Preparation and Solidification of Redispersible Nanosuspensions

To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and acceptable redispersibility.     

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.     

Development of a chemically stable 10-hydroxycamptothecin nanosuspensions

The purpose of this study was to prepare and characterize nanosuspensions loading the active lactone form of 10-hydroxycamptothecin (10-HCPT). Nanosuspensions were prepared in terms of microprecipitation–high-pressure homogenization method. As for the preparation processes, three important parameters, i.e. the agitation rate of stabilizer solution, homogenization pressure and cycle numbers, were investigated and optimized, and the optimal values were 1000 rpm, 1000 bar and 20 times, respectively. The particle size and zeta potential of the 10-HCPT-nanosuspensions were 131 nm and −25.5 mV. The particle morphology was determined by transmission electron microscopy and the 10-HCPT nanoparticles were baculine or trabecular in shape. The solid state of 10-HCPT in nanoparticles was analyzed using X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). The XRD and the DSC results both indicated that 10-HCPT was present as an amorphous state in the lyophilized powders for nanosuspension. The chemical stability tests demonstrated that near 90% lactone form of 10-HCPT was present in the nanosuspensions but it was easily transferred to the carboxylate form in the solution at pH 7.0–8.0. In vitro dissolution tests showed the dissolution rate of nanosuspensions, compared with the coarse suspensions, had been significantly increased.     

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.     

Flocculated Amorphous Nanoparticles for Highly Supersaturated Solutions

Purpose  To recover polymer-stabilized amorphous nanoparticles from aqueous dispersions efficiently by salt flocculation and to show that the particles redisperse and dissolve rapidly to produce highly supersaturated solutions. Methods  Nanoparticle dispersions of itraconazole stabilized by nonionic polymers were formed by antisolvent precipitation and immediately flocculated with sodium sulfate, filtered and dried. The size after redispersion in water, crystallinity, and morphology were compared with those for particles produced by spray drying and rapid freezing. Results  Particle drug loading increased to ∼90% after salt flocculation and removal of excess polymer with the filtrate. The formation of the flocs at constant particle volume fraction led to low fractal dimensions (open flocs), which facilitated redispersion in water to the original primary particle size of ∼300 nm. Amorphous particles, which were preserved throughout the flocculation–filtration–drying process, dissolved to supersaturation levels of up to 14 in pH 6.8 media. In contrast, both spray dried and rapidly frozen nanoparticle dispersions crystallized and did not produce submicron particle dispersions upon addition to water, nor high supersaturation values. Conclusions  Salt flocculation produces large yields of high surface area amorphous nanoparticle powders that de-aggregate and dissolve rapidly upon redispersion in pH 6.8 media, for supersaturation levels up to 14.     

Spontaneous formation of drug-containing acrylic nanoparticles.

Nanoparticles containing ibuprofen, indomethacin or propranolol were formed spontaneously after the addition of solutions of the drugs and acrylic polymers (Eudragit RS or RL 100) in the water-miscible solvents, acetone or ethanol, to water without sonication or microfluidization. The colloidal dispersions were stabilized by quaternary ammonium groups and did not require the addition of surfactants or polymeric stabilizers. The nanoparticles were compared to nanoparticles prepared either by a microfluidization-solvent evaporation method with a water-immiscible organic solvent, methylene chloride, or by a melt method with respect to particle size and redispersibility of freeze- or spray-dried samples. Nanoparticles prepared by microfluidization or the melt method were easily redispersed while Eudragit RS nanoparticles prepared by spontaneous emulsification were not redispersible. Flexible films were formed from the nanosuspensions after the addition of 15 per cent triethyl citrate, a water-soluble plasticizer. The release of propranolol from the films increased with increasing proportion of RL, but was independent of the order of mixing of the two polymers or nanosuspensions during film preparation. The drug release from indomethacin films was increased by adding water-soluble polymers to the nanosuspension.     

Spray granulation: Importance of process parameters on in vitro and in vivo behavior of dried nanosuspensions

The use of fluid bed granulation for drying of pharmaceutical nanoparticulates on micron-sized granule substrates is a relatively new technique, with limited understanding in the current literature of the effects of process parameters on the physical properties of the dried nanoparticle powders. This work evaluated the effects of spray mode, spray rate and atomizing pressure for spray granulation of drug nanosuspensions through a systematic study. Naproxen and a proprietary Novartis compound were converted into nanosuspensions through wet media milling and dried onto a mannitol based substrate using spray granulation. For naproxen, various physical properties of the granules, as well as the in vitro re-dispersion and dissolution characteristics of the nano-crystals, were measured. It was found that the spray mode had the most drastic effect, where top spray yielded smaller re-dispersed particle sizes and faster release rates of drug from granules than bottom spray. This was attributed to the co-current spraying in bottom spray resulting in denser, homogenous films on the substrate. Similar in vitro results were obtained for the proprietary molecule, Compound A. In vivo studies in beagle dogs with Compound A showed no significant difference between the liquid and the dried forms of the nanosuspension in terms of overall AUC, differences were observed in the t_max which correlated with the rank ordering observed from the in vitro dissolution profiles. These findings make spray granulation amenable to the production of powders with desired processing and handling properties, without compromising the overall exposure of the compound under investigation.     

Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam

The rate of dissolution of drugs remains one of the most challenging aspects in formulation development of poorly water-soluble drugs. The meloxicam, a low molecular analgetic for oral administration, exhibits a slow dissolution. To improve the dissolution rate, the drug was formulated in a nanosuspension by using an emulsion–diffusion method, high-pressure homogenization or sonication. Optimization of the technological parameters (organic solvents, stabilizers, homogenization procedure and recovery of particles) allowed the formation of nanosuspensions with a particle size of 200–900 nm. SEM imaging confirmed the nanosized drug particles. Use of an SMCR method on the XRPD patterns of the nanosuspensions revealed the crystalline form of the drug and the strong interaction between meloxicam and the stabilizer. The rate of dissolution of the dried meloxicam nanosuspension was enhanced (90% in 5 min), relative to that of raw meloxicam (15% in 5 min), mainly due to the formation of nanosized particles. 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.     

Incorporation of Fenofibrate Nanoparticles Prepared by Melt Emulsification into Polymeric Films

The aims of this study are to develop polymeric films loaded with nanoparticles of fenofibrate (FNB), a poorly water-soluble drug, prepared via melt emulsification (ME) and study the short-term physical stability of the ME-based suspensions, with the ultimate goal of enhancing FNB dissolution. FNB particles in water were heated above the melting point to form an oil-in-water emulsion, whose cooling turned FNB droplets into solidified FNB nanoparticles. The resulting FNB suspensions, along with a suspension of as-received FNB, were mixed with hydroxypropyl methylcellulose (HPMC)–glycerin solution to prepare film precursor suspensions, which were then casted and dried into films. The effects of the presence of Pluronic F68 (PF68) as stabilizer and the sonication during the cooling step on the physical stability of the suspensions were investigated. For films, drug content, redispersibility, and drug release in a USP IV dissolution test were studied. The results show that cooling the FNB–PF68 emulsion in the presence of sonication produced suspensions with acceptable 7-day physical stability, whereas cooling the same without sonication led to severe particle aggregation within 20 min. The film redispersion in water led to effective recovery of FNB nanoparticles only when PF68 and sonication during the cooling step were used. Good drug content uniformity and enhanced FNB dissolution were obtained from the films containing FNB nanoparticles stabilized with PF68, but the impact of sonication on the FNB dissolution was not discernible. Overall, feasibility of films carrying ME-based drug nanoparticles for enhanced dissolution has been demonstrated.     

Enhanced dissolution of inhalable cyclosporine nano-matrix particles with mannitol as matrix former

This study aims to improve the dissolution of inhalable cyclosporine A nanoparticles by formulating the drug with mannitol as a hydrophilic nano-matrix former. The effect of mannitol content on the aerosol performance of the nano-matrix particles was also examined. Cyclosporine A nanosuspensions were produced by anti-solvent precipitation using a multi-inlet vortex mixer. Various amounts of mannitol were dissolved into the suspensions before spray drying to obtain micron-sized aggregates (nano-matrix powders). Dissolution properties of the powders in an aqueous medium, with the drug content, aggregate size distribution, surface roughness, physicochemical properties and aerosol performance were determined. The powders contained amorphous cyclosporine A and α-crystalline mannitol, with drug content being very close to the theoretical doses. Inclusion of mannitol enhanced the dissolution rate of the drug, without significantly affecting the aggregate size distribution, surface roughness and aerosol performance. This formulation approach may be applicable to improving the dissolution rate and bioavailability of hydrophobic drugs.     

Development and characterization of solid oral dosage form incorporating candesartan nanoparticles

Sparingly water-soluble drugs such as candesartan cilexetil offer challenges in developing a drug product with adequate bioavailability. The objective of the present study was to develop a tablet dosage form of candesartan cilexetil incorporating drug nanoparticles to increase its saturation solubility and dissolution rate for enhancing bioavailability while reducing variability in systemic exposure. The bioavailability of candesartan cilexetil is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of candesartan cilexetil was developed. Candesartan cilexetil nanoparticles were prepared using a wet bead milling technique. The milled nanosuspension was converted into solid intermediate using a spray drying process. The nanosuspensions were characterized for particle size before and after spray drying. The spray dried nanoparticles were blended with excipients for tableting. The saturation solubility and dissolution characteristics of the nanoparticle formulation were investigated and compared with commercial candesartan cilexetil formulation. The drug nanoparticles were evaluated for solid-state transitions before and after milling. This study demonstrated that tablet formulation incorporating drug nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared to commercially available tablet formulation. Systemic exposure studies in rats indicated a significant increase in the rate and extent of drug absorption.     

Enhanced bioavailability of rebamipide nanocrystal tablets: Formulation and in vitro/in vivo evaluation

The purpose of this study was to formulate rebamipide nanocrystal tablets (REB-NTs) by wet-milling technique to enhance its dissolution rate and oral bioavailability. The formulation and preparation technology were screened by single factor tests with particle size and distribution as indicators. Rebamipide nanocrystals (REB-NSs) was then achieved by freeze-dry from the prepared nanosuspensions which were characterized by differential scanning calorimetry (DSC) and x-ray powder diffraction (XRD), while the vitro dissolution and the plasma drug concentration of the nanocrystal tablets were investigated. The results indicated that the prepared nanosuspensions got an average particle size of 286 nm, PI of 0.173 and the average Zeta potential of −18.2 mv. The average particle size of obtained REB-NSs’ redispersibility was 278 nm, and the crystalline of REB-NSs was the same as the rebamipide bulk drug as shown by DSC and XRD. The drug dissolution rate of self-made nanocrystal tablets in different dissolutions was slightly faster than that from the reference tablets, REB-MTs (Mucosta^®), while the C_max and AUC_0–24 of REB-NTs were 1 and 1.57 times higher than that of REB-MTs, which means the nanotechnology could significantly improve the oral bioavailability of rebamipide.     

Aerosol Delivery of Nanoparticles in Uniform Mannitol Carriers Formulated by Ultrasonic Spray Freeze Drying

Purpose

While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation.

Methods

Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying. This process was contrasted to particle formation by conventional spray drying.

Results

Spray freeze drying a solution of nanoparticles and mannitol (2 wt% solids) resulted in particles with an average diameter of 21?±?1.7 μm, regardless of the fraction of nanoparticles loaded (0–50% of total solids). Spray freeze dried (SFD) powders with a 50% nanoparticle loading had a fine particle fraction (FPF) of 60%. After formulation in a mannitol matrix, nanoparticles redispersed in water to < 1 μm with hand agitation and to < 250 nm with the aid of sonication. Powder production by spray drying was less successful, with low powder yields and extensive, irreversible aggregation of nanoparticles evident upon rehydration.

Conclusions

This study reveals the unique advantages of processing by ultrasonic spray freeze drying to produce aerosol dry powders with controlled properties for the delivery of therapeutic nanoparticles to the lungs.     

Development of pectin nanoparticles through mechanical homogenization for dissolution enhancement of itraconazole

A simple method to fabricate itraconazole (ITZ)-loaded pectin nanoparticles prepared from nanoemulsion templates is described in this study. Nanoemulsions containing ITZ were prepared by a mechanical homogenization using pectin as emulsifier. After freeze-drying, the morphology, crystallinity state, thermal properties, drug dissolution and stability of the obtained pectin nanoparticles were characterized. The results demonstrated that the morphology of freeze-dried products was different, depending on the type of internal phase; the nanoparticles prepared from chloroform-based nanoemulsions were completely dried and provided a fragile characteristic. The pectin nanoparticles also demonstrated good properties in terms of redispersibility, thermal properties, drug crystallinity and dissolution. The ITZ-loaded pectin nanoparticles showed high percentage of drug dissolved (about 60–80% within 2 h), and maintained their good dissolution properties even after 1-year storage. The results suggested that freeze-dried pectin nanoparticles prepared from nanoemulsions could be used as an effective carrier for enhancement of ITZ dissolution.     

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.     

Drug nano- and microparticles processed into solid dosage forms: physical properties

The use of nanoparticles of relatively insoluble drugs has enormously widened the window of achievable pharmacokinetic performance. For the successful development of this technology, it is essential to understand the characteristics of nanoparticles. In this study, the processability and solid dosage performance of nanoparticulates are compared with those of microparticulates. Nanoparticle suspensions are first prepared by wet comminution in the presence of stabilizers. Spray drying converts them into dried particles from which compacts are prepared. Nanoparticles easily form aggregates during spray drying. These aggregates can be slowly redispersed into nanoparticles in water. Compacts show differences in their internal structure and micromechanical deformations, according to the size of their primary particles. Stress to break and indentation hardness are found to be only slightly higher in nanoparticulate systems.     

纳米混悬剂物理稳定性的研究进展

随着纳米科技的快速发展,纳米混悬剂在药剂学领域日益受到关注.纳米混悬剂是纯药物亚微米颗粒的胶状分散体系,依靠表面活性剂维持稳定.本文综述了纳米混悬剂的物理稳定性问题,包括沉淀、团聚、晶体生长和晶型变化等,概述了纳米混悬剂的稳定机制并探讨了解决其稳定性问题的主要方法.     

Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid

The aim of this study was to prepare spray dried inhalable powders containing isoniazid-loaded chitosan/tripolyphosphate (TPP) nanoparticles for sustained delivery of the drug to the lung. Nanoparticles were prepared by ionic gelation method. In-vitro drug release study indicated that the rate of drug release from nanoparticles was decreased by increasing the amount of chitosan. Entrapment of isoniazid into chitosan/TPP nanoparticles decreased minimum inhibitory concentrations (MIC) of the drug against mycobacterium avium intracellulare. Nanoparticles were spray dried using excipients such as lactose, mannitol and maltodextrin alone or with leucine. Results showed that the obtained powders had different aerosolization property. It was observed that by adding leucine, the particle size of microparticles deceased and the process yield and fine particle fraction (FPF) increased significantly. The in-vitro deposition data indicated that spray drying of isoniazid-loaded nanoparticles with lactose in the presence of leucine resulted in the production of inhalable powders with the highest FPF (45%).     

The nano spray dryer B-90

INTRODUCTION: Spray drying is an extremely well-established technology for the production of micro-particulate powders suited for a variety of drug delivery applications. In recent years, the rise in nanomedicine has placed increased pressure on the existing systems to produce nanoparticles in good yield and with a narrow size distribution. However, the separation and collection of nanoparticles with conventional spray dryer set ups is extremely challenging due to their typical low collection efficiency for fine particles < 2 μm. Currently, nanoparticles have to be agglomerated into larger microparticles, via a two-step approach, in order to collect them in a sizeable amount. However, this method has to contend with the issue of adequate redispersibility of the primary particles to reap the full benefits of nanosizing. AREAS COVERED: An overview on the advances in spray drying technology is provided in this review with particular emphasis on the novel Buchi? Nano Spray Dryer B-90. Readers will appreciate the limitations of conventional spray drying technology, understand the mechanisms of the Buchi? Nano Spray Dryer B-90, and also learn about the strengths and shortcomings of the system. EXPERT OPINION: The Buchi? Nano Spray Dryer B-90 offers a new, simple and alternative approach for the production of nanoparticles suited for a variety of drug delivery applications.