Mesoporous silica formulation strategies for drug dissolution enhancement: a review

Introduction: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture.

Areas covered: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered.

Expert opinion: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.     

Chitin biomass-nifedipine amorphous solid dispersion for enhancement of hydrophobic drug dissolution in aqueous media

Solid dispersions of poorly-water soluble nifedipine using microparticles fabricated from chitin biomass were prepared to improve the drug dissolution in an aqueous medium. After the drug loading and solvent evaporation, the drug loading capacity of 1, 6, and 19 %w/w was obtained. In the microstructure, the drug was dispersed on the porous chitin carrier with minor agglomeration leading to reduced crystallization and improved dissolution, nearly 100%, as compared to the pure nifedipine powder and the physical mixture with chitin. There was an interaction between functional groups of the drug and polymer, consequently the release prolonged for the entire 6 h with the maximum drug solubility of about 300 μg/ml. An in vitro release study showed that nifedipine effectively released from chitin into a simulated gastric releasing medium (pH 1.2). In this case, the release mechanism was best fitted with a Zero-order model based on the Fick's Law in the first 2 h. This research indicated that employing microparticle obtained from chitin biomass in the solid dispersion system lowered the drug recrystallization, facilitated drug release, and provided the sustainability in pharmaceutical science.     

Preparation and evaluation of itraconazole dihydrochloride for the solubility and dissolution rate enhancement

The purpose of this work was to explore the feasibility of preparing itraconazole hydrochloride to improve the solubility and dissolution rate. Itraconazole dihydrochloride was synthesized by bubbling anhydrous hydrogen chloride gas into the acetone suspension of itraconazole. Results of the elementary analysis gave the molecular formula of C(35)H(38)Cl(2)N(8)O(4).2HCl and its structure was confirmed by Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-Ray diffraction (PXRD) suggested that a new crystalline form of the salt was formed. The morphology and mean size distribution study by scanning electron microscopy (SEM) and dynamic light scattering (DLS) confirmed that the salt was dispersable nanoparticle aggregation. Aqueous solubility measurements showed that the solubility of the salt, its 1:1, 1:2 and 1:3 (w/w) physical mixtures with beta-cyclodextrin (beta-CD) was 6, 99, 236 and 388 times greater than itraconazole. More than 94% of itraconazole was dissolved out of the salt/beta-CD 1/3 physical mixture after 60min. The stability studies indicated that the physical mixture remained stable for 24 months in assay, the related substances and dissolution. Based on the present results, it is concluded that hydrochloride formation can significantly increase solubility and dissolution rate of itraconazole, and the formulation of itraconazole dihydrochloride/beta-CD (1/3) would be an environment-friendly, economic and practical alternative to the commercially available itraconazole capsules (Sporanox)     

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.     

Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability

The objective of this study was to elucidate the feasibility to improve the solubility and bioavailability of poorly water-soluble itraconazole via solid dispersions by using supercritical fluid (SCF). Solid dispersions of itraconazole with hydrophilic polymer, HPMC 2910, were prepared by the aerosol solvent extraction system (ASES) under different process conditions of temperature/pressure. The particle size of solid dispersions ranged from 100 to 500 nm. The equilibrium solubility increased with decrease (15 to 10 MPa) in pressure and increase (40 to 60 degrees C) in temperature. The solid dispersions prepared at 45 degrees C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60 degrees C/10 MPa showed approximately 610-fold increase and no endothermic peaks corresponding to pure itraconazole were observed, indicating that itraconazole might be molecularly dispersed in HPMC 2910 in the amorphous form. The amorphous state of itraconazole was confirmed by DSC/XRD data. The pharmacokinetic parameters of the ASES-processed solid dispersions, such as Tmax, Cmax, and AUC(o-24 h) were almost similar to Sporanox capsule which shows high bioavailability. Hence, it was concluded that the ASES process could be a promising technique to reduce particle size and/or prepare amorphous solid dispersion of drugs in order to improve the solubility and bioavailability of poorly water-soluble drugs.     

Single-step preparation and deagglomeration of itraconazole microflakes by supercritical antisolvent method for dissolution enhancement

Itraconazole (ITZ) microflakes were produced by supercritical antisolvent (SAS) method and simultaneously mixed with pharmaceutical excipients in a single step to prevent drug agglomeration. Simultaneous ITZ particle formation and mixing with fast-flo lactose (FFL) was performed in a high-pressure stirred vessel at 116 bar and 40 °C by the SAS-drug excipient mixing (SAS-DEM) method. The effects of stabilizers, such as sodium dodecyl sulfate and poloxamer 407 (PLX), on particle formation and drug dissolution were studied. Drug-excipient formulations were characterized for surface morphology, crystallinity, drug-excipient interactions, drug content uniformity, and drug dissolution rate. Mixture of drug microflakes and FFL formed by the SAS-DEM process shows that the process was successful in overcoming drug-drug agglomeration. PLX produced crystalline drug flakes in loose agglomerates with superior dissolution and flow properties even at higher drug loadings. Characterization studies confirmed the crystallinity of the drug and absence of chemical interactions during the SAS process. The dissolution of ITZ was substantially higher due to SAS and SAS-DEM processes; this improvement can be attributed to the microflake particle structures, effective deagglomeration, and wetting of the drug flakes with the excipients.     

伊曲康唑固体分散体制备及体外溶出实验

目的:运用固体分散体技术提高难溶性药物伊曲康唑的溶解度及体外溶出速率.方法:选用聚乙烯吡咯烷酮(PVPK30)为载体,采用喷雾干燥法制备伊曲康唑固体分散体,通过差热分析及X射线衍射对固体分散体进行鉴定,比较考察伊曲康唑及其物理混合物和固体分散体的溶出特性.结果:差热分析、X射线衍射图谱表明药物以无定形状态分散于载体中;体外溶出结果表明固体分散体能显著增加药物在水及人工胃液中的溶出度(45 min时1:4固体分散体体外溶出度为伊曲康唑的11.5倍.1:4固体分散体在0.1 mo1·L-1盐酸中溶解度是伊曲康唑的67倍).结论:伊曲康唑固体分散体能明显提高伊曲康唑的溶解度及体外溶出速率.     

Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability

The objective of this study was to prepare a solid supersaturatable self-emulsifying drug delivery system (S-sSEDDS) using docetaxel (DTX). Different from conventional self-emulsifying drug delivery systems (SEDDSs), a solid supersaturatable self-emulsifying drug delivery system of docetaxel (DTX-S-sSEDDS) was prepared by spray drying, using lactose as the solid carrier and hydroxypropyl methylcellulose (HPMC) as the supersaturation promoter. Physicochemical properties and in vitro dissolution was observed while taking into account factors such as formulations, supersaturated promoters, solid carriers, and preparation methods. The bioavailability of the DTX-S-sSEDDS(1) compared with other formulations of DTX was evaluated in rats. The results showed that the presence of HPMC effectively sustained the supersaturated state by retarding the precipitation kinetics. Although the total amount of emulsifying excipients in the DTX-S-sSEDDS(1) was only 3/5 as much as that of the conventional SEDDS (DTX-SEDDS(2)), the percent of the accumulated dissolved DTX-S-sSEDDS(1) at 2 h reached 90.96%, which was higher than that of the DTX-SEDDS(2) (76.26%) and approximately 29.8 times as much as that of the DTX crude powder. The in vivo studies indicated that the area under the concentration-time curve (AUC(0-∞)) of the DTX-S-sSEDDS(1) increased by nearly 8.77-fold, 1.45-fold more than those of the DTX powder and the conventional SEDDS without the presence of HPMC (DTX-SEDDS(1)) at a dose of 10 mg/kg. In conclusion, the S-sSEDDS provides an effective approach for improving the dissolution and bioavailability of docetaxel with a low level of emulsifying excipients and provides a reference for good stabilization and the safety of SEDDSs.     

Diverse approaches for the enhancement of oral drug bioavailability

In conscious and co-operating patients, oral drug delivery remains the preferable route of drug administration. However, not all drugs possess the desirable physicochemical and pharmacokinetic properties which favor oral administration mainly due to poor bioavailability. This has in some cases led to the choice of other routes of administration, which may compromise the convenience and increase the risk of non-compliance. Poor bioavailability has necessitated the administration of higher than normally required oral doses which often leads to economic wastages, risk of toxicity, erratic and unpredictable responses. The challenge over the years has been to design techniques that will allow oral administration of most drugs, irrespective of their properties, to achieve a therapeutic systemic availability. This will be a worthy achievement since over 90% of therapeutic compounds are known to possess oral bioavailability limitations. In this review, an attempt has been made to explore various approaches that have been used in recent years to improve oral drug bioavailability, including physical and chemical means. This review strives to provide a comprehensive overview of advances made over the past 10 years (2000-2010) in the improvement of the oral bioavailability of drugs. Briefly, the design of prodrugs to bypass metabolism or to enhance solubility as well as modification of formulation techniques such as the use of additives, permeation enhancers, solubilizers, emulsifiers and non-aqueous vehicles have been discussed. Arising approaches, such as formulation modification techniques; novel drug delivery systems, which exploit the gastrointestinal regionality of drugs, and include the pharmaceutical application of nanotechnology as an emerging area in drug delivery; inhibition of efflux pumps; and inhibition of presystemic metabolism have been more extensively addressed. This critical review sought to assess each method aimed at enhancing the oral bioavailability of drugs in terms of the purpose, scientific basis, limitations, commercial application, as well as the areas in which current research efforts are being focused and should be focused in the future.     

Effects of solid carriers on the crystalline properties, dissolution and bioavailability of flurbiprofen in solid self-nanoemulsifying drug delivery system (solid SNEDDS)

In order to investigate the effects of solid carriers on the crystalline properties, dissolution and bioavailability of flurbiprofen in a solid self-nanoemulsifying drug delivery system (solid SNEDDS), different solid SNEDDS formulations were prepared by spray-drying the solutions containing liquid SNEDDS and various carriers. The liquid SNEDDS, composed of Labrafil M 1944 CS/Labrasol/Trasncutol HP (12.5/80/7.5%) with 2% w/v flurbiprofen, gave a z-average diameter of about 100 nm. Silicon dioxide, a hydrophobic solid carrier, produced an excellent conventional solid SNEDDS with a nanoemulsion droplet size of less than 100 nm, similar to the liquid SNEDDS and smaller than the other solid SNEDDS formulations. The drug was in an amorphous state in this solid SNEDDS. Furthermore, it greatly improved the dissolution rate and oral bioavailability of flurbiprofen in rats because it allowed the spontaneous formation of an interface between the oil droplets and the water. Magnesium stearate, a hydrophobic carrier, produced a solid SNEDDS with the largest diameter. However, it greatly enhanced the dissolution rate and oral bioavailability due to the formation of a simple eutectic mixture. The hydrophilic carriers such as polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (Na-CMC) and hydroxypropyl-β-cyclodextrantrin (HP-β-CD) did not form a solid SNEDDS but rather a solid dispersion (or microcapsule). HP-β-CD improved the dissolution rate but did not improve the oral bioavailability as much as the hydrophobic polymers. PVA and Na-CMC hardly improved the dissolution rate but maintained constantly high plasma levels in rats for a long period. Thus, the selection of carrier is an important factor in the development of solid SNEDDS, since the carriers had significant effects on the crystalline properties, dissolution and oral bioavailability of flurbiprofen and on the formation of solid SNEDDS.     

Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions

Solid dispersions of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] in an amphiphilic vehicle [Gelucire 44/14; 2] and in polyethylene glycol (PEG) 1000, PEG 1450, and PEG 8000 were prepared. The vehicle 2 was a mixture of hydrogenated fatty acid esters with a mp of 44 degrees C, and had a HLB value of 14. Compound 1 was dissolved or dispersed in molten vehicles at elevated temperatures. The pulverization and compression of solid dispersions were avoided by encapsulating the hot solutions directly into hard gelatin capsules. At room temperature, the dispersions solidified forming plugs inside the capsules. On storage, greater than 180 mg of 1 remained dissolved per gram of vehicle, while the excess drug formed fine crystals (less than 20 micron). When mixed with water, the dissolved drug separated as a metastable liquid. Due to the surfactant property of 2, the oily form of 1 that separated from this vehicle formed an emulsified system with a globular size of less than 1 micron, while greater than 80% of 1 that separated from the other three formulations coalesced to form large oily masses. As a result of the large difference in surface area, the dissolution rate of 1 in simulated gastric fluid from capsules containing 2 was much higher than that of a PEG-based formulation. The bioavailability (AUC) of 1 in dogs from capsules containing 2 was also higher than that from PEG 1000-based capsules.     

Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation of itraconazole in healthy volunteers.

Self-microemulsifying drug delivery systems (SMEDDS) represent a possible alternative to traditional oral formulations of lipophilic compounds. This study was designed to compare the oral bioavailability and food-effect of SMEDDS of itraconazole (ITRA-GSMP capsule containing 50mg itraconazole) to that of the currently marketed formulation (Sporanox capsule containing 100mg itraconazole). Eight healthy volunteers received Sporanox or ITRA-GSMP capsule in the fasted state or after a high-fat diet on four separate dosing occasions with a 2-week washout period. Blood samples were collected and analyzed. After administration of the ITRA-GSMP capsule, AUC0-24 and Cmax were 1.9- and 2.5-fold higher in the fasted state and 1.5- and 1.3-fold higher in the fed state, respectively, than those of the Sporanox capsule. Moreover, ITRA-GSMP capsules yielded more reproducible blood-time profiles than Sporanox capsules. Food had a marked effect on itraconazole absorption from the Sporanox capsule, whereas the influence was less pronounced for the ITRA-GSMP capsule. Collectively, our data suggest that a new self-microemulsifying formulation may provide an alternative oral formulation for itraconazole with improved oral bioavailability and reduced food-effect.     

Design,formulation and evaluation of Azithromycin binary solid dispersions using Kolliphor series for the solubility and in vitro dissolution rate enhancement

The main purpose of this investigation is increasing of the solubility and dissolution rate of Azithromycin by solid dispersion technique using Kolliphor P 237, Kolliphor P 338 and Kolliphor P 407. Kolliphor (P 237, P 338 and P 407) in various properties by weight {(1:0.5), (1:1), (1:1.5) and (1:2)}, utilizing solvent evaporation method. Dissolution studies carried out in phosphate buffer with pH 6.0 according to US pharmacopoeia method. The drug release profiles were studied, so we found that the dissolution rate of the drug (by calculating the dissolution parameters) was significantly increase compared to pure drug, also solubility of physical mixtures as well as solid dispersions increased compared to the intact drug. For example solubility of the drug increased from 85–753 μg mL^?1 (for Kolliphor P 237; 8 times more). The best results were as follows: Kolliphor P 237 > Kolliphor P 338 > Kolliphor P 407. IR spectra revealed no chemical incompatibility between drug and polymer. Drug-polymer interactions were investigated using differential scanning calorimetry, powder X-ray diffraction and scanning election microscopy. The dissolution rate and solubility of Azithromycin solid dispersions was improved significantly using Kolliphor. In addition, the simplicity of this method is very effective and have been met the project objectives.     

Effect of particle dissolution rate on ocular drug bioavailability

Aqueous ophthalmic drug solutions typically exhibit low bioavailability due to various loss processes such as drainage, tear turnover, nonproductive absorption, and protein binding. Suspensions may improve bioavailability, but because of a short residence time and a low corneal permeability rate constant, the dissolution rate of the drug and its intrinsic solubility must be considered. The relationship between the various parameters affecting the relative dissolution rate have not heretofore been examined with respect to the eye. In the present study, a kinetic model that predicts ocular tissue drug levels for suspensions has been developed and tested using a steroid, fluorometholone, as the test drug suspension. The proposed model is able to predict the effects of particle size, concentration, and changes in drainage rate such that a reasonable a priori prediction of drug levels can be made.     

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.     

Enhanced solubility and dissolution rate of itraconazole by a solid dispersion technique.

The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, itraconazole, by a solid dispersion technique. Solid dispersion particles of itraconazole were prepared with various pH-independent and -dependent hydrophilic polymers and were characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. Of the polymers tested, pH-dependent hydrophilic polymers, AEA and Eudragit E 100, resulted in highest increases in drug solubility (range, 141.4-146.9-fold increases). The shape of the solid dispersion particles was spherical, with their internal diameter ranging from 1-10 microm. The dissolution rate of itraconazole from the tablets prepared by spray drying (SD-T) was fast, with > 90% released within 5 min.SD-T prepared with AEA or Eudragit E 100 at a 1:1 drug hydrophilic polymer ratio (w/w) showed approximately 70-fold increases in the dissolution rate over a marketed product.     

Statistical method for evaluation of dissolution stability in the formulation development of solid dosage forms: tablets of amonafide

A statistical method for the evaluation of the dissolution stability results and for selecting the most stable formulation within a solid dosage form development is discussed. Three types of tablets of an antineoplastic drug, amonafide, stored at a relative humidities (RH), 45% and 75%, were used. The drug release from tablets was tested before and after storage. The experimental data were statistically fitted to empirical model equations. Furthermore, the best mathematical fit was the statistical comparison of the residuals. From the selected model equation, time-dependent dissolution (Q45 and DE45) and dissolved quantity-dependent parameters (t70, t100 and MDT) were calculated. A useful parameter to present and evaluate the results obtained in comparative stability studies was defined: the Modification Factor (MF). It allowed the selection of the most stable formulation in the easiest and fastest way: the most stable formulation should present the smallest modification of the studied characteristics, in other words, the smallest MF value. In this way, tablets II (manufactured by wet granulation and with Emcompress as main excipient) showed the greater dissolution stability of the three types of tablets studied. Amonafide tablets must be packaged in impermeable containers, since the environmental relative humidity strongly modifies their dissolution characteristics.     

Comparison of surface modification and solid dispersion techniques for drug dissolution

Surface modification and solid dispersion formulations using hydrophilic excipients can significantly alter the dissolution behaviour of hydrophobic drug materials. The effect of these techniques used individually and in combination on the dissolution properties of the hydrophobic drug, phenylbutazone (PB), are compared. PB was treated with a poloxamer, Synperonic((R)) F127 by an adsorption method. Solid dispersions (10 and 20% w/w) were prepared with untreated PB or PB previously modified with Synperonic((R)) F127 (PBT) in molten F127. Dissolution tests of capsule formulations of PB, PBT and solid dispersion formulations, in pH 6.4 buffer at 37+/-0.5 degrees C demonstrated that after 140 min, release of PB was 16.7%, but 71.4% from the solid dispersion, whereas from the PBT formulation 85.6% was released. The Synperonic((R)) F127 content of PBT was only 0.05% of that in the solid dispersion formulation which suggests that it is the nature of the drug polymer contact rather than the amount of polymer which is more critical in influencing dissolution behaviour. Comparison of PBT and the 10% w/w solid dispersion of PBT in F127 showed similar amounts of drug in solution after 140 min. However there was a significantly higher release rate for PBT. Both formulation techniques offer significant improvements in drug release over untreated PB, and a combination of techniques changes the rate but not the extent of release in comparison with the surface modification technique alone.