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ABSTRACT: Poorly water-soluble drug with a short half-life such as isradipine (IDP) offer challenges in the controlled release formulation because of low dissolution rate and poor bioavailability. Self-emulsifying solid dispersions (SESD) of IDP consisted of surfactant and fatty acid in poloxamer 407 (POX 407) as a carrier and were manufactured by the melting method. Then, controlled release HPMC matrix tablet containing SESD were prepared via direct compression. The dissolution behaviors and in vivo bioavailability of controlled release matrix tablet in healthy human volunteers were investigated. The physical properties of solid dispersion were also examined using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). It was shown that structure of IDP was amorphous in the solid dispersion. The dissolution rate of IDP from SESD was markedly enhanced because of increased solubility and wetting effect. Controlled release HPMC matrix tablets containing SESD released drug in a controlled manner and were stable during storage over 3 months at 40°C/75% RH. Furthermore, the tablet containing 5mg IDP SESD showed significantly increased oral bioavailability and extended plasma concentration compared with the marketed 5mg Dynacirc(®) capsule. A combined method of solid dispersion and controlled release technology could provide versatile dosage formulations containing IDP with poor water solubility and short half-life.
International journal of pharmaceutics 04/2013; · 2.96 Impact Factor
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ABSTRACT: Many new drugs have been discovered in pharmaceutical industry and exposed their surprised potential therapeutic effects. Unfortunately, these drugs possess low absorption and bioavailability since their solubility limitation in water. Solid dispersion (SD) is the current technique gaining so many attractions from scientists due to its effect on improving solubility and dissolution rate of poorly water-soluble drugs. A number of patents including the most recent inventions have been undertaken in this review to address various respects of this strategy in solubilization of poorly water-soluble drugs including type of carriers, preparation methods and view of technologies used to detect SD properties and mechanisms with the aim to accomplish a SD not only effective on enhanced bioavailability but also overcome difficulties associated with stability and production. Future prospects are as well discussed with an only hope that many developments and researches in this field will be successfully reached and contributed to commercial use for treatment as much as possible.
Recent patents on drug delivery & formulation. 12/2012;
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ABSTRACT: For the past few decades biomedical engineering has imprinted its significant impact on the map of science through its wide applications on many other fields. An important example obviously proving this fact is the versatile application of magnetic nanoparticles in theranostics. Due to preferable properties such as biocompatibility, non-toxicity compared to other metal derivations, iron oxide-based magnetic nanoparticles was chosen to be addressed in this review. Aim of this review is to give the readers a whole working window of these magnetic nanoparticles in the current context of science. Thus, preparation of magnetic iron oxide nanoparticles with the so-far techniques, methods of characterizing the nanoparticles as well as their most recent biomedical applications will be stated.
Archives of Pharmacal Research 12/2012; 35(12):2045-61. · 1.59 Impact Factor
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ABSTRACT: For the quality evaluation of raw materials, the influence of various types of solvents on the polymorphic crystallization behaviors and dissolution rates of two sources of valsartan (VAL) from China and India was investigated. Samples were prepared by recrystallization from water or organic solvents, such as acetonitrile, acetone and ethanol, using methods with and without heating. Recrystallization behaviors were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Scanning electron microscopy (SEM) was also used to observe the morphology of samples. The dissolution rate of recrystallized samples in water was evaluated and compared to the original VAL sample. There were significant differences in morphology, crystal structure and dissolution rate among the samples recrystallized using organic solvents. VAL was transformed into another polymorphic form by the solvents and recrystallization conditions. These physical properties of VAL also differed between the two sources of VAL. Thus, the physicochemical differences of raw materials should be carefully considered in early dosage formulation approaches.
Archives of Pharmacal Research 07/2012; 35(7):1223-30. · 1.59 Impact Factor
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ABSTRACT: In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.
Pharmaceutical Research 05/2011; 28(10):2353-78. · 4.09 Impact Factor
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ABSTRACT: The stability of solid dispersions (SD) during storage is of concern. We prepared the pH-modulated SD (pSD) and compressed tablets consisting of polyethylene glycol (PEG) 6000 as a carrier, drug and MgO (alkalizer). Telmisartan (TEL), an ionizable poorly water-soluble drug, was chosen as a model drug. The changes in physicochemical factors such as the dissolution rate, drug crystallinity, microenvironmental pH (pH(M)) and intermolecular interactions of the pSD and the tablets were investigated over 3 months under different temperature and relative humidity (RH) conditions: refrigerator (5-8 °C), 25 °C/32% RH, 25 °C/55% RH, 25 °C/75% RH, 40°C/32% RH, 40 °C/55% RH, and 40 °C/75% RH. Differential scanning calorimetry (DSC) analysis of all samples revealed no distinct changes in the drug melting point. In contrast, powder X-ray diffraction (PXRD) diffractograms revealed that samples stored at 40 °C/75% RH for 1 month, 25 °C/75% RH for 3 months and 40 °C at all humidity conditions for 3 months showed gradual recrystallization of the drug. Fourier transform infrared (FTIR) spectra indicated a reduced intensity of intermolecular interactions between TEL and MgO in the pSD and tablet. The pH(M) also gradually decreased. These altered physicochemical factors under the stressed conditions resulted in decreased dissolution profiles in intestinal fluid (pH 6.8). In contrast, the dissolution rate in gastric fluid (pH 1.2) was almost unchanged because of the high intrinsic solubility of TEL at this pH.
International journal of pharmaceutics 05/2011; 414(1-2):48-55. · 2.96 Impact Factor
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ABSTRACT: The purpose of this study was to investigate the effects of alkalizers in dissolution rate and crystal structure of valsartan (VAL) in Poloxamer 407 (POX)-based solid dispersions (SD). VAL, a poorly-water soluble drug was selected as a model drug because of its low solubility at low pH. The POX-based SDs containing alkalizers (Na₂CO₃, MgO, meglumine and arginine) were prepared by melting method. The dissolution tests were performed using the United States Pharmacopeia (USP) paddle II method in enzyme-free simulated gastric fluid (pH 1.2) for 2 h. Microenvironmental pH (pH(M)) was examined potentiometrically by using a surface pH electrode. Dissolution rate of SD incorporating Na₂CO₃ was drastically increased. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) data indicated that crystalline structure of VAL in SD was transformed to amorphous form by the addition of alkalizers but could not explain the differences in the dissolution rates. The molecular interaction between VAL and Na₂CO₃ was observed in the Fourier transform infrared spectroscopy (FT-IR) spectra by the shift of C=O band from 1732 to 1719 cm⁻¹ and the disappearance of carbonyl group at 1598 cm⁻¹. Furthermore, Na₂CO₃ efficiently modulated pH(M) by providing a favorable microenvironment for drug dissolution. A combination of SD method and use of alkalizer is a promising approach to modulate release rate of poorly water-soluble and ionizable drug with an aid of changes of drug crystallinity, molecular interaction and pH(M).
Chemical & pharmaceutical bulletin 01/2011; 59(7):844-50. · 1.70 Impact Factor
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ABSTRACT: The aim was to design a pH-sensitive pulsatile drug delivery system that allows for an on-off pulsed release of a drug using polyacrylic acid (PAA) blended with ethyl cellulose (EC) in different ratios. PAA, a polyelectrolyte polymer, exhibits a highly coiled conformation at low pH but a highly extended structure at high pH. Fumaric acid, which is an internal acidifying agent, was incorporated into the hydroxypropyl methylcellulose-based core tablets to create an acidic microenvironmental pH (pH(M)). The concentration of fumaric acid inside the core tablet and the ratio of PAA/EC in the coating layer were very crucial in modulating drug release behaviors. When the fumaric acid was retained in the core tablet, it gave a more acidic pH(M), so that the PAA was kept in a highly coiled state in the coated film, which hindered drug release ("off" release pattern). Interestingly, the release profiles of the drug and fumaric acid from coated tablets showed the on-off pulsed pattern upon dissolution. Imaging analyses using scanning electron microscopy, near-infrared imaging, confocal laser scanning microscopy, and Fourier transform infrared spectroscopy confirmed this on-off release behavior of the drug and fumaric acid from coated tablets.
AAPS PharmSciTech 12/2010; 12(1):46-55. · 1.43 Impact Factor
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ABSTRACT: The aim of this study was to investigate the physicochemical properties of polyethylene oxide (PEO)-based controlled release solid dispersions (CR-SDs) containing aceclofenac, Gelucire 44/14, poloxamer 407 and pH modifier (Na2CO3).
The immediate release solid dispersions containing the pH modifier greatly enhanced the drug dissolution rate to approximately 100%, while the CR-SDs with PEO showed controlled release. A bigger droplet size and a higher surface charge for the CR-SDs were observed compared with the immediate release solid dispersions. The pH modifier played an important role in modulating the release rate of the drug through changes in the drug crystallinity and the hydrogen-bonding interaction, as well as the microenvironmental pH. Near-infrared images revealed a modulation of the PEO concentration to preserve the pH modifier within the system for controlled release of the drug.
The dissolution process of PEO-based solid dispersions containing a water-insoluble drug was governed by the changing net effect of the microenvironmental pH, the surface charge, the particle size and the release rate of the pH modifier, as well as the function of PEO in controlling drug release.
Therapeutic delivery 07/2010; 1(1):51-62.
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ABSTRACT: Although the solid dispersion method has been known to increase the dissolution rate of poorly water-soluble drugs by dispersing them in hydrophilic carriers, one obstacle of the solid dispersion method is its limited solubilization capacity, especially for pH-dependent soluble drugs.
pH-modified solid dispersion, in which pH modifiers are incorporated, may be a useful method for increasing the dissolution rate of weakly acidic or basic drugs. Sufficient research, including the most recent reports, was undertaken in this review.
How could the inclusion of the pH the pH modifiers in the solid dispersion system change drug structural behaviors, molecular interactions, microenvironmental pH, and/or release rate of pH modifiers, relating with the enhanced dissolution of weakly acidic or weakly basic drugs with poor water solubility? These questions have been investigated to determine the dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs.
It is believed that step-by-step mechanistic approaches could provide the ultimate solution for solubilizing several poorly water-soluble drugs with pH-dependent solubility from a solid dispersion system, as well as provide ideas for developing future dosage systems.
Expert Opinion on Drug Delivery 03/2010; 7(5):647-61. · 4.90 Impact Factor
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ABSTRACT: The roles of acidifiers in polyvinylpyrrolidone-based solid dispersions and physical mixtures were originally investigated on dissolution rate of drug, acidifier release, structural crystallinity and micro-environmental pH. A poorly water-soluble and weakly basic isradipine was used as a model drug. The solid dispersion and physical mixtures were prepared with drug and polyvinylpyrrolidone without or with pH modifiers using the solvent evaporation method and then compressed into tablet. The dissolution rate of drug from solid dispersions containing acidifiers were more pronounced when compared to physical mixtures. The dissolution rate of isradipine from solid dispersion was ranked by acidifiers in a decreasing order: fumaric acid, citric acid, glycolic acid and malic acid. In contrast, the acidifiers in physical mixtures had no significant difference in drug dissolution rate. It was attributed by the rank of acidifiers leading to the decrease of micro-environmental pH and slower release rate of acidifier as well as the maintenance of structural amorphousness. The selection of acidifiers with optimal micro-environmental pH, retarded release rate and maintaining structural amorphousness of drug could maximize the dissolution rate of weakly basic drug in solid dispersion.
International journal of pharmaceutics 09/2009; 384(1-2):60-6. · 2.96 Impact Factor
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ABSTRACT: We examined how melatonin absorption was affected by pharmaceutical excipients using the Ussing chamber technique with mounted rat gastrointestinal (GI) segments. Melatonin absorption occurs throughout the GI tract, with the greatest absorption being in the rectum and ileum and the least in the stomach. Melatonin can be classified as a low permeability drug. P-glycoprotein (P-gp) does not affect melatonin absorption but transported rhodamine 123, a well-known P-gp substrate. The possibility of saturating P-gp by melatonin was excluded. Sodium cholate (0.5%) increased melatonin absorption, but decreased absorption at higher concentrations (1.0% and 5.0%). Sodium oleate (0.5% and 1.0%) consistently decreased melatonin absorption. Pharmaceutical excipients increased the absorption of Lucifer yellow (100 microg/mL), a paracellular probe but decreased the absorption of melatonin above the critical micelle concentration (cmc), suggesting that melatonin was transported mainly by transcellular pathway. Sodium cholate and sodium oleate, when above the cmc, resulted in micellar complexes as revealed by (1)H NMR spectra and particle size distribution. Histology tests showed mucosal damage of jejunum tissues in the presence of these excipients. The balance of tissue damage by the formation of micellar complexes could affect the melatonin absorption. This information on melatonin absorption behaviors and its modulation by pharmaceutical excipients can be used in further oral dosage formulations to affect circadian rhythm.
International journal of pharmaceutics 06/2009; 378(1-2):9-16. · 2.96 Impact Factor
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ABSTRACT: We investigated the dissolution-modulating mechanism of alkalizers and polymers in nanoemulsifying Gelucire 44/14 (GUC)-based solid dispersions (SDs) for controlled release. Aceclofenac (AFC), an ionizable and poorly water-soluble drug, was chosen because of its extremely low solubility at low pH. Nanoemulsifying SD systems containing alkalizers and/or polymers were prepared by the melting method. Drug crystallinity, microenvironmental pH (pH(M)), dissolution rate, and droplet size in the media from nanoemulsifying SD were then characterized. Ternary SD containing alkalizers, mainly Na(2)CO(3) and NaHCO(3), enhanced the initial release rate of AFC in simulated gastric fluid (pH 1.2), but resulted in spring-like precipitation. However, adding a secondary polymer, Poloxamer 407, prevented precipitation in the quaternary SD system. Poloxamer 407 and alkalizer (Na(2)CO(3)) facilitated nanoemulsion formation (80-140 nm) with a smaller droplet size in a medium of pH 1.2 as visualized by TEM. The surface and inner pH(M) were also modulated by the alkalizers, but not by the polymers. The drug's crystalline structure was further changed to partially or almost amorphous form by the alkalizers and polymers in SD as characterized by instrumental analysis. The synergistic effects of alkalizers and secondary polymers in SD on reduction of drug crystallinity and modulation of pH(M) via molecular interactions could modulate dissolution rates of ionizable and poorly water-soluble model drug without spring-like precipitation by providing more favorable nanoemulsion-forming environment.
European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 01/2009; 72(1):83-90. · 3.15 Impact Factor
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ABSTRACT: The present work is an original evaluation of the microenvironmental pH (pH(M)) and crystallinity of an ionizable drug in order to enhance its dissolution using alkalizers in polyethylene glycol 6000 (PEG 6000) based solid dispersions (SDs). Telmisartan (TEL) was chosen as a model drug due to its poor and pH-dependent water solubility. The nine alkalizers used to modify the pH of TEL were MgO, NaOH, KOH, Na2CO3, NaHCO, bentonite, Na2HPO4, K2HPO4 and arginine. MgO, NaOH, KOH and Na2CO3 in the SD system significantly increased the drug dissolution rate in intestinal fluid (pH 6.8) and water. Modulation of pH(M) was clearly observed as a function of time at different fractional dimensions of tablet. Structural change in drug crystallinity to an amorphous form was also a contributing factor based on differential scanning calorimetry (DSC) thermograms and powder X-ray diffraction (PXRD) patterns. The drug frequency of the CO band decreased and the O-H broad band in the Fourier transform infrared (FTIR) spectra disappeared when these alkalizers were added. It was evident that the alkalizers in PEG 6000 based SDs synergistically enhanced dissolution of TEL not only by modulating pH(M) but also by changing drug crystallinity to an amorphous form via molecular interactions.
Journal of Controlled Release 08/2008; 129(1):59-65. · 5.73 Impact Factor
