Drug nanocrystals are nanosized solid drug particles, the most important application of which is the improvement of solubility properties of poorly soluble drug materials. Drug nanocrystals can be ...produced by many different techniques, but the mostly used are different kinds of media milling techniques; in milling, particle size of bulk sized drug material is decreased, with the aid of milling beads, to nanometer scale. Utilization of Quality by Design, QbD, approach in nanomilling improves the process-understanding of the system, and recently, the number of studies using the QbD approach in nanomilling has increased. In the QbD approach, the quality is built into the products and processes throughout the whole production chain. Definition of Critical Quality Attributes, CQAs, determines the targeted final product properties. CQAs are confirmed by setting Critical Process Parameters, CPPs, which include both process parameters but also input variables, like stabilizer amount or the solid state form of the drug. Finally, Design Space determines the limits in which CPPs should be in order to reach CQAs. This review discusses the milling process and process variables, CPPs, their impact on product properties, CQAs and challenges of the QbD approach in nanomilling studies.
Objectives Wet milling is a common technique to produce drug nanocrystals. Stability of the nanocrystals is a critical question, and different kinds of stabilizers, e.g. polymers, celluloses, ...surfactants and lipids, have been tested for various drugs. Still, the question about how to select the best stabilizer to a certain drug material and also to a selected process is open.
Key findings Many different factors, such as surface energy, hydrophobicity, solubility, viscosity and functional groups, affect the stability of the formed nanosuspensions. Affinity of the stabilizer to the particle surfaces seems to be the most important parameter. This affinity is partly related to the surface energy and hydrophobicity of the surfaces and stabilizers.
Summary In this review the most important factors affecting nanocrystal formulation and efficacy of stabilizers are presented. In order to widen understanding of the milling process, the most important variables related to milling techniques and particle fracturing processes during the milling are briefly presented.
The aim of the study was to prepare indomethacin nanocrystal-loaded, 3D-printed, fast-dissolving oral polymeric film formulations. Nanocrystals were produced by the wet pearl milling technique, and ...3D printing was performed by the semi-solid extrusion method. Hydroxypropyl methyl cellulose (HPMC) was the film-forming polymer, and glycerol the plasticizer. In-depth physicochemical characterization was made, including solid-state determination, particle size and size deviation analysis, film appearance evaluation, determination of weight variation, thickness, folding endurance, drug content uniformity, and disintegration time, and drug release testing. In drug nanocrystal studies, three different stabilizers were tested. Poloxamer F68 produced the smallest and most homogeneous particles, with particle size values of 230 nm and PI values below 0.20, and was selected as a stabilizer for the drug-loaded film studies. In printing studies, the polymer concentration was first optimized with drug-free formulations. The best mechanical film properties were achieved for the films with HPMC concentrations of 2.85% (w/w) and 3.5% (w/w), and these two HPMC levels were selected for further drug-loaded film studies. Besides, in the drug-loaded film printing studies, three different drug levels were tested. With the optimum concentration, films were flexible and homogeneous, disintegrated in 1 to 2.5 min, and released the drug in 2–3 min. Drug nanocrystals remained in the nano size range in the polymer films, particle sizes being in all film formulations from 300 to 500 nm. When the 3D-printed polymer films were compared to traditional film-casted polymer films, the physicochemical behavior and pharmaceutical performance of the films were very similar. As a conclusion, 3D printing of drug nanocrystals in oral polymeric film formulations is a very promising option for the production of immediate-release improved- solubility formulations.
Drug nanocrystals are a versatile option for drug delivery purposes, and while the number of poorly soluble drug materials is all the time increasing, more research in this area is performed. Drug ...nanocrystals have a simple structure-a solid drug core is surrounded by a layer of stabilizing agent. However, despite the considerably simple structure, the selection of an appropriate stabilizer for a certain drug can be challenging. Mostly, the stabilizer selection is based purely on the requirement of physical stability, e.g., maintaining the nanosized particle size as long as possible after the formation of drug nanocrystals. However, it is also worth taking into account that stabilizer can affect the bioavailability in the final formulation via interactions with cells and cell layers. In addition, formation of nanocrystals is only one process step, and for the final formulation, more excipients are often added to the composition. The role of the stabilizers in the final formulation can be more than only stabilizing the nanocrystal particle size. A good example is the stabilizer's role as cryoprotectant during freeze drying. In this review, the stabilizing effect, role of stabilizers in final nanocrystalline formulations, challenges in reaching in vitro-in vivo correlation with nanocrystalline products, and stabilizers' effect on higher bioavailability are discussed.
The number of poorly soluble drug candidates is increasing, and this is also seen in the research interest towards drug nanoparticles and (nano-)cocrystals; improved solubility is the most important ...application of these nanosystems. In order to confirm the functionality of these nanoparticles throughout their lifecycle, repeatability of the formulation processes, functional performance of the formed systems in pre-determined way and system stability, a thorough physicochemical understanding with the aid of necessary analytical techniques is needed. Even very minor deviations in for example particle size or size deviation in nanoscale can alter the product bioavailability, and the effect is even more dramatic with the smallest particle size fractions. Also, small particle size sets special requirements for the analytical techniques. In this review most important physicochemical properties of drug nanocrystals and nano-cocrystals are presented, suitable analytical techniques, their pros and cons, are described with the extra input on practical point of view.
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Poor solubility of active pharmaceutical ingredients (APIs) is a great challenge for the pharmaceutical industry and, hence, drug nanocrystals are widely studied as one solution to overcome these ...solubility problems. Drug nanocrystals have comparatively simple structures which make them attractive for the formulation for poorly soluble drugs, and their capability to improve the dissolution in vitro is easily demonstrated, but turning the in vitro superior properties of nanocrystals to success in vivo, is often demanding: controlled (including enhanced) drug dissolution followed by successful permeation is not guaranteed, if for example, the dissolved drug precipitates before it is absorbed. In this review critical quality attributes related to nanocrystal formulations from production to final product performance in vivo are considered. Many important parameters exist, but here physical stability (aggregation tendency and solid state form), solubility properties influencing dissolution and supersaturation, excipient use to promote the maintenance of supersaturation, and finally the fate of nanocrystals in vivo are the main subjects of our focus.
In order to improve the solubility properties of BCS class II drug itraconazole, fast dissolving oral polymeric film formulations based on itraconazole nanocrystals were produced. Drug nanocrystals ...were manufactured by the wet pearl milling technique. In polymeric film formulations, hydroxypropyl methyl cellulose (HPMC) was used as a film forming polymer, and glycerin was used as a plasticizer. For nanocrystal suspensions and film formulations, thorough physicochemical characterization was performed, including particle sizing and size deviation, film appearance, weight variation, thickness, folding endurance, drug content uniformity, disintegration time, and dissolution profile. After milling, the nanoparticles were 369 nm in size with a PI value of 0.20. Nanoparticles were stable and after redispersion from film formulations, the particle size remained almost the same (330 nm and PI 0.16). The produced films were flexible, homogeneous, fast disintegrating, and drug release rate from both the nanosuspension and film formulations showed immediate release behavior. Based on the study, the film casting method for production of itraconazole nanocrystal based immediate release formulations is a good option for improved solubility.
With the emerging bio-based technologies, the fractionation of complex biomass is essential to obtain value-added functional molecules for material, chemical, and energy production. Softwood extracts ...obtained through environmentally friendly pressurized hot water extraction are heterogeneous mixtures rich in hemicelluloses and lignin. Here we developed a simple, fast, organic solvent-free, and sustainable method to fractionate softwood extracts using centrifugal forces. The characteristics of each obtained fraction in terms of composition, macromolecular properties (particle size, molar mass, charge), interfacial activity, and stabilization capacity were highly dependent on the centrifugal force and time applied. The hemicellulose and lignin contents in the fractions were balanced by centrifugal forces to obtain functional emulsifiers that efficiently stabilized the oil/water interface. Through fractionation of softwood extracts, we also found that both the hemicelluloses and lignin particles are involved in emulsion interface formation and stabilization. We demonstrated that centrifugation at low centrifugal forces (<20 000
g
) can effectively separate softwood extracts into hemicellulose-rich and lignin-rich fractions. Organic-solvent free centrifugation is a scalable concept that can be feasibly and easily introduced into the biorefinery system and used to optimize the composition of biomass fractions for targeted purposes, reducing at the same time biorefineries' environmental impact.
Centrifuging softwood extracts separated the hemicellulose-rich fraction and lignin-rich micro- and nanoparticles. The hemicellulose-rich fraction and lignin-rich nanoparticles formed stable emulsions.
Accelerated leukocyte telomere shortening has been previously associated to self-perceived stress and psychiatric disorders, including schizophrenia and mood disorders. We set out to investigate ...whether telomere length is affected in patients with anxiety disorders in which stress is a known risk factor. We also studied the effects of childhood and recent psychological distress on telomere length. We utilized samples from the nationally representative population-based Health 2000 Survey that was carried out between 2000-2001 in Finland to assess major public health problems and their determinants. We measured the relative telomere length of the peripheral blood cells by quantitative real-time PCR from 321 individuals with DSM-IV anxiety disorder or subthreshold diagnosis and 653 matched controls aged 30-87 years, who all had undergone the Composite International Diagnostic Interview. While telomere length did not differ significantly between cases and controls in the entire cohort, the older half of the anxiety disorder patients (48-87 years) exhibited significantly shorter telomeres than healthy controls of the same age (P = 0.013). Interestingly, shorter telomere length was also associated with a greater number of reported childhood adverse life events, among both the anxiety disorder cases and controls (P = 0.005). Childhood chronic or serious illness was the most significantly associated single event affecting telomere length at the adult age (P = 0.004). Self-reported current psychological distress did not affect telomere length. Our results suggest that childhood stress might lead to accelerated telomere shortening seen at the adult age. This finding has potentially important implications supporting the view that childhood adversities might have a considerable impact on well being later in life.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nanosizing techniques are important tools for improving the bioavailability of water insoluble drugs. Here, a rapid wet milling method was employed to prepare nanosuspensions: 4 types of stabilizers ...at 4 different concentrations were tested on 2 structurally different drug compounds: indomethacin and itraconazole. Photon correlation spectroscopy (PCS) results showed that the finest nanosuspensions were obtained when 80
wt% (to drug amount) pluronic F68 was the stabilizer for indomethacin and 60
wt% pluronic F127 for itraconazole. Compared to physical mixtures, dissolution rates of the nanosuspensions showed significant increases. The morphology of nanoparticles was observed by transmission electron microscopy (TEM). Crystalline state of the drugs before and after milling was confirmed using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The physical and chemical stabilities of the nanosuspensions after storage for 2 months at room temperature and at 4
°C were investigated using PCS, TEM and HPLC. No obvious changes in particle size and morphology and no chemical degradation of the drug ingredients were seen.
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