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     

Fabrication of drug nanoparticles by evaporative precipitation of nanosuspension

Evaporative precipitation of nanosuspension (EPN) was used to fabricate nanoparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of enhancing its dissolution rate. We investigated the nanoparticle fabrication of ART via a full factorial experimental design considering the effects of drug concentration and solvent to antisolvent ratio on the physical, morphological and dissolution properties of ART. Characterization of the original ART powder and EPN prepared ART nanoparticles was carried out by scanning electron microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and dissolution tester. DSC and XRD studies suggested that the crystallinity of EPN prepared ART nanoparticles decreased with increasing drug concentration and ratio of solvent to antisolvent. The particle diameters of EPN prepared ART nanoparticles were found to be 100–360 nm. The dissolution of EPN prepared ART nanoparticles markedly increased as compared to the original ART powder. A percent dissolution surface-response model was used to elucidate the significant and direct relationships between drug concentration and solvent to antisolvent ratio on one hand and percent dissolution on the other hand. The best dissolution percent was found to be 75.9%, at the drug concentration of 15 mg/mL and solvent to antisolvent ratio (by volume) of 1:20.     

Development and evaluation of self-microemulsifying liquid and pellet formulations of curcumin,and absorption studies in rats

This study describes the development and characterization of self-microemulsifying drug delivery systems (SMEDDS) in liquid and pellet forms that result in improved solubility, dissolution, and in vivo oral absorption of the poorly water-soluble compound curcumin. Solubility of curcumin was determined in various vehicles, including oils, surfactants and co-surfactants. Pseudo-ternary phase diagrams were constructed to identify the most efficient self-emulsification region. The optimized SMEDDS used for curcumin formulations in liquid and pellet forms contained 70% mixtures of two surfactants: Cremophor EL and Labrasol (1:1), and 30% mixtures of oil: Labrafac PG and Capryol 90 (1:1). The curcumin-SMEDDS in liquid and pellet formulations rapidly formed fine oil-in-water microemulsions, with particle size ranges of 25.8–28.8 nm and 29.6–32.8 nm, respectively. The in vitro rate and extent of release of curcumin from liquid SMEDDS and SMEDDS pellets was about 16-fold higher than that of unformulated curcumin. Plasma concentration–time profiles from pharmacokinetic studies in rats dosed with liquid and pelleted SMEDDS showed 14- and 10-fold increased absorption of curcumin, respectively, compared to the aqueous suspensions of curcumin. Curcumin-SMEDDS liquid and curcumin-SMEDDS pellets were found to be stable up to 6 months under intermediate and accelerated conditions. These studies demonstrate that the new self-microemulsifying systems in liquid and pellet forms are promising strategies for the formulation of poorly soluble lipophilic compounds with low oral bioavailability.     

Development and characterization of an orodispersible film containing drug nanoparticles

In this study, a novel orodispersible film (ODF) containing drug nanoparticles was developed with the goal of transforming drug nanosuspensions into a solid dosage form and enhancing oral bioavailability of drugs with poor water solubility. Nanosuspensions were prepared by high pressure homogenization and then transformed into ODF containing drug nanoparticles by mixing with hydroxypropyl methylcellulose solution containing microcrystalline cellulose, low substituted hydroxypropylcellulose and PEG-400 followed by film casting and drying. Herpetrione, a novel and potent antiviral agent with poor water solubility that extracted from Herpetospermum caudigerum, was chosen as a model drug and studied systematically. The uniformity of dosage units of the preparation was acceptable according to the criteria of Japanese Pharmacopoeia 15. The ODF was disintegrated in water within 30 s with reconstituted nanosuspensions particle size of 280 ± 11 nm, which was similar to that of drug nanosuspensions, indicating a good redispersibility of the fast dissolving film. Result of X-ray diffraction showed that HPE in the ODF was in the amorphous state. In the in vitro dissolution test, the ODF containing HPE nanoparticles showed an increased dissolution velocity markedly. In the pharmacokinetics study in rats, compared to HPE coarse suspensions, the ODF containing HPE nanoparticles exhibited significant increase in AUC_0–24h, C_max and decrease in T_max, MRT. The result revealed that the ODF containing drug nanoparticles may provide a potential opportunity in transforming drug nanosuspensions into a solid dosage form as well as enhancing the dissolution rate and oral bioavailability of poorly water-soluble drugs.     

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.     

Preparation of cyclosporine A nanoparticles by evaporative precipitation into aqueous solution

Amorphous nanoparticle suspensions of a poorly water-soluble drug, cyclosporine A, are produced by a new process, evaporative precipitation into aqueous solution (EPAS). The rapid evaporation of a heated organic solution of the drug, which is atomized into an aqueous solution, results in fast nucleation leading to nanoparticles suspensions. Hydrophilic stabilizers, introduced in the organic or aqueous phases, limit particle growth and inhibit crystallization for drug concentrations as high as 35 mg/ml, and drug/surfactant ratios up to 1.0. The suspensions may be used in parenteral formulations to enhance bioavailability or may be dried to produce oral dosage forms with the potential for high dissolution rates due to the low crystallinity, small particle size and hydrophilic stabilizer that enhances wetting.     

PHARMACEUTICAL TECHNOLOGY: Micro-CT Analysis of Matrix-Type Drug Delivery Devices and Correlation With Protein Release Behaviour

A series of matrix-type drug delivery devices comprising a continuous phase of microporous poly(ε-caprolactone) (PCL) and a dispersed phase of protein particles (gelatin) with defined size ranges (45–90, 90–125 and 125–250 μm) were produced by rapidly cooling suspensions in dry ice followed by solvent extraction from the hardened material. High protein loadings (38–44%, w/w) were achieved and highly efficient protein release (90% of the initial load) was obtained over time periods of 3–11 days depending on particle loading and size range. The duration of protein release was extended from 3 to 11 days reducing the protein load. Quantitative analysis of Micro-CT images identified a three to four times increase in the population of sub-40 mm pores in those matrices which gave rise to accelerated protein release in 24 h (40% rising to 80%) and reduced duration of protein release (11-3 days). Formation of a high density of channels and fissures (connects) between the particles is indicated, which facilitate fluid ingress and diffusion of solubilised protein molecules. Micro-CT analysis also confirmed the uniformity of particle distribution in the matrices and provided measurements of macroporosity within 530% of the theoretical value for materials displaying irregular shaped macropores larger than 90 mm. These findings demonstrate the utility of Micro-CT for optimising the formulation and performance of matrix-type delivery devices for macromolecular entities.     

Enhanced drug dissolution using evaporative precipitation into aqueous solution

A new process, evaporative precipitation into aqueous solution (EPAS) has been developed to coat poorly water soluble drugs, in this case carbamazepine, with hydrophilic stabilizers to enhance dissolution rates. A heated organic solution of the drug in dichloromethane is sprayed though a fine nozzle into a heated aqueous solution. The rapid evaporation of the organic solvent produces high supersaturation and rapid precipitation of the drug in the form of a colloidal suspension that is stabilized by a variety of low molecular weight and polymeric surfactants. The stabilizer adsorbs to the drug surface and prevents particle growth and crystallization during the spray process. The suspensions are dried by spray drying or ultra-rapid freezing. The high dissolution rates are a consequence of the following advantages of the EPAS process: a small primary particle size, a hydrophilic coating on the particles that enhances wetting, and low crystallinity.     

Dissolution rate improvement of telmisartan through modified MCC pellets using 32 full factorial design

Context: Microcrystalline cellulose (MCC) is the most widely used excipient for the production of pellets but it retards the release of poorly water soluble drugs. Objective: The present investigation reports incorporation of camphor, cross carmellose sodium (CCS) and spray dried lactose (SDL) into MCC pellets to enhance the dissolution rate of telmisartan. Materials and methods: A full factorial design (3²) was used in the study. Concentration of camphor and CCS was selected as independent variables whereas percentage porosity and percentage drug release at 60 min were selected as dependent variables. Pellets were produced by extrusion–spheronization technique and evaluated for percentage yield, particle size analysis, flow characteristics, percentage porosity, drug content and in vitro drug release. Contour plots and 3-D surface plots were presented for graphical expression of the results. Results and discussion: Pellet formulations exhibited acceptable morphological, flow and mechanical properties. As against to 38.54% drug release after 60 min with MCC pellets, pellets prepared with optimized formulation, composed of proper combination of MCC, SDL, camphor and CCS, released 100% drug after 60 min. Conclusion: Our study underlines the fact that dissolution of telmisartan from MCC pellets can be successfully enhanced by incorporating water soluble excipient, disintegrant and pore formers.     

Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base

ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.     

New Co-Spray-Dried Tobramycin Nanoparticles-Clarithromycin Inhaled Powder Systems for Lung Infection Therapy in Cystic Fibrosis Patients

The aim of the study was to produce easily dispersible and porous agglomerates of tobramycin nanoparticles surrounded by a matrix composed of amorphous clarithromycin. Nanoparticles of tobramycin with a median particle size of about 400 nm were produced by high-pressure homogenisation. The results from the spray-dried powders showed that the presence of these nanoparticles enhanced powder dispersion during inhalation. Moreover, local drug deposition profiles were similar for the two antibiotics, allowing them to reach the target simultaneously. The dissolution-release profiles showed that tobramycin and clarithromycin might dissolve without any difficulties in the lung. The fine particle fraction increased from 35% and 31% for the physical blend for tobramycin and clarithromycin, respectively, to 63% and 62% for the spray-dried formulation containing nanoparticles. These new formulations, showing high lung deposition properties, even at sub-optimal inspiratory flow rates, represent a great possibility for advancing pulmonary drug administration and local therapy of lung infections.     

介孔二氧化硅纳米粒的制备及对载药与药物溶出度的影响

目的为提高水难溶性药物的分散性及溶出度,制备介孔二氧化硅纳米粒作为水难溶性药物的载体。方法探索得到简单有效地制备球状介孔二氧化硅纳米粒的工艺条件,采用扫描电镜及氮气吸附-脱附等手段分析表征载体的外观形貌,比表面积及孔径分布,并选取水难溶性药物西洛他唑作为模型药物,以溶剂浸渍挥干法载药制得药物固体分散体,采用热分析、氮气吸附-脱附曲线以及溶出度实验研究药物固体分散体的基本性质。结果制得的二氧化硅载体的形貌近球状,粒径大小分布在200～250 nm,载体的比表面积最高可达1 101.54 m2.g-1,孔径分布主要集中在3.0～4.0 nm。载药过程对西洛他唑在载体中的存在形式没有影响,固体分散体中西洛他唑的溶出度得到显著提高,当药物与载体的质量比为1∶3时,药物60 min累计溶出达85%。结论介孔二氧化硅纳米粒有望成为水难溶性药物的优良载体。     

Dissolution of a poorly water-soluble drug dry coated with magnesium and sodium stearate

The purpose of this research was to investigate the influence of dry coating micronized cohesive powders of a poorly water-soluble drug, indomethacin with force control agents, on its dissolution performance. A dry mechanical fusion method (mechanofusion) was used to coat indomethacin powders with magnesium stearate (0.25%, 1%, 5%) and sodium stearate (5%). After mechanofusion, significantly increased bulk and tapped densities and decreased intrinsic cohesion were observed for all samples. X-ray photoelectron spectroscopy analysis confirmed that a thicker magnesium stearate surface coating was achieved with increasing concentrations of the material. Dissolution was studied using the USP paddle method in buffer pH 5.0; several modelling approaches were used to explore the dissolution mechanisms. Whilst the bi-exponential equation represented dissolution of mechanofused indomethacin powders occurring from dispersed and agglomerated particles, it provided unrealistic parameter estimates for the two coating materials of contrasting properties. Initial increases in indomethacin dissolution were dependent on the concentration of magnesium stearate mechanofused onto the drug powders. The dissolution enhancing effect of indomethacin powders mechanofused with 5% sodium stearate was attributed to its surfactant properties that increased dispersion of indomethacin agglomerates. Initial drug release from the coated powders was described by a matrix-diffusion system according to the Higuchi model.     

Spray freeze drying for dry powder inhalation of nanoparticles

Formulating nanoparticles for delivery to the deep lung is complex and many techniques fail in terms of nanoparticle stability. Spray freeze drying (SFD) is suggested here for the production of inhalable nanocomposite microcarriers (NCM). Different nanostructures were prepared and characterized including polymeric and lipid nanoparticles. Nanoparticle suspensions were co-sprayed with a suitable cryoprotectant into a cooled, stainless steel spray tower, followed by freeze drying to form a dry powder while equivalent compositions were spray dried (SD) as controls. SFD-NCM possess larger specific surface areas (67–77 m²/g) and lower densities (0.02 g/cm³) than their corresponding SD-NCM. With the exception of NCM of lipid based nanocarriers, SFD produced NCM with a mass median aerodynamic diameter (MMAD) of 3.0 ± 0.5 μm and fine particle fraction (FPF ⩽ 5.2 μm) of 45 ± 1.6% with aerodynamic performances similar to SD-NCM. However, SFD was superior to SD in terms of maintaining the particle size of all the investigated polymeric and lipid nanocarriers following reconstitution (S_f/S_i ratio for SFD ≈ 1 versus >1.5 for SD). The SFD into cooled air proved to be an efficient technique to prepare NCM for pulmonary delivery while maintaining the stability of the nanoparticles.     

Templated Open Flocs of Anisotropic Particles for Pulmonary Delivery with Pressurized Metered Dose Inhalers

The challenges in forming stable drug suspensions in hydrofluoroalkane (HFA) propellants have limited drug dosages and efficiency of drug delivery with pressurized metered dose inhalers (pMDI). Herein, stable suspensions of weakly flocculated particles, in the shape of thin plates or needles, of a poorly water-soluble drug, itraconazole (Itz), are efficiently delivered by pMDI at high doses, up to 2.4 mg/actuation. These anisotropic particles pack inefficiently and form low-density flocs that stack upon each other to prevent settling. In contrast, spherical particles formed dense aggregates that settled within minutes. Upon actuation of the pMDI, atomized propellant droplets shear apart and thus template the highly friable flocs. Evaporation of the HFA compacts the flocs to yield porous particles with optimal aerodynamic properties. High fine particle fractions (49–64%) were achieved with the stable suspensions for drug loadings up to 50mg/mL. Furthermore, the micron-sized particles, ideal for pulmonary delivery, are composed of nanoparticles that dissociate and facilitate rapid dissolution of poorly water-soluble drugs. Pulmonary delivery of stable suspensions of templated, open flocs is broadly applicable to a range of anisotropic particle morphologies for poorly water-soluble drugs and proteins for efficient delivery of high doses, up to several milligrams, using minimal amounts of excipients.     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs

Purpose

The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano? continuous crystallizer (PCC).

Method

Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent–antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo.

Results

The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size.

Conclusions

PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.

     

Enhancement of the dissolution of albendazole from pellets using MTR technique

Albendazole (ABZ), a broad-spectrum anthelmintic agent, is poorly absorbed after oral administration due to its low aqueous solubility. The aim of this study was to improve albendazole dissolution rate by formulating avicel pellets loaded with 10% w/w drug using extrusion/spheronization technique. In addition the wet masses were characterized by mix torque rheometry (MTR) prior to pelletization process. Different additives (i.e., lactose, Tween 80 and low molecular weight chitosan) were formulated with avicel to enhance the dissolution rate of ABZ from the produced pellets. Moreover, mix torque rheometer was used to quantitatively determine the suitable moisture content in the pastes before the extrusion process. The produced pellets were characterized for their ABZ content, particle size, particle shape, dissolution profile and thermal behaviors. The maximum consistencies (the peak torques) of the wet granules were obtained using 0.667–1.333 ml/g of water or water containing surfactant. Also, the produced pellets have size range from 1036 to 1246 μm. The calculated drug RDR₃₀ for 10%, 30% and 50% lactose concentrations were 1.08, 1.08 and 2.03, respectively, while that calculated for 10%, 30% and 50% w/w chitosan concentrations were 1.71, 3.62 and 3.62, respectively. The results revealed also that increasing the weight ratio of lactose and chitosan was accompanied by a significant reduction of the peak torque magnitude and this was accompanied by an enhanced ABZ dissolution rate.     

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.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.