Spray drying of a poorly water-soluble drug nanosuspension for tablet preparation: formulation and process optimization with bioavailability evaluation

Spray drying experiments of an itraconazole nanosuspension were conducted to generate a dry nanocrystal powder which was subsequently formulated into a tablet formulation for direct compression. The nanosuspension was prepared by high pressure homogenization and characterized for particle-size distribution and surface morphology. A central composite statistical design approach was applied to identify the optimal drug-to-excipient ratio and spray drying temperature. It was demonstrated that the spray drying of a nanosuspension with a mannitol-to-drug mass ratio of 4.5 and at an inlet temperature of 120?°C resulted in a dry powder with the smallest increase in particle size as compared with that of the nanosuspension. X-ray diffraction results indicated that the crystalline structure of the drug was not altered during the spray-drying process. The tablet formulation was identified by determining the micromeritic properties such as flowability and compressibility of the powder mixtures composed of the spray dried nanocrystal powder and other commonly used direct compression excipients. The dissolution rate of the nanocrystal tablets was significantly enhanced and was found to be comparable to that of the marketed Sporanox®. No statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox® capsules was found. In conclusion, the nanosuspension approach is feasible to improve the oral absorption of a BCS Class II drug in a tablet formulation and capable of achieving oral bioavailability equivalent to other well established oral absorption enhancement method.     

PVP and surfactant combined carrier as an effective absorption enhancer of poorly soluble astilbin in vitro and in vivo

Context: Astilbin is considered to be a new and promising immunosuppressant for immune related diseases, but limited in clinical application due to its poor water solubility, difficult oral absorption and low bioavailability.

Objective: The present work studied the effect of PVP and surfactant combined carrier on its capability to improve drug absorption.

Materials and methods: PVP K30-Tween 80 combined carries was applied into the astilbin solid dispersions, tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers.

Results and discussion: In the animal studies a many fold increase in plasma AUC was observed for the solid dispersions of drug in PVP K30-Tween 80 combined carries compared to active pharmaceutical ingredient (API). The applicability of Caco-2 monolayers as a tool for predicting the in vivo transport behavior of Astilbin in combination with a solubility enhancing carries was shown. In vitro transport studies confirmed the effect of combined carries on the absorption behavior of the astilbin. MTT studies showed the cell viability gradually decreased with the increase of the drug concentration in a dose dependent manner for astilbin and that in solid dispersions. The permeability and apparent permeability coefficients (P_app) increased with drug in the Caco-2 cell.

Conclusion: In this study, it was found that PVP K30 and Tween 80 promoted the permeability of drugs best within a certain amount. For astilbin PVP K30 and surfactant combined carrier had a strong potential to improve oral bioavailability.     

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation

Abstract

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na₂CO₃ at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12?h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.     

Development of a novel starch-derived porous silica monolith for enhancing the dissolution rate of poorly water soluble drug

A novel starch-derived porous silica monolith (PSM) and porous starch foam (PSF) were developed as a carrier in order to improve the dissolution of lovastatin. PSM was prepared by the starch gel template method and PSF was prepared by the solvent exchange method. The morphology and structure of PSM and PSF were characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. Lovastatin was loaded into PSM and PSF by immersion/solvent evaporation. Nano-pore spatial confinement effect on the drug dissolution was systematically studied by SEM, Fourier transform infrared spectroscopy (FTIR), thermogravametric analysis (TGA), x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and in-vitro drug dissolution studies. Lovastatin adsorbed in PSM was amorphous and lovastatin absorbed on PSF was partially present as microcrystal in the pores of PSF and partially in crystalline form distributed on the surface of PSF. PSM and PSF allowed immediate release of lovastatin and enhanced the dissolution rate. These results provide important information about the mechanism of drug adsorption and release. Accordingly, PSM and PSF have a promising future as a vehicle for the oral delivery of poorly water soluble drugs. Moreover, the effect of PSM is better than that of PSF.     

Bile salt/lecithin mixed micelles optimized for the solubilization of a poorly soluble steroid molecule using statistical experimental design

Bile salts and lecithin combine physiologically to form mixed micelles which aid the solubilization and absorption of dietary fats and drug molecules. In this series of experiments, we have shown how experimental design procedures aid the optimization of a formulation incorporating a bile salt, lecithin, and water with fluticasone propionate (FP) as the model poorly soluble drug. The initial inclusion of a categorical variable ruled out the use of classic response surface designs; therefore the experimental design was constructed using a d-optimal selection from a candidate set of all possible experimental combinations. A separate 2-factor central composite design was used to determine the optimum lecithin and bile salt concentrations over an extended range after the categorical variable had been eliminated. It has been demonstrated that an increase in either lecithin or cholic acid concentration produces an increase in solubility of FP, while sodium taurocholate appears to depress the solubility of FP compared with the other two bile salts. The increase in solubility associated with the increase in bile salt and lecithin is further demonstrated by a linear relationship between FP solubility and the total lipid in the formulation. The influence of molar ratio of lecithin to bile salt in the formulation is also significant. The physical properties of the mixed micellar system (solution turbidity and viscosity ranking) were used to further discriminate between formulations. The optimization showed that the dominant effect was the lecithin, which improves the solubilizing characteristics of the formulation with increasing concentration. The effect of salt concentration is less marked though slightly quadratic in nature. The overall increase in solubility demonstrated was from <1 microg/mL in water to 205 microg/mL in the optimized mixed micellar system.     

Development of a bioluminescence resonance energy-transfer assay for estrogen-like compound in vivo monitoring

A new bioluminescence resonance energy transfer (BRET) homogeneous assay to evaluate the presence of estrogen-like compounds has been developed and optimized. The assay is based on the direct evaluation of estrogen alphareceptor (ERalpha) homodimerization as a result of estrogen-like compound binding. ERalpha monomer was genetically fused either to Renilla luciferase (Rluc) or to enhanced yellow fluorescent protein (EYFP). In the presence of estrogens, ERalpha dimerization brings Rluc and EYFP molecules close enough for an energy transfer. An in vitro BRET assay was first developed using purified fusion proteins (ERalpha-Rluc and ERalpha-EYFP) expressed in Escherichia coli to evaluate and optimize the analytical performances of the assay in the presence of 17-beta estradiol. The "in vivo" BRET quantitative assay was then developed by coexpressing the two fusion proteins in live HepG2 cells. The assay can be performed in 96-well microplate format with a 30-min incubation and allows detection with adequate accuracy and precision of as low as 1 nM of 17-beta estradiol. This new "in vivo" BRET assay allows evaluating the estrogen-like activity and synthetic xenoestrogens from biological and environmental samples.     

Simple waves and shocks in a thin film of a perfectly soluble anti-surfactant solution

We consider the dynamics of a thin film of a perfectly soluble anti-surfactant solution in the limit of large capillary and Péclet numbers in which the governing system of nonlinear equations is purely hyperbolic. We construct exact solutions to a family of Riemann problems for this system, and discuss the properties of these solutions, including the formation of both simple-wave and uniform regions within the flow, and the propagation of shocks in both the thickness of the film and the gradient of the concentration of solute.     

The effect of MgO on the solubility behavior and cell proliferation in a quaternary soluble phosphate based glass system

This paper presents a systematic study of the MgO–CaO–Na₂O–P₂O₅ glass system, which has great potential to be used as temporary hard and soft tissue implant materials. An overall study of solubility behavior of ternary and quaternary-based phosphate glass system have been carried out in order to understand the out-leaching progress of different ions and to determine their effect on cell proliferation. Originally, soluble phosphate based glasses within the ternary glass system of Na₂O–CaO–P₂O₅ have been developed to create a simple baseline system. This paper, however, presents the development of this system by introducing magnesium oxide as a partial calcium oxide substitute and solubility behaviors as well as cell studies have been carried out to check the effect on magnesium ions. Glasses have been prepared via standard glass melting techniques and their solubility behavior has been tested in distilled water via simple weight loss, pH and ion measurements. The way the glasses dissolve is an inverse exponential behavior which is mirrored by the calcium ion release. Other ions show a less exponential behavior. The MTT test has been used to check preliminary in vitro studies on a human MG63 cell line and the result indicates that cell proliferation is increased for glasses with minimal CaO substitution.     

Exploring the importance of the relative solubility of matrix and analyte in MALDI sample preparation using HPLC

New insight into the role of solubility in the sample preparation process for MALDI MS is reported. Reversed-phase gradient HPLC conditions were developed that enable the analysis of a broad range of analyte polarities with a single method. This HPLC method was used to establish a relative polarity scale for a series of 15 MALDI matrix materials, a set of example peptides, and a series of model polymer materials with a broad range of polarity. Examples of each polymer type within the range of 6000-10,000 were analyzed with six matrixes that cover a broad range of polarity using MALDI TOFMS. With regard to polymer signal-to-noise ratio, the matrix and polymer combinations that had a close match of HPLC retention time produced the best MALDI spectra. Conversely, the matrix and polymer combinations that have a large difference in HPLC retention time produced poor MALDI spectra. The results suggest that there is a relationship between polarity (solubility) and effective MALDI sample preparation. The relative HPLC retention time of an unknown polymer can serve as a starting point for predicting the matrix (or range of matrixes) that would be most effective.     

Study on the release of fenofibrate nanosuspension in vitro and its correlation with in situ intestinal and in vivo absorption kinetics in rats

As an oral delivery carrier for poorly water soluble drugs, the nanosuspension was prepared by melt emulsification method combined with high-pressure homogenization. The objective of this study was to clarify the absorption mechanism in rats of fenofibrate nanosuspension using the model of in situ gut perfusion. The release rate of drug from nanosuspension was fast which about 70% of the drug would be released within 5 minutes. The absorption of fenofibrate nanosuspension in the gastrointestinal (GI) tract was studied by the in situ closed loop method in rats. It was found that the absorption process in intestine was first-process with passive diffusion mechanism, and the whole intestine was the major segment for the drug absorption. Additionally, GI absorption in situ studies indicated that the fenofibrate nanosuspension had great success in regard to enhancement of intestinal absorption compared to the fenofibrate suspension of coarse powder. The pharmacokinetic characteristics were studied in rats after oral administration of fenofibrate nanosuspension or suspension at the dosage of 27?mg/kg. The plasma concentration-time curve was fitted to the one-compartment model. The correlation between in vitro dissolution (P), in situ intestinal absorption (F) and in vivo absorption (Fa) in rats was investigated with the results as follows: Fa?=?6.2061P–456.38(r?=?0.9559), F?=?3.6911P–2.2169(r?=?0.970), F?=?0.5095P?+?44.189(r?=?0.9609). The highest level A could be obtained from the in vitro--in vivo correlation (IVIVC) between dissolution percentage and intestinal absorption of the fenofibrate nanosuspension in rats. Consequently, the in situ intestinal perfusion model could be used to predict the in vivo pharmacokinetic characteristics in rats.     

Particle size reduction for improvement of oral absorption of the poorly soluble drug UG558 in rats during early development

Background: The exposure of UG558 was not good enough using traditional microsuspensions. Aim: The aim of this study was to find out whether nanosuspensions were a better choice compared with a microsuspension, for an acidic substance with a water solubility in the order of 2 μM (pH 6.8, small intestinal pH) and no permeability limitations. Methods: UG558 was ground by a planetary ball mill. The particle size was measured by laser diffraction and the stability of the particle sizes was followed. The pharmacokinetic parameters of UG558 administered as nanosuspension have been compared with those from microsuspension using rat as in vivo specie. Both formulations were administered orally. The nanosuspension was also administered intravenously. Results: The particle size of the nanosuspensions was about 190 nm and about 12 μm for the microsuspensions. At the administered doses, solutions were no alternative (e.g. due to limited solubility). Already at the lowest dose, 5 μmol/kg (5 ml/kg), a significant difference was observed between the two suspensions. These results were further confirmed at a high dose (500 μmol/kg, 5 mL/kg). Thus, the study demonstrated a clear correlation between particle size and in vivo exposures, where the nanosuspensions provided the highest exposure. Furthermore, no adverse events were observed for the substance nor the nanosuspension formulations (i.e., the particles) in spite of the higher exposures obtained with the nanoparticles. To make it possible to calculate the bioavailability, 5 μmol/kg doses of the nanosuspensions (5 ml/kg) were also administered intravenously. No adverse events were observed. Conclusions: The nanoparticles have a larger surface, resulting in faster in vivo dissolution rate, faster absorption, and increased bioavailability, compared to microparticles. The lower overall bioavailability observed at the high dose, compared with the low dose, was due to a combination of low dissolution rate, low solubility, and a narrow intestinal absorption window for UG558.     

In vitro and in vivo evaluations of a novel pulsed and controlled osmotic pump capsule

Objective: For better treatment of circadian cardiovascular events, a novel Propranolol hydrochloride (PNH) delayed-release osmotic pump capsule was developed.

Methods: The capsule body was designed of asymmetric membrane and the capsule cap was made impermeable. The physical characteristics of capsule body walls and membrane permeability were compared among different coating solutions.

Results: The formulation with the glycerin and diethyl phthalate (DEP) ratio of 5:4 appeared to be the best. The lag time and subsequent drug release were investigated through assembling the capsule body with capsule caps of different length. WSR N-10 was chosen as the suspending for its moderate expanding capacity. The influence of factors (WSR N-10 content, NaCl content and capsule cap length) on the responses (lag time and drug release rate) was evaluated using central composite design-response surface methodology. A second-order polynomial equation was fitted to the data and actual response values were in good accordance with the predicted ones. The optimized formulation displayed complete drug delivery, zero-order release rate with 4-h lag time. The results of in vivo pharmacokinetics in beagle dogs clearly suggested the controlled and sustained release of PNH from the system and that the relative bioavailability of this preparation was about 1.023 comparing the marketed preparation.

Conclusions: These results indicate that by the adjustment of capsule cap length, PNH could be developed as a novel pulsatile and controlled drug delivery system.     

Nucleation studies in supersaturated potassium dihydrogen orthophosphate solution and the effect of soluble impurities

Nucleation rates as indicated by induction period have been studied for supersaturated solutions of potassium dihydrogen orthophosphate with and without the addition of soluble impurities in the temperature range 20 to 40° C. The effects of temperature, supersaturation and impurity content are reported. The interfacial tension, energy of formation and critical radius of nuclei of the crystal are calculated based on classical nucleation theory. The presence of soluble impurities enhances the nucleation rate of potassium dihydrogen orthophosphate crystals.Nomenclature G energy of formation of nucleus - B a constant - J frequency of formation of nuclei - k Boltzmann constant - K a constant - m slope of line plot ln against 1/ln² (X/X ₀) - N Avogadro's number - R gas constant - r radius of sphere inscribed in the crystal nucleus in equilibrium with solution - T temperature (K) - U ₁ energy of activation for the molar transition from phase 1 (solution) to phase 2 (crystal) - v volume per molecule in solid phase - V molar volume of crystal - x mole fraction of solute in the supersaturated salt solution at temperaturet - x ₀ mole fraction of solute in the salt solution saturated at temperaturet - ₁ chemical potential of supersaturated solution - ₁₀ chemical potential of saturated solution - _r chemical potential of nucleus of radiusr - chemical potential of nucleus of infinite radius - interfacial tension of crystal - induction period     

Self-emulsifying drug delivery system for enhanced solubility of asenapine maleate: design,characterization, in vitro,ex vivo and in vivo appraisal

Self-emulsifying drug delivery systems (SES) were developed to improve oral bioavailability of asenapine maleate (ASM), an antipsychotic drug with challenging amphiphobic nature and extensive pre-systemic metabolism. ASM-SES was prepared by choosing the proportion of oil, surfactant, co-surfactant from constructed phase diagram. The in vitro and ex vivo evaluation was done. In vivo evaluation was done through pharmacokinetic and pharmacodynamic studies. Role of lymphatic absorption was studied by lymphatic absorption inhibition study. A formulation consisting of 9.9%, 59.4%, 29.7% and 1% of oil, surfactant, co-surfactant, and drug respectively was considered as optimized formulation. After various evaluation test, the globule size and zeta potential for optimized formulation (SES₄) were found to be 137.9?nm and ?28.8?mV respectively. A maximum of 99.64?±?0.16% of ASM was released from SES₄ in 60?minutes of time. The flux (ex vivo study) increased by 2.33 folds, which prove the enhanced release and permeation of ASM when loaded into SES. The animals administered with SES₄ showed higher activity and good pharmacodynamic response than the control and ASM-Suspension, which may be due to the greater availability of the drug. The maximum pharmacodynamic response was observed at the t_max determined by Pharmacokinetic studies. The bioavailability increased by 1.64 folds with 16.55?±?3.11% as extend of lymphatic absorption (r?=?0.9732). Good in vitro in vivo correlation was observed. ASM-SES is a novel approach to effectively deliver ASM and improve the oral bioavailability.     

Study of the complexation behavior of tenoxicam with cyclodextrins in solution: improved solubility and percutaneous permeability

Complexation of tenoxicam (TEN) with γ-, HPγ-, β-, HPβ-, and Mβ-cyclodextrin (CD) in aqueous solution at pH 7.4 has been investigated using phase solubility diagrams. TEN formed soluble complexes with 1:1 stoichiometry with all the CDs studied, although the inclusion stability constants (K_1:1) obtained had low values. The presence of propylene glycol (PG) in the dissolution medium decreased the stability constants and led to a higher fraction of free drug by competitive displacement and by an increase in the lipophility of the media.

Among the CDs tested, MβCD was chosen for further studies since TEN-MβCD complexes yielded the best results: good solubility and the highest stability constant. The effect of MβCD and PG on the TEN partitioning coefficient was also studied in skin-buffer systems. Although each substance reduced the partitioning value, the combination of PG and MβCD increased this parameter.

The noticeable increase in solubility of the drug found in the presence of MβCD allowed the formulation of carbopol gels with higher doses of TEN and a reduced amount of cosolvent. The presence of MβCD improved the percutaneous penetration of TEN through abdominal rat skin by increasing the solubility of the drug in the vehicle and by affecting the partitioning behavior of TEN in the skin. In addition, TEN retention in the skin was found to be related to the flux values attained with the corresponding gels.     

Nanoparticulation of probucol, a poorly water-soluble drug, using a novel wet-milling process to improve in vitro dissolution and in vivo oral absorption

To improve the dissolution and oral absorption properties of probucol, a novel wet-milling process using the ULTRA APEX MILL was investigated. The particle size of bulk probucol powder was 17.1 μm. However, after wet-milling with dispersing agents such as Gelucire 44/14, Gelucire 50/13, vitamin E-TPGS, and Pluronic F-108, the probucol particle sizes decreased to about 77-176 nm. Scanning electron microscopy (SEM) analysis also suggested that the probucol particles were successfully milled into the nanometer range. An in vitro dissolution study showed that the dissolution rates of all nanopowders were several folds higher than those of the corresponding mixed powders. When orally administered to rats, the AUC values of probucol nanopowders treated with Gelucire 44/14 and 50/13, and vitamin E-TPGS were about 3.06-3.54-folds greater than that of the bulk powder. Therefore, through this study, we have developed a new pharmaceutical technique to improve the dissolution rate and oral absorption of probucol using the ULTRA APEX MILL by wet-milling with various dispersing agents.     

Facile synthesis of soluble graphene via a green reduction of graphene oxide in tea solution and its biocomposites

The chemical reduction of graphene oxide (GO) typically involves highly toxic reducing agents that are harmful to human health and environment, and complicated surface modification is often needed to avoid aggregation of the reduced GO during reduction process. In this paper, a green and facile strategy is reported for the fabrication of soluble reduced GO. The proposed method is based on the reduction of exfoliated GO in green tea solution by making use of the reducing capability and the aromatic rings of tea polyphenol (TP) that contained in tea solution. The measurements of the resultant graphene confirm the efficient removal of the oxygen-containing groups in GO. The strong interactions between the reduced graphene and the aromatic TPs guarantee the good dispersion of the reduced graphene in both aqueous and a variety of organic solvents. These features endow this green approach with great potential in constructing of various graphene-based materials, especially for high-performance biorelated materials as demonstrated in this study of chitosan/graphene composites.     

Effect of casting solvent,film-forming agent and solubilizer on orodispersible films of a polymorphic poorly soluble drug: an in vitro/in silico study

Abstract

In the current work, a full factorial experimental design was utilized to formulate piroxicam into orodispersible films while investigating the effects of some formulation factors on the properties of the resulting films. These factors were (A) the casting solvent: water and acetone/water mixture; (B) the film-forming agent: HPMC K4M and Na-alginate; (C) the solubilization system: no solubilizer, L-arginine, poloxamer and L-arginine/poloxamer mixture. Sixteen formulation runs were prepared by solvent casting method to obtain 10?mg piroxicam dosage units. Drug particle size in the prepared formulations and dissolution efficiency at 30?min were selected as responses variables. Additionally, the prepared films from each formulation were evaluated for other characters as drug content, thickness, residual water…etc. A selected formulation was then evaluated for its in vivo disintegration, palatability and stability. Utilizing acetone in the casting solution, Na-alginate as film-forming agent or both of them resulted in formation of films with larger drug particles and slower dissolution. Combined use of L-arginine and poloxamer showed better drug dissolution than using each alone. HPMC was more favorable than Na-alginate regarding mechanical properties and moisture absorption. Films from the selected formulation showed fast in vivo disintegration and acceptable palatability. These films were stable for 6?months under accelerated storage conditions. According to the computer simulation using GastroPlus?, the in vitro/in vivo behavior of piroxicam in the tested formulation was similar to that of an immediate-release formulation containing BCS class I drug. The selected formulation is therefore would satisfy the WHO perquisites for applying the biowaiver.