Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles

The slow dissolution rate exhibited by poorly water-soluble drugs is a major challenge in the drug development process. Following oral administration, drugs with slow dissolution rates generally show erratic and incomplete absorption which may lead to therapeutic failure. The aim of this study was to improve the dissolution rate and subsequently the oral absorption and bioavailability of a model poorly water-soluble drug. Microparticles containing the model drug (griseofulvin) were produced by spray drying the drug in the absence/presence of a hydrophilic surfactant. Poloxamer 407 was chosen as the hydrophilic surfactant to improve the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried griseofulvin/Poloxamer 407 particles were significantly increased compared to the control. Although spray drying griseofulvin alone increased the drug's in vitro dissolution rate, no significant improvement was seen in the absolute oral bioavailability when compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.     

Inhibition of Crystal Nucleation and Growth by Water-Soluble Polymers and its Impact on the Supersaturation Profiles of Amorphous Drugs

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2273–2281, 2013     

Dissolution kinetics of griseofulvin in sodium dodecylsulphate solutions

The rate-limiting step in the absorption of poorly water-soluble drugs is often the dissolution process of these compounds. Surface-active agents influence the dissolution process by wetting and solubilizing. In order to study the effect of solubilization, a rotating-disk apparatus was used with griseofulvin as a model drug substance and sodium dodecylsulphate (SDS) as a model surfactant. The dissolution kinetics of griseofulvin in SDS solutions could adequately be described by the convective-diffusion model and the phase-separation model for micellar systems. The calculated micellar diffusion coefficient of SDS was in close agreement with values reported in the literature.     

Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system

This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22–55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69–85%) was slightly affected. Zafirlukast absorption (33–36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.     

In vitro dissolution/permeation system to predict the oral absorption of poorly water-soluble drugs: effect of food and dose strength on it

The aim of the present work was to confirm the usefulness of the dissolution/permeation system (D/P system) in the estimation of human oral absorption of poorly water-soluble drugs. The D/P system, which can simultaneously evaluate drug absorption processes, dissolution and permeation, can predict the oral absorption of poorly water-soluble drugs in fasted and fed humans, with a correlation between in vivo oral absorption (% of absorbed) and in vitro permeated amount (% of dose/2 h) in the D/P system. The oral absorption (fraction of absorbed dose, %) of poorly water-soluble drugs in the fasted and fed states was predicted using the D/P system. The effect of food on the oral absorption of various drugs estimated by the D/P system significantly correlated with clinical data (correlation coefficient: r(2)=0.924). Moreover, the proportion of oral absorption of cilostazol was predicted to decrease with an increase in its dose strength, which significantly correlated with in vivo human absorption. Consequently, the D/P system was demonstrated to be a useful in vitro system for prediction of the oral absorption of poorly water-soluble drugs.     

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications

The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs.     

Effect of the melt granulation technique on the dissolution characteristics of griseofulvin

This work describes a melt granulation technique to improve the dissolution characteristics of a poorly water-soluble drug, griseofulvin. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 degrees C and an impeller speed of approximately 20,000 rpm. The effect of drug loading (2.5/5%), binder (PEG 3350/Gelucire 44/14), filler (starch/lactose), and HPMC on the dissolution of griseofulvin was investigated using a half two level-four factor factorial design. The granules were characterized using powder XRD, DSC and SEM techniques. A significant enhancement in the in vitro dissolution profiles of the granules was observed compared to the pure drug and drug excipient physical mixtures. The factorial design results indicated that higher drug loading and the presence of HPMC reduced the extent of dissolution of the drug, whereas, the presence of starch enhanced the dissolution rate. XRD data confirmed crystalline drug in formulation matrices. DSC results indicated monotectic mixtures of griseofulvin with PEG in the granulated formulations. In conclusion, the results of this work suggest that melt granulation is a useful technique to enhance the dissolution rate of poorly water-soluble drugs, such as, griseofulvin.     

Fast-dissolving microparticles fail to show improved oral bioavailability

Oral dosage forms are the preferred means of delivering drugs for systemic absorption. However, development problems occur for drugs with poor water solubility and/or gastrointestinal permeability. It is generally believed that the in-vivo bioavailability of poorly water-soluble drugs from Class II of the Biopharmaceutics Classification System can be improved by increasing the dissolution rate. We have attempted to increase the in-vivo oral bioavailability of a model Class II drug (griseofulvin) by preparing rapidly-dissolving particles. The solvent-diffusion method was used to prepare particles with hydrophilic surfactants (Brij 76/Tween 80 surfactant blend) and in-vivo studies were conducted in rats. The griseofulvin particles produced were bipyramidal in habit with a particle size of 2.18 +/- 0.12 microm; they contained crystalline drug and a relatively large proportion (12% w/w) of hydrophilic surfactant. The latter and the small particle size ensured rapid particle dispersion and dissolution in-vitro. Thus, within 30 min of the in-vitro dissolution test, the bipyramidal particles had released approximately 70% of drug compared with approximately 10% from the starting material (particle size 12.61 +/- 1.11 microm). However, the rapid and increased drug dissolution in-vitro was not translated to rapid and enhanced absorption in-vivo, and the oral bioavailability of the model drug was found to be the same from the control and from the bipyramidal particles. The poor in-vivo performance of the bipyramidal particles showed that although the dissolution rate of a Class II drug is thought to be a good indicator of its in-vivo bioavailability, this is not always the case.     

Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

INTRODUCTION: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation. AREAS COVERED: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration. EXPERT OPINION: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk-benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.     

Dissolution rate enhancement by adsorption of poorly soluble drugs on hydrophilic silica aerogels

The aim of this work is to evaluate the feasibility of hydrophilic silica aerogels as drug carriers and to investigate the influence of the aerogels properties on the release rate of poorly water-soluble drugs. Hydrophilic silica aerogels of different densities were loaded with two model drugs, ketoprofen and griseofulvin, by adsorption from their solution in supercritical CO2. It is demonstrated that up to 30 wt% of ketoprofen and 5.4 wt% of griseofulvin can be deposited on hydrophilic aerogels through physical adsorption. The obtained drug-aerogel formulations were characterized by IR- and UV-spectroscopy, X-ray diffraction and scanning electron microscopy. Release kinetics of both drugs were studied in vitro. The release rate of ketoprofen from the drug-aerogel formulation is much faster than that of the corresponding crystalline drugs. The release rate of ketoprofen increases in 500% and that of griseofulvin in 450%, respectively. The reasons for the release enhancement are the enlarged specific surface area of drugs by adsorption on aerogels compared to their crystalline form and the immediate collapse of aerogel network in aqueous media. The dissolution rate of poorly water soluble drugs can be significantly enhanced by adsorption on highly porous hydrophilic silica aerogels.     

Griseofulvin---phenobarbital interaction: a formulation-dependent phenomenon

The reported interaction of griseofulvin with phenobarbital was studied in the rat following oral administration of different dosage forms. A single oral dose of 15 mg of phenobarbital/kg 24 hr prior to the oral administration of a suspension of 100 mg og griseofulvin/kg in 0.5% polysorbate 80 significantly reduced plasma griseofulvin levels. An increase in the concentration of polysorbate 80 to 2% reduced the extent of the interaction from 50 to 32%. Phenobarbital did not influence plasma griseofulvin levels when griseofulvin was given in either 70% polyethylene glycol 300 (suspensions of 20 or 100 mg/kg) or 100% polyethylene glycol 600 (solution of 50 mg/kg). It is concluded that the observed interaction is formulation dependent and is a result of diminished dissolution and, consequently, reduced absorption of griseofulvin.     

Liquisolid technology for dissolution rate enhancement or sustained release

Importance of the field: Most of the drugs that have been invented are of BCS Class II. Therefore, dissolution rate enhancement is the key aspect for absorption of these drugs. Liquisolid technology is very efficient in the dissolution rate enhancement of these drugs. Moreover, use of other polymers such as Eudragit and hydroxypropyl methylcellulose in the liquisolid approach can cause sustained release of drugs. This review focuses on the formulation approaches of liquisolid tablets or compacts along with its fundamental principles.

Areas covered in this review: The review focuses on the developments in liquisolid technology from 1998 to 2009 with in vitro and in vivo performance of the dosage forms prepared using this technology.

What the reader will gain: Benefits of this review include a concise evaluation of this technology by focusing on the scope of future developments to be done using this technique.

Take home message: Liquisolid technology, the next generation of powder solution technology, can be helpful for enhancing dissolution rates of poorly water-soluble drugs as well as effective at sustaining drug release.     

Dry elixir formulations of dexibuprofen for controlled release and enhanced oral bioavailability

The objective of this study was to achieve an optimal formulation of dexibuprofen dry elixir (DDE) for the improvement of dissolution rate and bioavailability. To control the release rate of dexibuprofen, Eudragit(?) RS was employed on the surface of DDE resulting in coated dexibuprofen dry elixir (CDDE). Physicochemical properties of DDE and CDDE such as particle size, SEM, DSC, and contents of dexibuprofen and ethanol were characterized. Pharmacokinetic parameters of dexibuprofen were evaluated in the rats after oral administration. The DDE and CDDE were spherical particles of 12 and 19 μm, respectively. The dexibuprofen and ethanol contents in the DDE were dependent on the amount of dextrin and maintained for 90 days. The dissolution rate and bioavailability of dexibuprofen loaded in dry elixir were increased compared with those of dexibuprofen powder. Moreover, coating DDE with Eudragit(?) RS retarded the dissolution rate of dexibuprofen from DDE without reducing the bioavailability. Our results suggest that CDDE may be potential oral dosage forms to control the release and to improve the bioavailability of poorly water-soluble dexibuprofen.     

Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

Introduction: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation.

Areas covered: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration.

Expert opinion: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk–benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.     

Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations

Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.KEY WORDS: amorphous formulation, kinetic solubility, nonsink dissolution testing, poorly water-soluble drug, supersaturation rate     

Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: a case study

Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 μg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 μg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced oral bioavailability of the tested compound could be attributed to generation and prolongation of a supersaturated drug concentration in vivo by the solubilizing agents and precipitation inhibitors. The study demonstrates that the combination approach of solubilization agents and precipitation inhibitors provides improved oral bioavailability for a poorly water-soluble weakly basic compound.     

纳米晶体技术在水难溶性药物口服制剂中应用的研究进展

目的综述水难溶性药物纳米晶体的制备方法,稳定剂在纳米晶体形成过程中的主要应用原理及产品物理性质的表征,为改善水难溶性药物溶解度或口服生物利用度提供理论依据。方法查阅国内外相关文献27篇,回顾纳米晶体技术的发展历程,提供药物纳米晶体技术的最新研究进展。结果药物纳米晶体不仅制备工艺简单,性质考察方便;还能够提高难溶性药物在胃肠道中的溶解度,改善难溶性药物的口服生物利用度。结论药物纳米晶体技术具有实际生产意义和广阔的应用前景。     

Controlled-release of diclofenac sodium from wax matrix granule

A twin-screw compounding extruder was used to prepare wax matrix granules (WMG) consisting of carnauba wax, diclofenac sodium (DS) as a model drug, and rate-controlling agents such as hydroxypropylcellulose (HPC-SL), methacylic acid copolymer L (Eudragit L-100), and sodium chloride (NaCl). In this preparation, a wax matrix with high mechanical strength was obtained even at temperatures lower than the wax melting point. Dissolution behaviors of DS from WMG were strongly influenced by granule formulation, in which an increase in the content of HPC-SL or Eudragit L-100 brought a significant increase in the dissolution rate. The extent of this enhancing effect in HPC-SL was identical in two different dissolution mediums (pH 6.8 buffer solution and water), but in Eudragit L-100 was more significant in pH 6.8 buffer solution than in water. Only a small increase in the dissolution rate was observed in NaCl-containing WMG. These different behaviors were attributed to the physicochemical properties (i.e. swelling and solubility) of the rate-controlling agent in the dissolution medium. Further, mechanical strengths of the wetted WMG after dissolution studies were > 70 g/mm² suggesting that burst release of DS in the gastrointestinal tract would be avoided.     

Effect of chitosan on gastrointestinal absorption of water-insoluble drugs following oral administration in rats

Chitosan is widely used as a dietary weight-loss supplement in Japan. In the present study, we examined the effect of chitosan on the gastrointestinal absorption profiles of the water-insoluble drugs, indomethacin and griseofulvin, and the water-soluble drugs, acetaminophen and cephalexin, after oral administration in rats. Rats received oral administration of chitosan (5 mg/kg or 25 mg/kg) dissolved in 5% acetic acid or vehicle 15 min before oral administration of each drug. Chitosan at a dose of 25 mg/kg, but not 5 mg/kg, significantly decreased the plasma concentrations of indomethacin and griseofulvin after administration as a suspension with a significant delay of the time to reach maximum concentration compared to the corresponding control values (vehicle-pretreated rats). However, pretreatment of chitosan (25 mg/kg) did not change the pharmacokinetics of indomethacin administered as a solution. Further, the same dose of chitosan had no effect on the pharmacokinetics of acetaminophen. The gastrointestinal absorption profile of an amino-beta-lactam antibiotic, cephalexin, which is actively absorbed via carrier-mediated transport system, was also unchanged. The present findings at least suggest the possibility that chitosan at high dose reduces the gastrointestinal absorption of water-insoluble drugs such as indomethacin and griseofulvin, but not water-soluble drugs, by diminishing the surfactant-like effect of bile acids.     

Formulation and pharmacokinetic evaluation of once-daily sustained-released system of nifedipine with solid dispersion and coating techniques

A novel sustained-release system was developed for poorly water-soluble drugs by applying solid dispersion (SD) technique to improve the solubility. The SD systems composed of polyvinyl pyrrolidone and stearic acid could not control the release of nifedipine. When the above SD granules were coated with ethylcellolulose (EC10, 45 and 100cp), the dissolution rate extended from 16 to 20 h. When the concentration of EC100cp was increased to 4–6 %, the sustained-release formulation F7 and F8 prepared with 4 % EC100cp and 6 % EC100cp, respectively, could control the drug release in a better manner, namely, they could control drug release in the initial hours with a high cumulative amount of drug at 24 h. The mechanism of drug release from F7 and F8 was diffusion coupled with erosion. When immediate-release capsules was orally administered to rabbits, its absorption was very rapid with a short elimination half-life, while a prolonged maintenance of the plasma drug level up to 24 h was obtained for F7 and F8. Furthermore, the oral bioavailability of F7 and F8 was significantly improved. The results suggested that this novel sustained-release system would be a promising system to improve the solubility and sustain the absorption of poorly water-soluble drugs.