Improved Dissolution Behavior Research Articles

Self-assembled micellar formulation of chafuroside A with improved anti-inflammatory effects in experimental asthma/COPD-model rats

Chafuroside A (CFA), a poorly water-soluble flavone C-glycoside, was firstly isolated from oolong tea, and it acts as a potent anti-inflammatory agent. The present study was undertaken to develop a water-soluble formulation of CFA using a self-assembled micellar (SAM) system, with the aim of improved dissolution behavior and potent anti-inflammatory effects. The SAM formulation of CFA (CFA/SAM) was characterized in terms of its morphology, particle size distribution, crystallinity, and dissolution behavior. In dissolution testing, the CFA/SAM exhibited marked improvement in dissolution behavior when compared with crystalline CFA, and then, nano-micellar particles were constituted with a mean diameter of 84 nm. The therapeutic potential of the crystalline CFA and CFA/SAM was assessed using an experimental asthma/chronic obstructive pulmonary disease (COPD)-like model. Orally-administered CFA at 0.5 mg/kg or higher could attenuate inflammatory symptoms in a dose-dependent manner, as evidenced by decreases of infiltrated granulocytes, including macrophages and neutrophils, and myeloperoxidase, a specific biomarker for neutrophilia. Biomarker profiling demonstrated that the CFA/SAM at 0.1 mg CFA/kg was equipotent to CFA at 1.0 mg/kg in ameliorating antigen-induced airway inflammation, suggesting the better pharmacological effect of CFA/SAM due to improved dissolution behavior. From these observations, the SAM formulation might be an efficacious approach for enhancing the therapeutic potential of CFA for treatment of inflammatory diseases.

Inhalable dry-emulsion formulation of cyclosporine A with improved anti-inflammatory effects in experimental asthma/COPD-model rats

The main purpose of the present study was to develop a novel respirable powder (RP) formulation of cyclosporine A (CsA) using a spray-dried O/W-emulsion (DE) system. DE formulation of CsA (DE/CsA) was prepared by spray-drying a mixture of erythritol and liquid O/W emulsion containing CsA, polyvinylpyrrolidone, and glyceryl monooleate as emulsifying agent. The DE/CsA powders were mixed with lactose carriers to obtain an RP formulation of DE/CsA (DE/CsA-RP), and its physicochemical, pharmacological, and pharmacokinetic properties were evaluated. Spray-dried DE/CsA exhibited significant improvement in dissolution behavior with ca. 4500-fold increase of dissolution rate, and then, nanoemulsified particles were reconstituted with a mean diameter of 317 nm. Laser diffraction analysis on the DE/CsA-RP suggested high dispersion of DE/CsA on the surface of the lactose carrier. Anti-inflammatory properties of the inhaled DE/CsA-RP were characterized in antigen-sensitized asthma/COPD-model rats, in which the DE/CsA-RP was more potent than the RP formulation of physical mixture containing CsA and erythritol in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Pharmacokinetic studies demonstrated that systemic exposure of CsA after intratracheal administration of the DE/CsA-RP at a pharmacologically effective dose (100 μg-CsA/rat) was 50-fold less than that of the oral CsA dosage form at a toxic dose (10 mg/kg). From these findings, use of inhalable DE formulation of CsA might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure.

Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations

Introduction:Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered.Areas covered:The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed.Expert opinion:Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions.

Development of Inhalable Nanocrystalline Solid Dispersion of Tranilast for Airway Inflammatory Diseases

Tranilast (TL), an antiallergic agent, has been clinically used in the treatment of bronchial asthma, although the clinical use of TL is limited because of its poor solubility and systemic side effects. To overcome these drawbacks, a novel respirable powder (RP) of TL for inhalation therapy was developed using nanocrystal solid dispersion of TL (CSD/TL). In the CSD/TL, wet-milled crystalline TL particles with a mean diameter of 122 nm were dispersed, and there was a marked improvement in dissolution behavior of the CSD/TL-RP compared with that of a physical mixture of TL and carrier. Laser diffraction and cascade impactor analyses on the CSD/TL-RP demonstrated high dispersibility and deposition in the respiratory organs with emitted dose and fine particle fraction of ca. 98 and 60%, respectively. Inhaled CSD/TL-RP could attenuate antigen-induced inflammatory events in rats, as evidenced by histochemical analyses and inflammatory biomarkers such as lactate dehydrogenase, eosinophil peroxidase, and myeloperoxidase. The CSD/TL-RP seemed to be more potent than the physical mixture in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Systemic exposure of TL after intratracheal administration of CSD/TL-RP at a pharmacologically effective dose (100 μg of TL/rat) was found to be fivefold less than that of the oral TL dosage form at clinical dose (1.67 mg/kg). Given the improved pharmacodynamics and lower systemic TL concentration, the inhalable TL formulation might provide an interesting alternative to oral therapy with a better safety margin for the treatment of asthma and other airway inflammatory diseases.

Formation of submicron poorly water-soluble drugs by rapid expansion of supercritical solution (RESS): Results for Naproxen

Numerous results of multitude investigations indicate that the particular properties of supercritical fluids can be conveniently exploited for the formation of submicron particles. In case of pharmaceutical substances the poor dissolution behaviour and therewith bioavailability of drugs in biological media can be enhanced dramatically by reduction of the particle size. In this paper we report the application of RESS (Rapid Expansion of Supercritical Solutions) and RESSAS (Rapid Expansion of Supercritical Solution into Aqueous Solution) to produce submicron particles of Naproxen, a poorly water-soluble drug. Thereby the effect of various process conditions on the obtained product properties was investigated. The experimental results show, that the RESS processing of Naproxen leads to particles in the range from 0.56 to 0.82 μm which is about 22 times smaller than the unprocessed powder. RESSAS experiments show, that stabilized Naproxen particles have an average diameter of 0.3 μm for drug concentrations up to 1 g/dm 3 in 0.4 wt% PVP solution while expansion into a 0.4 wt% Tween ® 80 solution produced particles 8 μm in diameter. Furthermore, it is shown that the improved dissolution behaviour of the processed powder depends on the particle size and hence increased surface area and on the pH-value of the dissolution media.

Glucosamine HCl as a new carrier for improved dissolution behaviour: Effect of grinding

The co-grinding technique is one of the most effective methods for improving the dissolution rate of poorly water-soluble drugs and it is superior to other approaches from an economical as well as an environmental stand point, as the technique does not require any toxic organic solvents. The present work is an attempt to use d-glucosamine HCl (G-HCl) as a potential excipient to improve dissolution rate of carbamazepine (CBZ) from physical mixtures and co-grinding formulations. The effect of order of grinding on dissolution of CBZ was also investigated. Co-ground of drug and G-HCL were prepared using different ratios using ball mill. The samples were subjected to different grinding times. In order to investigate the effect of grinding process on dissolution behaviour of CBZ, the drug was ground separately in the absence of glucosamine. Then the mixture of ground CBZ and un-ground d-glucosamine HCl were prepared. Physical mixtures of CBZ and G-HCl were also prepared for comparison. The properties of prepared co-ground systems and physical mixtures were studied using a dissolution tester, FT-IR, SEM, XRPD, and DSC. These results showed that the presence of glucosamine can increase dissolution rate of CBZ compared to pure CBZ. The results showed the order of grinding had a big impact on the dissolution performance of CBZ formulations containing glucosamine. All dissolution profiles generally showed that the fastest dissolution rate was obtained when ground CBZ was mixed with un-ground glucosamine. This was closely followed by the co-grinding of CBZ with glucosamine where lower grinding times showed the fastest dissolution. XRPD showed that the grinding of CBZ can reduce the percentage crystallinity of drug crystals. DSC study of ground CBZ showed that the grinding induced polymorphism transformations in the CBZ crystals and the limit and type of these transformations were related to the grinding time.

Improvement of Dissolution Behavior for Poorly Water-Soluble Drug by Application of Cyclodextrin in Extrusion Process: Comparison between Melt Extrusion and Wet Extrusion

The purpose of this study was to improve dissolution behavior of poorly water-soluble drugs by application of cyclodextrin in extrusion processes, which were melt extrusion process and wet extrusion process. Indomethacin (IM) was employed as a model drug. Extrudates containing IM and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in 1:1 w/w ratio were manufactured by both melt extrusion process and wet extrusion process. In vitro drug release properties of IM from extrudates and physiochemical properties of extrudates were investigated. The dissolution rates of IM from extrudates manufactured by melt extrusion and wet extrusion with HP-beta-CyD were significantly higher than that of the physical mixture of IM and HP-beta-CyD. In extrudate manufactured by melt extrusion, gamma-form of IM changed to amorphous completely during melt extrusion due to heating above melting point of IM. On the other hand, in extrudate manufactured by wet extrusion, gamma-form of IM changed to amorphous partially due to interaction between IM and HP-beta-CyD and mechanical agitating force during process. Application of HP-beta-CyD in extrusion process is useful for the enhancement of dissolution rate for poorly water-soluble drugs.

Formulation of nanosuspensions of gymnemic acids for oral administration

Integration of ayurveda and pharmaceutical technological advances are being used to make effective drug delivery system of gymnemic acids. In recent years, there has been a considerable interest in the development of novel drug delivery systems using nanotechnology. In the present work an attempt has been made to prepare and formulate gymnemic acids nanocrystal in order to improve the dissolution velocity and enhance the bioavailability. The gymnemic acids nanosuspension prepared was dried by lyophilisation and characterised for its physico-chemical properties and the re-dispersion of it in water was intensively investigated. Morphology of the particles was also analysed. Finally, gymnemic acids nanocrystal-loaded tablets were developed using direct compression and its dissolution behaviour was evaluated in various dispersion media. The improved dissolution behaviour of the gymnemic acids nanocrystal-loaded tablet should lead to a better bioavailability of the poorly soluble gymnemic acids in the body.

In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy

Cyclosporine A (CsA) has been clinically used as immunosuppressant, and new application for airway inflammation was also proposed. However, the clinical use of CsA was limited due to severe adverse effects after systemic exposure and the poor solubility. In the present investigation, novel respirable powder (RP) of CsA was developed for pulmonary administration with use of solid dispersion of wet-milled CsA (WM/CsA), and the physicochemical and pharmacological properties of the WM/CsA and its RP formulation were characterized. CsA in the solid dispersion was found to be amorphous by X-ray powder diffraction and differential scanning calorimetry. It exhibited the improved dissolution behavior as compared to active pharmaceutical ingredients. Laser diffraction and cascade impactor analysis of newly developed WM/CsA-RP, consisting of jet-milled WM/CsA and lactose carriers, suggested high dispersion and deposition in the respiratory organs with the emitted dose and the fine particle fraction of 96 and 54%, respectively. Intratracheal administration of WM/CsA-RP (100 µg CsA) in experimental inflammatory rats led to 71 and 85% reduction of granulocyte recruitment in bronchoalveolar lavage fluids and lung tissues, respectively, with showing ca 10 2-fold reduced AUC and C max values of plasma CsA as compared to the oral dosage form of CsA at toxic concentration (10 mg/kg). Upon these findings, WM/CsA-RP would be efficacious dosage form for clinical treatment of airway inflammations with minimal systemic side effects.

Manufacture of submicron drug particles with enhanced dissolution behaviour by rapid expansion processes

In the case of pharmaceutical substances the particle size is quite important since it can limit the bioavailability of poorly soluble drugs. As an example we can refer to the data obtained for Griseofulvin. In 1962 Atkinson has studied the concentration of the drug in the blood, taken from healthy volunteers at given intervals of time after dosing, as a function of its specific area. The quantity absorbed for a particle size of 2.7 μm is twice as high compared with a particle size of 10 μm. The present article gives a survey of published knowledge about particle and product design with focus on the RESS process and some promising modifications of this technique. Experimental results confirm that each of these processes is a promising technique for the formation of submicron particles (≤100 nm) and that the improved dissolution behaviour is influenced by particle size, surface area, and wettability of the processed powders as well as by the pH-value of the dissolution media.

Improved dissolution behaviour of steam-granulated piroxicam

In this paper we prepared and characterized improved release granulates containing Piroxicam and β-cyclodextrins (1:2.5 molar ratio), obtained by steam-aided granulation, using a one-step rotogranulator, Rotolab ®. These granulates were compared to those prepared by traditional wet granulation, to the physical mixture, and to the kneaded and dry granulates. The experimental data showed a significant reduction of the water amount required (50%) and of the working time, with respect to traditional wet granulation. The samples examined by scanning electron microscopy and fractal analysis revealed morphological differences related to the method of preparation: the steam-granulated material showed a diffuse porosity, as confirmed by the porosity test. Differential scanning calorimetry, infrared and X-ray analysis revealed the absence of polymorphs in the solid state of the drug. The results of the dissolution tests suggest that the steam-aided granulation may be considered a useful method to improve the in vitro dissolution rate of Piroxicam, enabling also a considerable reduction in the processing time.

Improved Dissolution Behavior of Fenbufen by Spherical Crystallization

Fenbufen is an analgesic, antipyretic and anti-inflammatory drug that is characterized by poor water solubility, a defect increased by very low wettability. Poor water solubility, particularly at low pH, could decrease absorption in the upper part of the gastrointestinal tract, which would be inconvenient for good bioavailability. Different spherical crystallization processes have been considered as methods to improve fenbufen dissolution behavior. A two-solvent system, in the presence of a bridging liquid, is the only method capable of producing spherical fenbufen crystals. In a first step, fenbufen solubility was considered in different solvents. The drug crystals formed were typically needle shaped. This characteristic was considered as a favorable parameter to obtain spherical crystals. After the selection of the best fenbufen solvent, several ratios of solvent (S)–nonsolvent (NS) (tetrahydrofuran [THF]–demineralized water) were studied. The addition of a bridging liquid (isopropyl acetate) improved spherical crystallization. The results from this method were reproducible batch to batch. The spherical crystals obtained showed a clear improvement in dissolution capacity, probably due to better wettability. Dissolution studies were then carried out on these spherical crystals stored for 1 month at different relative humidities (RHs). The dissolution profiles remained unchanged.

Surface modification of titanium alloy implants

Hip replacement stems manufactured from Ti6AI4V titanium alloy were surface treated in one of four ways and tested for dissolution resistance in bovine serum. Those stems treated thermally were found to have significantly lower metal ion release compared with those receiving standard commercial treatments. The improved dissolution behaviour is associated with a change in the surface oxide structure from mixed titanium oxides to a more stable rutile structure.

Increasing bioavailability of nifedipine from matrix granules prepared using macrogol and trilaurin

New nifedipine (NP) granules prepared using macrogol 1540 (M-1540) as a water-soluble drug carrier to improve dissolution behavior of NP in water, and a triacylglycerol, trilaurin, as a digestive (lipase-sensitive) material creating a dosage vehicle having a pH-independent dissolution profile of NP in intestinal juice, were investigated. In the dissolution test in vitro, the dissolution percentages of NP from the macrogol-trilaurin matrix granules for 2 h at pH 1.2 were very low (less than 10%), while NP from these matrix granules in pH 6.4 phosphate buffer solution (PBS) containing lipase and cholic acid was almost completely dissolved (close to 100%). The mean value of the area under the plasma NP concentration-time curve (AUC) obtained following oral administration of NP granules in rabbits was significantly (p < 0.05) higher (approx. 3 times) than that of the AUC in the case of NP powder. A preparation of NP matrix granules using macrogols and trilaurin may therefore provide a useful approach to achieving high bioavailability and delayed-release characteristics.

Effect of cholesterol on the aging of griseofulvin-phospholipid coprecipitates

Coprecipitates of griseofulvin (Gris), dimyristoylphosphatidylcholine (DMPC), egg phosphatidylcholine (EPC) and cholesterol (CHOL) prepared from chloroform solutions were subjected to dissolution studies, differential thermal analysis (DTA), and weight loss determinations after various storage times. The addition of CHOL to certain compositions of Gris: DMPC coprecipitates increased the dissolution of Gris, reduced the residual chloroform content and decreased the aging towards lower dissolution behavior. Coprecipitates of Gris: lipid, 4:1 weight ratio (1:0.33 DMPC: CHOL mole ratio) exhibited maximum dissolution and the lowest degree of aging. Fusion temperatures, heats of fusion (Δ H f ), and chloroform contents of the coprecipitates varied with CHOL content and with aging but neither individually correlated with the dissolution data. Instead, the aging factor = ΔH f [CHCl 3] linearly correlated with the storage time and with dissolution. When DMPC was replaced with EPC at the optimum mole ratio of 1:0.33 EPC: CHOL, aging of the coprecipitate up to 90 days resulted in increased dissolution of Gris, the level of which remained constant for samples aged up to 135 days. Chromatographic evidence and oxidation indices of EPC suggest that the unexpected behavior of these systems is possibly a result of the degradation of EPC. Generally, the results indicate that over a narrow range of concentration, CHOL addition augments the dissolution of freshly-prepared Gris: phospholipid coprecipitates and reduces their desolvation on storage thereby minimizing the aging of these systems and maintaining the improved dissolution behavior of Gris.

Bioavailability and stability of nifedipine-enteric coating agent solid dispersion.

The absorption behavior and stability of nifedipine-enteric coating agent solid dispersions were studied using hydroxypropylmethylcellulosephthalate (HP-55) and methacrylic acid-methacrylic acid methyl ester copolymer (Eudragit L) as carriers. In the rat in situ absorption study, the dissolution behavior of HP-55 solid dispersion in the gastrointestinal tract was confirmed to be pH-dependent. After oral administration of these solid dispersions in beagle dog, area under the blood concentration curve (AUC) values were equivalent to that of polyvinylpyrrolidone solid dispersion, which showed remarkably improved dissolution behavior and bioavailability as compared with nifedipine alone. These systems were stable chemically and physically at 40 C and 40 C/80% R. H. during 6 months, and could be useful sustained absorption dosage forms with good bioavailability.