wear debris particles or intravenously administered magnetic resonance contrast agents suggest that toxicity of small particles is generally related to their chemistry rather than their particle size. Overall, the weight of scientific evidence suggests that insoluble NP used in sunscreens pose no or negligible risk to human health, but offer large health benefits, such as the protection of human skin against UV-induced skin ageing and cancer.     

Micronization of drugs using supercritical carbon dioxide.

Particles from gas saturated solutions, a novel method for high pressure material processing, has been used for micronization of practically insoluble calcium-channel blockers nifedipine and felodipine and the hypolipidemic agent fenofibrate with the aim of increasing their dissolution rate and hence their bioavailability. Dependent on the pre-expansion conditions, a mean particle size of between 15 and 30 microm was achieved for micronized nifedipine and 42 microm for micronized felodipine. The particle size of processed fenofibrate, on the other hand, increased due to agglomeration. The highest dissolution rate was achieved by preparation of drug coprecipitates with PEG 4000. Copyright     

Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate

The present work was aimed at formulating a SMEDDS (self-microemulsifying drug delivery system) of fenofibrate and evaluating its in vitro and in vivo potential. The solubility of fenofibrate was determined in various vehicles. Pseudoternary phase diagrams were used to evaluate the microemulsification existence area, and the release rate of fenofibrate was investigated using an in vitro dissolution test. SMEDDS formulations were tested for microemulsifying properties, and the resultant microemulsions were evaluated for clarity, precipitation, and particle size distribution. Formulation development and screening was done based on results obtained from phase diagrams and characteristics of resultant microemulsions. The optimized formulation for in vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%). The SMEDDS formulation showed complete release in 15 minutes as compared with the plain drug, which showed a limited dissolution rate. Comparative pharmacodynamic evaluation was investigated in terms of lipid-lowering efficacy, using a Triton-induced hypercholesterolemia model in rats. The SMEDDS formulation significantly reduced serum lipid levels in phases I and II of the Triton test, as compared with plain fenofibrate. The optimized formulation was then subjected to stability studies as per International Conference on Harmonization (ICH) guidelines and was found to be stable over 12 months. Thus, the study confirmed that the SMEDDS formulation can be used as a possible alternative to traditional oral formulations of fenofibrate to improve its bioavailability.     

Investigation into physical–chemical variables affecting the manufacture and dissolution of wet-milled clarithromycin nanoparticles

Abstract

A critical problem associated with poor water-soluble drugs is their low and variable bioavailability, which is derived from the slow dissolution and erratic absorption. Nano-formulation has been identified as one approach to enhance the rate and extent of drug absorption for compounds that demonstrate limited water solubility. This study aimed to investigate the physico-chemical variables that affect the manufacture, dissolution and consequent bioavailability of wet-milled clarithromycin (CLA) nanoparticles, a macrolide antibiotic. CLA nanoparticles were prepared using wet milling method followed by freeze-drying. Different stabilizer systems, consisting of surfactants and polymers alone or their combinations were studied to determine the optimum conditions for producing nano-sized CLA particles. In vitro characterizations of the CLA nanoparticles were performed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry and dissolution efficiency test. Results showed that in general the wet milling process did not modify the crystallinity of the CLA nanoparticles. The poloxamers and polyvinyl alcohol (PVA) stabilizers resulted in nanoparticles with the smallest particle size and best dissolution rates. Furthermore, poloxamers F68 and F127, and PVA stabilizers demonstrated the best performance in increasing dissolution efficacy.     

Fabrication of quercetin nanocrystals: Comparison of different methods

The main aim of this study was to prepare quercetin nanocrystals using three fabrication methods, viz. high-pressure homogenization, bead milling, and cavi-precipitation. The three fabrication methods were compared in terms of particle size, saturation solubility, and dissolution of the products obtained. The average particle size of the coarse quercetin was 50.1 μm. The three methods produced quercetin particles in the nanometre range (276-787 nm) and the smallest nanocrystals of around 276.7 nm were fabricated by bead milling. The particle size, polydispersity index, zeta potential, and saturation solubility values for the products fabricated by both high-pressure homogenization and bead mill were similar and thus both represented an efficient means to fabricate quercetin nanosuspensions. According to X-ray diffraction analysis, all nanocrystals were still in the crystalline state after being fabricated by the three methods. The cavi-precipitated product exhibited larger particle size and did not show an optimum stability as suggested by the zeta potential values. However, cavi-precipitated quercetin nanosuspension showed the higher saturation solubility due to the presence of ethanol. The bead milled products with the lowest particle size exhibited a saturation solubility of 25.59 ± 1.11 μg/ml, approximately nine times higher than coarse quercetin. Overall, the dissolution rates of the quercetin nanosuspensions fabricated by these three methods enhanced compared to the coarse quercetin.     

Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs

Nanocrystals, a carrier-free colloidal delivery system in nano-sized range, is an interesting approach for poorly soluble drugs. Nanocrystals provide special features including enhancement of saturation solubility, dissolution velocity and adhesiveness to surface/cell membranes. Several strategies are applied for nanocrystals production including precipitation, milling, high pressure homogenization and combination methods such as NanoEdge™, SmartCrystal and Precipitation-lyophilization-homogenization (PLH) technology. For oral administration, many publications reported useful advantages of nanocrystals to improve in vivo performances i.e. pharmacokinetics, pharmacodynamics, safety and targeted delivery which were discussed in this review. Additionally, transformation of nanocrystals to final formulations and future trends of nanocrystals were also described.     

A Modified Approach to Predict Dissolution and Absorption of Polydisperse Powders

Purpose  Particle size of a drug is an important factor that affects thermodynamic solubility and oral absorption of drug molecules. Weight fraction of different particle sizes in a polydisperse powder together with Noyes Whitney parameters (diffusion coefficient, solubility, density of the drug, boundary layer thickness and dissolution volume) can be used to predict dissolution and absorption of drug molecules. Such a simulation can be a valuable tool in setting up guidance with regards to dependence of dissolution and absorption on particle size. Materials and methods  In this note a modified method is reported to predict dissolution of polydisperse drug powder. These use simplified equations developed from a set of differential equations described previously. The idea was to convert all the terms in one single equation which can then be solved by a Matlab program. Conclusion  Discrepancies not reported earlier have been discussed to get the same results as reported previously.     

NanoClusters Surface Area Allows Nanoparticle Dissolution with Microparticle Properties

Poorly water-soluble drugs comprise the majority of new drug molecules. Nanoparticle agglomerates, called NanoClusters, can increase the dissolution rate of poorly soluble compounds by increasing particle surface area. Budesonide and danazol, two poorly soluble steroids, were studied as model compounds. NanoCluster suspensions were made using a Netzsch MiniCer media mill with samples collected between 5 and 15 h and lyophilized. Differential scanning calorimetry (DSC) and powder X-ray Diffraction were used to evaluate the physicochemical properties of the powders, and Brunauer, Emmett and Teller (BET) analysis was used to determine surface area. Scanning electron microscopy confirmed NanoClusters were between 1 and 5 μm. NanoCluster samples showed an increase in dissolution rate compared with the micronized stock and similar to a dried nanoparticle suspension. BET analysis determined an increase in surface area of eight times for budesonide NanoClusters and 10–15 times for danazol NanoClusters compared with the micronized stock. Melting temperatures decreased with increased mill time of NanoClusters by DSC. The increased surface area of NanoClusters provides a potential micron-sized alternative to nanoparticles to increase dissolution rate of poorly water-soluble drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1787–1798, 2014     

Effect of magnesium carbonate on the solubility,dissolution and oral bioavailability of fenofibric acid powder as an alkalising solubilizer

To investigate the possibility of developing a novel oral pharmaceutical product using fenofibric acid instead of choline fenofibrate, the powder properties, solubility, dissolution and pharmacokinetics in rats of fenofibrate, choline fenofibrate and fenofibric acid were compared. Furthermore, the effect of magnesium carbonate, an alkalising agent on the solubility, dissolution and oral bioavailability of fenofibric acid was assessed, a mixture of fenofibric acid and magnesium carbonate being prepared by simple blending at a weight ratio of 2/1. The three fenofibrate derivatives showed different particle sizes and melting points with similar crystalline shape. Fenofibric acid had a significantly higher aqueous solubility and dissolution than fenofibrate, but significantly lower solubility and dissolution than choline fenofibrate. However, the fenofibric acid/magnesium carbonate mixture greatly improved the solubility and dissolution of fenofibric acid with an enhancement to levels similar with those for choline fenofibrate. Fenofibric acid gave lower plasma concentrations, AUC and C_max values compared to choline fenofibrate in rats. However, the mixture resulted in plasma concentrations, AUC and C_max values levels not significantly different from those for choline fenofibrate. Specifically, magnesium carbonate increased the aqueous solubility, dissolution and bioavailability of fenofibric acid by about 7.5-, 4- and 1.6-fold, respectively. Thus, the mixture of fenofibric acid and magnesium carbonate at the weight ratio of 2/1 might be a candidate for an oral pharmaceutical product with improved oral bioavailability.     

Jet milling industrialization of sticky active pharmaceutical ingredient using quality-by-design approach

Jet milling is frequently used in pharmaceutical industry to achieve different objectives. It can be used as enabling technology to overcome poor water solubility linked to hydrophobic active of pharmaceutical ingredient (API) by reducing the particle size and therefore increasing the dissolution rate. Alternatively, jet milling can be used either to enhance blending efficiency of API with excipient in case of formulation at low dosage strength or to achieve the required particle size for inhalation therapy. In this study, development of commercial manufacturing process of sticky API and its industrialization are described. The methodology used is based on quality-by-design approach to deliver safe, effective and robust manufacturing process. The study showed that the specific energy is a key factor that drives particle size during jet milling and the scale-up from lab to industrial scale. After understanding the process, a design space was built where different zones such as operating point, operating space (where the product is compliant to specification despite variability of process parameters), and the knowledge space were outlined. Finally, an industrial installation was proposed to deliver product with high productivity yield, compliant with safety regulation, and cleanable in place.     

Electrospun Nanofibers in Oral Drug Delivery

In order to enhance the delivery of drugs with limited absorption due to poor solubility/dissolution, approaches are being developed to improve the dissolution rates and solubility of drug molecules. These approaches include identification of water-soluble salts of parent drugs, preparation of stable amorphous drug formulations, inclusion of solubility-enhancing agents in the dosage form, and particle size reduction. Technologies to reduce drug particle size to sub-micrometer range are being applied to product development more frequently. Electrospinning is being considered as one of the technologies which can produce nanosized drugs incorporated in polymeric nanofibers. In vitro and in vivo studies have demonstrated that the release rates of drugs from these nanofiber formulations are enhanced compared to those from original drug substance. This technology has the potential to be used for enhancing the oral delivery of poorly soluble drugs.