Effect of food intake on the oral absorption of poorly water-soluble drugs: in vitro assessment of drug dissolution and permeation assay system

The aim of the present work was to establish appropriate conditions for the dissolution/permeation system (D/P system) to estimate the effect of food intake on oral drug absorption. The D/P system is an in vitro assay system to evaluate the drug dissolution and permeation processes after oral administration. Caco-2 monolayer was used as a model membrane of the intestinal epithelium. In this study, two types of simulated intestinal fluid reflecting the fasted and the fed state conditions of the human gastrointestinal tract were used. Drugs were applied to the D/P system as a powder, then, permeated amounts of drugs into the basal side were monitored. A sigmoidal correlation was obtained between in vivo oral absorption (% absorbed of dose) and in vitro permeated amount (% of dose/2 h) under both states. From the D/P system, the estimated absorption of albendazole in both states was found to correspond well with in vivo observation. Moreover, the D/P system could estimate the effect of self-emulsifying formulation on the oral absorption of danazol, quantitatively. In conclusion, the D/P system was proved to be a useful assay system not only for the oral absorption of drugs, but also for the food effect on the absorption.     

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.     

Effect of particle size on the dissolution behaviors of poorly water-soluble drugs

This study examined the effects of the particle size of various poorly water-soluble drugs on their dissolution behavior through physicochemical and mathematical analysis. As model drugs, hydrochlorothiazide, aceclofenac, ibuprofen and a discovery candidate were selected. The materials were crystallized using an evaporation method and milled without transformation behavior of crystal forms. The particles were sieved and divided into four size groups (< 45 μm, 45～150 μm, 150～250 μm, and 250～600 μm). The specific surface area with regard to the particle size was measured using a BET surface area measurement. The specific surface area increased with decreasing particle size of the drug, resulting in an increase in dissolution rate. During the initial period of the dissolution study, significant differences in dissolution rate were observed according to the particle size and specific surface areas. On the other hand, in the later stages, the surface-specific dissolution rate was almost consistent regardless of the particle size. These observations were evaluated mathematically and the results suggested that the dissolution rate of poorly soluble drugs is strongly related to the particle size distribution. Moreover, physicochemical analysis helped explain the effect of particle size on the dissolution profiles.     

The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs

The effects of types of surfactants on the solubilization and dissolution of poorly soluble acidic drugs were compared to identify the most suitable surfactant for conducting an acidic drug dissolution test. Cetyltrimethylammonium bromide (CTAB) as a cationic surfactant, sodium lauryl sulfate (SLS) as an anionic surfactant, and polysorbate 80 as a non-ionic surfactant were used in the study. And, mefenamic acid, nimesulide, and ibuprofen were selected as model drugs. The dissolution rates of these acidic drugs were substantially enhanced in medium containing CTAB. Electrostatic interactions between acidic drugs and cationic surfactants were confirmed by measuring UV spectra of each drug. Solubility of drugs in various media and the partition coefficients of drugs into micelles were found to depend on drug characteristics. For acidic drugs, the ability of media containing a cationic surfactant to discriminate rates of dissolution of acidic drugs seemed to be greater than that of media containing other surfactant types.     

A compaction process to enhance dissolution of poorly water-soluble drugs using hydroxypropyl methylcellulose

The purpose of this study was to develop a technique to enhance the dissolution rate of poorly water-soluble drugs with hydroxypropyl methylcellulose (HPMC) without the use of solvent or heat addition. Three poorly water-soluble drugs, naproxen, nifedipine, and carbamazepine, were studied with low-viscosity HPMC USP Type 2208 (K3LV), HPMC USP Type 2910 (E3LV and E5LV), and methylcellulose. Polymer and drug were dry-blended, compressed into slugs on a tablet press or into ribbons on a roller compactor, and then milled into a granular powder. Dissolution testing of the milled powder was performed on USP Apparatus II, 100 rpm, 900 ml deionized water, 37 degrees C. Drug distribution vs. particle size was also studied. The compaction processes enhanced drug dissolution relative to drug alone and also relative to corresponding loosely mixed physical mixtures. The roller compaction and slugging methods produced comparable dissolution enhancement. The mechanism for dissolution enhancement is believed to be a microenvironment HPMC surfactant effect facilitated by keeping the HPMC and drug particles in close proximity during drug dissolution. The compaction methods in this study may provide a lower cost, quicker, readily scalable alternative for formulating poorly water-soluble drugs.     

An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs

We developed an in vitro system simulating the physiological condition in the gastrointestinal (GI) tract for prediction of oral absorption of relatively water-soluble drugs and ester prodrug pivampicillin. This evaluation system includes a drug-dissolving vessel (DDV, assumed stomach), a pH adjustment vessel (PAV, assumed intestine) and a side-by-side diffusion chamber that is mounted by a Caco-2 monolayer, which is grown on a polycarbonate filter, or by a rat intestine between the donor and receiver compartments. Our proposed system can accommodate large amounts of solid drugs, simulating a drastic pH change process in GI tract, that is, an orally administered solid drug is dissolved in the stomach (pH 1-2) and transferred to the intestine (pH 6), and that dissolution process can also be monitored. The optimal flow rates for our system are 0.35-1.10 ml/min. Using this system, cumulative permeations of eight relatively water-soluble drugs were compared, and these cumulative permeations indicated the ability of drug absorption in humans. Drugs that permeated across a Caco-2 monolayer at cumulative permeation of more than 0.03% or over 0.04% in rat intestine can be almost completely absorbed in humans. If the cumulative permeation across a Caco-2 monolayer is lower than 0.03% or below 0.04% in the rat intestine, there was a good linear correlation between cumulative permeation across a Caco-2 monolayer and oral absorption in humans, or between cumulative permeation across a rat intestine and oral absorption in humans. In the case of relatively water-soluble drugs, a good linear correlation was obtained between cumulative permeation across a Caco-2 monolayer and cumulative permeation across a rat intestine. This result indicates that it is possible to predict the oral absorption of a relatively water-soluble drug in humans based on the cumulative permeation of the drug across a Caco-2 monolayer and/or a rat intestine. The time course of permeation of the ester prodrug pivampicillin, which is metabolized in a Caco-2 monolayer or in a rat intestine, was also evaluated. It stated clearly that it is also possible to predict the oral absorption of pivampicillin in humans based on the cumulative permeation across a Caco-2 monolayer or rat intestine. Our newly developed system enables more kinds of oral preparations and also pH-dependent soluble drugs to be evaluated.     

IVIVC in oral absorption for fenofibrate immediate release tablets using a dissolution/permeation system

The usefulness of a dissolution/permeation (D/P) system to predict the in vivo performance of solid dosage forms containing the poorly soluble drug, fenofibrate, was studied. Biorelevant dissolution media simulating the fasted and fed state conditions of the human gastrointestinal tract were used in order to simulate the effect of food on the absorption of fenofibrate. Moreover, the results obtained from the D/P system were correlated with pharmacokinetic parameters obtained following in vivo studies in rats. The in vitro parameter (amount permeated in the D/P system) reflected well the in vivo performance in rats in terms of AUC and C(max) of fenofibric acid. This study thus demonstrates the potential of the D/P system as valuable tool for absorption screening of dosage forms for poorly soluble drugs.     

应用纳米技术增加难溶性药物吸收的研究进展

随着高通量筛选等新技术的出现,涌现出许多难溶性的候选药物。利用纳米技术能减小难溶性药物的粒径,增加其溶解度、溶出度和口服生物利用度,减少食物效应的影响。本文介绍了纳米粒的制备方法,商用的专利纳米技术以及应用纳米技术成功上市的药品。纳米技术对改善生物药剂学分类体系（BCS）Ⅱ类药物的吸收具有广阔的前景。     

Improvement of dissolution characteristics and bioavailability of poorly water-soluble drugs by novel cogrinding method using water-soluble polymer

A novel cogrinding method for improving dissolution characteristics of poorly water-soluble drugs was developed. A coground mixture of nifedipine (NP)-polyethylene glycol 6000-hydroxypropylmethyl cellulose system prepared in the presence of small amount of water showed remarkable effect with respect to NP dissolution and its apparent solubility. Although the performance of the coground mixture was superior to that of spray-dried powder with the same composition, the X-ray diffraction pattern indicated the mixture did not change to amorphous state. In addition, the transmission electron microscopy revealed that NP seemed to exist in coacervate-like fine particles (50–200 nm) in water. This cogrinding method was also effective for other poorly water-soluble drugs such as griseofluvin and indomethacin. Some drug–polymer interactions through hydroxypropoxyl groups seemed to participate in the mechanism of the improvement of dissolution characteristics, because the content of the functional group affected the extent of solubility-enhancing effect. Furthermore, the addition of small amount of water in cogrinding was especially effective, because it promoted the interactions. The coground mixture showed the same plasma concentration as NP solution of PEG 400 when it was orally administered to beagle dogs. From these results, it is clear that the present cogrinding method is very effective for improvement of bioavailability of poorly water-soluble drugs.     

Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs.     

Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system.

Poorly water-soluble drug candidates often emerge from contemporary drug discovery programs, and present formulators with considerable technical challenges. The absorption of such compounds when presented in the crystalline state to the gastrointestinal tract is typically dissolution rate-limited, and the drugs are typically BCS class II or class IV compounds. Class IV compounds, which have low membrane permeability as well as poor aqueous solubility, are often poor candidates for development, unless the dose is expected to be low. The rate and extent of absorption of class II compounds is highly dependent on the performance of the formulated product. These drugs can be successfully formulated for oral administration, but care needs to be taken with formulation design to ensure consistent bioavailability. Essentially the options available involve either reduction of particle size (of crystalline drug) or formulation of the drug in solution, as an amorphous system or lipid formulation. The performance of amorphous or lipid formulations is dependent on their interaction with the contents of the gastrointestinal tract, therefore, a formulation exercise should involve the use of techniques which can predict the influence of gut physiology. A major consideration is the fate of metastable supersaturated solutions of drug, which are formed typically after dispersion of the formulation and its exposure to gastrointestinal digestion. A better understanding of the factors which affect drug crystallization is required, and the introduction of standardised predictive in vitro tests would be valuable. Although many bioavailability studies have been performed with poorly water-soluble drugs, thus far this research field has lacked a systematic approach. The use of a lipid formulation classification system combined with appropriate in vitro tests will help to establish a database for in vitro-in vivo correlation studies.     

Using a novel multicompartment dissolution system to predict the effect of gastric pH on the oral absorption of weak bases with poor intrinsic solubility

A novel multicompartment dissolution system was developed by modifying a conventional six-vessel United States Pharmacopoeia dissolution system to study the dissolution and possible precipitation of poorly soluble weak bases after oral administration. The modified system includes a "gastric" compartment, an "intestinal" compartment, an "absorption" compartment, and a reservoir to simulate the dissolution and absorption in the gastrointestinal tract. Dissolution profiles of 50-mg dipyridamole (pK(a) 6.0, 12.5) tablet (2 * 25 mg Persantine tablets), 25- and 50-mg cinnarizine (pK(a) 1.95, 7.5) powders, which are poorly soluble weak bases, were generated in the system using dissolution medium with different pHs in the "gastric" compartment. The in vitro dissolution results were compared with the in vivo oral exposure data in humans. For both dipyridamole and cinnarizine, the in vitro dissolution using the multicompartment system was able to predict the pH effect on oral exposure. The results from the multicompartment system are more closely correlated with the in vivo data, compared with that from the conventional dissolution test. The system showed that although both dipyridamole and cinnarizine completely dissolved in the gastric compartment at lower pH, approximately 36% (at 25-mg dose) and 40% (at 50-mg dose) of cinnarizine precipitated in the "intestinal" compartment whereas the precipitation of dipyridamole was <10% of the initial dose. The difference in the amount "absorbed" between these two compounds in vitro is therefore primarily attributed to the precipitation potential, although no in vivo data are available to confirm this result. The difference in the amount precipitated may be explained by the lower solubility and consequently higher degree of supersaturation of cinnarizine in the "intestinal" compartment.     

Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility

The inclusion of certain polymers within solid dispersion or lipid-based formulations can maintain drug supersaturation after dispersion and/or digestion of the vehicle, leading to improvements in bioavailability and variability in exposure. This review presents an overview of the fundamental principles that underpin drug precipitation mechanisms, describes the mechanisms by which precipitation may be inhibited, discusses the methods that can be used to identify polymeric precipitation inhibitors (PPIs), and summarizes current literature evidence of the most effective PPIs. Preliminary data from our laboratory is also presented, which describes the precipitation inhibition behavior of 53 polymeric materials using supersaturated solutions of danazol as a model, poorly water-soluble drug. These studies identify a group of PPIs with superior precipitation inhibition qualities, the majority of which are cellulose-based. These new results in combination with previous published data indicate that PPIs represent an appealing new technology with the potential to improve drug absorption for poorly water-soluble drugs. The molecular determinants of polymer utility, however, remain relatively poorly understood, although the cellulose derivates appear, in general, to provide the most benefit. More detailed studies are therefore required to define the parameters that most effectively predict and quantify the drug–polymer relationships that control precipitation inhibition.     

Estimation of P-glycoprotein-mediated efflux in the oral absorption of P-gp substrate drugs from simultaneous analysis of drug dissolution and permeation

The purpose of this study was to establish an in vitro system that evaluates the effects of P-glycoprotein (P-gp)-mediated efflux on the oral absorption of P-gp substrates. An in vitro system (dissolution/permeation system, D/P system) was developed that consisted of apical and basal chambers and a Caco-2 cell monolayer mounted between the chambers. Both sides of the monolayer were filled with physiological solution and were stirred at 200rpm. The dissolution in the apical medium and permeation to the basal medium were monitored for 2h after P-gp substrates were applied to the apical side of the system. When erythromycin existed in the apical medium, the permeations of fexofenadine and talinolol were significantly enhanced without change in their dissolution. The prediction of oral absorptions of fexofenadine and talinolol from in vitro data indicated that co-administration of erythromycin results in 2.1- and 1.9-fold higher oral absorptions, respectively. Moreover, the D/P system could estimate the effect of cremophor EL on the oral absorption of saquinavir. These estimations corresponded well to in vivo human observations. Our in vitro system is useful in assessment of the effect of P-gp-mediated efflux on in vivo oral absorption of P-gp substrates.     

Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam

The rate of dissolution of drugs remains one of the most challenging aspects in formulation development of poorly water-soluble drugs. The meloxicam, a low molecular analgetic for oral administration, exhibits a slow dissolution. To improve the dissolution rate, the drug was formulated in a nanosuspension by using an emulsion–diffusion method, high-pressure homogenization or sonication. Optimization of the technological parameters (organic solvents, stabilizers, homogenization procedure and recovery of particles) allowed the formation of nanosuspensions with a particle size of 200–900 nm. SEM imaging confirmed the nanosized drug particles. Use of an SMCR method on the XRPD patterns of the nanosuspensions revealed the crystalline form of the drug and the strong interaction between meloxicam and the stabilizer. The rate of dissolution of the dried meloxicam nanosuspension was enhanced (90% in 5 min), relative to that of raw meloxicam (15% in 5 min), mainly due to the formation of nanosized particles. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate, and thus possibly enhance fast onset of therapeutic drug effect.     

Impact of FaSSIF on the solubility and dissolution-/permeation rate of a poorly water-soluble compound

The poorly water-soluble drug ABT-102, a potent TRPV1 (transient receptor potential cation channel subfamily V member 1) antagonist, was investigated in terms of its solubility and dissolution-permeation rate across Caco-2 cell monolayers in the presence and absence of fasted state simulated intestinal fluid (FaSSIF). ABT-102 showed a more than 30-fold higher apparent solubility in FaSSIF, compared to Hank's balanced salt solution (HBSS). On the other hand, the amount of truly dissolved API in the suspension, as assessed by inverse dialysis, was found hardly influenced by FaSSIF. Neither the drug nor FaSSIF adversely affected cell viability or integrity of the Caco-2 monolayer. P-gp-inhibition experiments confirmed that the drug was not a substrate of the export pump. The flux of ABT-102 across the Caco-2 barrier was found virtually the same in FaSSIF and in buffer, i.e. in vitro overall dissolution-/permeation rate of ABT-102 from suspensions appears not affected by its enhanced apparent solubility due to association with TC/PC-micelles.     

Mesoporous silica nanoparticles for increasing the oral bioavailability and permeation of poorly water soluble drugs

We investigate the effects of spherical mesoporous silica nanoparticles (MSNs) as an oral drug delivery system to improve the oral bioavailability of the model drug telmisartan (TEL) and examine their cellular uptake and cytotoxicity. Further, we explore the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by MSNs. An investigation of intestinal epithelial cellular binding, association and uptake was carried out by laser scanning confocal microscopy, transmission electron microscopy and fluorescence activated cell sorting. The results show that the cellular uptake is highly time-, concentration- and size-dependent. The model drug permeability studies in the human colon carcinoma (Caco-2) cell lines indicated that MSNs could significantly enhance TEL permeability and reduce rate of drug efflux. After loading TEL into MSNs, its oral bioavailability was compared with that of the marketed product Micardis and TEL-loaded ordered mesoporous silica microparticles (MSMs) in beagle dogs. The relative bioavailability of TEL-loaded MSN formulation and TEL-loaded MSM formulation was 154.4 ± 28.4% and 129.1 ± 15.6%, respectively. MSNs offer the potential to achieve enhanced oral bioavailability of poorly soluble drugs via improved drug dissolution rate and enhanced drug permeability.     

不同载体材料改善难溶性药物乙烷硒啉溶出性能的实验研究

目的:改善水不溶性药物乙烷硒啉的溶出性能,以提高乙烷硒啉固体制剂的药物溶出度.方法:以聚维酮(polyvinylpyrrolidone,简称PVP)、枸橼酸、酒石酸、羟丙基-β-环糊精(hydroxylpropyl-β-cyclodextrin,简称HP-β-CD)等辅料为载体材料,以溶剂溶解与分散法制备乙烷硒啉固体颗粒及其物理混合物,并进行体外溶出度试验.利用差示扫描量热法(Differential Scanning Calorimetry,简称DSC)和X-射线衍射法来验证药物的存在状态.结果:以PVP为载体材料所制固体颗粒的体外溶出行为显著优于其他载体材料,且载体材料的比例越大,药物溶出越快.结论:DSC和X-射线衍射图实验证明,PVP载体材料改变了乙烷硒啉的存在状态与亲水性,溶出性能得到显著改善.