Formulation and Stability Testing of Itraconazole Crystalline Nanoparticles
TL;DR: Itraconazole (ITZ) crystalline nanoparticles were prepared using relatively simple, low-cost sonoprecipitation technique, in which both the solvent and antisolvent were organic in nature.
Abstract: Itraconazole (ITZ) crystalline nanoparticles were prepared using relatively simple, low-cost sonoprecipitation technique, in which both the solvent and antisolvent were organic in nature. The effect of stabilizer type (hydroxypropyl methylcellulose, hydroxypropyl cellulose, Inutec SP1®, and pluronic F127), drying method (oven and freeze drying) and matrix former used (Avicel PH101, and Aerosil®200) on the dissolution performance as a key characteristic of nanocrystals was evaluated. In 10 min, all of the prepared nanocrystals showed 3.77−8.59 times improvement in percent drug dissolved compared to pure ITZ. Concerning the effect of stabilizer type, the following rank order can be given: pluronic F127 ≥ hydroxypropyl cellulose ≥ hydroxypropyl methylcellulose (HPMC) > inutec SP1. Freeze-dried ITZ nanocrystals containing Avicel PH 101 showed better dissolution rate compared to other nanocrystals. The chemical structure of itraconazole nanocrystals was not changed as revealed by Fourier transform infrared. Stability study of selected nanocrystals (F5, F7, and F8) revealed physical and chemical stability of F7 and F8, while a decrease in dissolution rate of F5 was observed (although being chemically stable) when stored under high relative humidity conditions. Although inutec is less potent than pluronic F127 and HPMC regarding their effect on dissolution rate enhancement, it is equipotent to pluronic F127 in preserving the rapid drug dissolution.
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TL;DR: The in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics were described and the technologies and evaluation associated with the solidification process of the drug Nanocrystals suspensions were discussed in detail.
Abstract: The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by “bottom up” or “top down” technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail.
175 citations
Journal Article•
TL;DR: The effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs is reviewed according to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced.
Abstract: The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability.
101 citations
Cites background from "Formulation and Stability Testing o..."
...6 times improvement in dissolution rate in 10 min (71)....
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TL;DR: Investigating the potential of spanlastics as an ophthalmic delivery system to improve the corneal permeability and antimycotic activity of itraconazole revealed thatspanlastics loaded with itraconsazole could be a potential nanosystem in ocular drug delivery systems.
Abstract: The objective of this study was to investigate the potential of spanlastics as an ophthalmic delivery system to improve the corneal permeability and antimycotic activity of itraconazole (ITZ). Spanlastics containing edge activators, including Tween 20 or 80, were produced by modified ethanol injection method and exhibited a particle size of approximately 287 nm and an entrapment efficiency of more than 88%. Less than 13% ITZ was released from spanlastics over 6 h compared to 35% from conventional niosomes. Spanlastics exerted a 1.34-fold increase in the amount of ITZ permeated through excised bovine cornea after 24 h compared to conventional niosomes. Antimycotic study revealed a significant (p < 0.05) increase in the zone of inhibition of Candida albicans culture demonstrated by spanlastics compared to ITZ powder at the same concentration level (10 mg). In vivo Draize test showed no signs of acute ocular toxicity upon application of the selected spanlastic formulation to the rabbit eye. Results r...
88 citations
Cites methods from "Formulation and Stability Testing o..."
...…using nanocarriers were developed to facilitate drug targeting to infected cells such as niosomes (Wagh & Deshmukh, 2012), microemulsion (Lee et al., 2010), nanosuspension (Nakarani et al., 2010), solid–lipid nanoparticles (Mukherjee et al., 2009) and nanocrystals (Badawi et al., 2011)....
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TL;DR: This paper aims to bridge formulation and process considerations along with patent reviews and may provide further insight into understanding the science and the white space.
85 citations
TL;DR: This review endeavors to provide important pharmaceutical techniques used for formulating various dosage forms for solubility enhancement of poorly water soluble drugs.
Abstract: A wide variety of new medication disclosures launched by specific benefits of the general public are laced with poor aqueous solubility problems that often obstruct their bioavailability and formulation development. Literature survey demonstrates that about 70% of active pharmaceutical ingredients and new chemical entities are considered as poorly soluble. Numerous formulation strategies and methodologies are accessible in literature like SMEDDS, micro/nanoparticles, liposomes, solid dispersions and co-crystals that have been broadly examined for enhancing the solubility of poorly water soluble drugs. The pharmaceutical techniques that are used for preparing these dosage forms play a crucial role in the overall formulation development and scalability. Hence, it seems highly essential to recognize various equipments and the importance of their critical processing parameters while using them to tailor specific product characteristics in the dosage forms. Providing a comprehensive overview, this review endeavors to provide important pharmaceutical techniques used for formulating various dosage forms for solubility enhancement of poorly water soluble drugs.
75 citations
References
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TL;DR: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption.
Abstract: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in
vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no
in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.
5,049 citations
"Formulation and Stability Testing o..." refers methods in this paper
...ITZ is classified as a class II drug according to the Biopharmaceutical Classification System (9)....
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TL;DR: Water insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future, and additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated.
Abstract: A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water insoluble, and therefore poorly bioavailable, leading to abandoned development efforts. These so-called 'brickdust' candidates can now be rescued by formulating them into crystalline nanosuspensions. In the process of overcoming issues involving solubility, additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated. As such, insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future.
1,388 citations
TL;DR: NanoCrystal Technology is an attrition process wherein large micron size drug crystals are media milled in a water-based stabilizer solution and the process generates physically stable dispersions consisting of nanometer-sized drug crystals.
1,245 citations
TL;DR: The physical background of the diminution process, effects of production parameters (power density, number of homogenisation cycles) on crystal size, clinical batch production and scaling up of the production are presented.
972 citations
"Formulation and Stability Testing o..." refers methods in this paper
...The antisolvent sonoprecipitation technique was chosen as it has the advantages of using relatively simple, low cost equipments and relatively easy scale up (12)....
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TL;DR: In this paper, the authors measured the solid-liquid phase transition temperatures and heats of fusion ΔH f of nonpolar organic solids confined in the pores of controlled pore glasses by differential scanning calorimetry.
Abstract: The solid–liquidphase transition temperatures and heats of fusion ΔH f of nonpolar organic solids confined in the pores of controlled pore glasses were measured by differential scanning calorimetry. The pore diameters d were in the range of 40–730 A and the organics studied were cis‐decalin, trans‐decalin, cyclohexane, benzene, chlorobenzene, naphthalene, and heptane. In accordance with previous reports on studies of primarily inorganic materials, the melting point of the pore solidT(d) decreased with decreasing pore diameter. In addition, a large reduction in the bulk enthalpy of fusion ΔH f of the pore solid was measured, which apparently has not been studied in detail by other workers. A linear correlation was found between the melting point depression (ΔT m ) and the reciprocal diameter, as predicted by theories of solidification in a capillary. The calculated values of the solid–liquid interfacial energy σsl were in reasonable agreement with values reported in the literature based on other methods of measurement.
773 citations
"Formulation and Stability Testing o..." refers background in this paper
...The shift in the ITZ peak to a lower temperature in the nanosized product compared to pure drug might be due to smaller ITZ crystals (19)....
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