Influence of polyvinylpyrrolidone quantity on the solubility,crystallinity and oral bioavailability of fenofibrate in solvent-evaporated microspheres

The objective of this study is to explore the influence of polyvinylpyrrolidone (PVP) quantity on the solubility, crystallinity and oral bioavailability of poorly water-soluble fenofibrate in solvent-evaporated microspheres. Numerous microspheres were prepared with fenofibrate, sodium lauryl sulphate (SLS) and PVP using the spray-drying technique. Their aqueous solubility, dissolution, physicochemical properties and pharmacokinetics in rats were assessed. The drug in the solvent-evaporated microspheres composed of fenofibrate, PVP and SLS at the weight ratio of 1:0.5:0.25 was not entirely changed to the amorphous form and partially in the microcrystalline state. However, the microspheres at the weight ratio of 1:4:0.25 provided the entire conversion to the amorphous form. The latter microspheres, with an improvement of about 115 000-fold in aqueous solubility and 5.6-fold improvement in oral bioavailability compared with the drug powder, gave higher aqueous solubility and oral bioavailability compared with the former. Thus, PVP quantity played an important role in these properties of fenofibrate in the solvent-evaporated microspheres.     

口服药物生物利用度预测研究进展

1997年“Lipinski 5原则”的提出标志着基于化合物结构的体内性质分析数学模型被成功引入药物设计的早期阶段”。通过虚拟筛选，可以缩短新药开发周期，有效降低开发成本。因此，药物体内性质的预测研究，即absorption—distribution—metabolism—excretion in silico（ADME in silico），在短期内得到了快速发展。ADME in silico研究内容主要包含脂水分配系数、水溶性、小肠吸收、血脑屏障穿透、生物利用度、药物相互作用、主动扩散和外源性物质代谢等方面。而其中脂水分配系数、水溶性、小肠吸收和代谢是生物利用度预测研究的重要组成部分。     

Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs

Importance of the field: Microemulsions have been studied extensively as potential drug delivery vehicles for poorly water-soluble drugs. An understanding of the physicochemical and biopharmaceutical characteristics of the microemulsions according to administration routes will provide guidance for designing the formulations of microemulsions.

Areas covered in this review: In this paper, the use and the characteristics of microemulsions as drug delivery vehicles are reviewed. As the formulations of the microemulsion always include a great amount of surfactant and co-surfactant, which may cause hemolysis or histopathological alterations of the tissue, the potential toxicity or the irritancy of microemulsions is also discussed in this paper.

What the reader will gain: Developments of microemulsions for poorly water-soluble drugs in recent years are included in this review. Several factors limiting the commercial or clinical use of microemulsions are also discussed.

Take home message: Considering the potential in enhanced drug uptake/permeation and facing the limitations, their unique properties make microemulsions a promising vehicle for poorly water-soluble drugs.     

Novel piroxicam-loaded nanospheres generated by the electrospraying technique: physicochemical characterisation and oral bioavailability evaluation

To determine if a novel electrospraying technique could be applied to an oral drug delivery system for improving the solubility and oral bioavailability of poorly water-soluble piroxicam; the nanospheres were generated with drug and polyvinylpyrrolidone (PVP) using electrospraying technique; and their physicochemical properties, solubility, release and pharmacokinetics were evaluated in comparison with piroxicam powder. All nanospheres had significantly increased drug solubility and dissolution rates in comparison with the drug powder. In particular, the nanosphere composed of piroxicam and PVP at a weight ratio of 2:8 gave about 600-fold higher solubility, 15-fold higher release rate and 3-fold higher AUC in comparison to piroxicam powder, leading to significantly enhanced oral bioavailability in rats, due to the mingled effect of nanonisation along with transformation to the amorphous state. Thus, this electrospraying technique can be utilised to produce a novel oral nanosphere delivery system with enhanced solubility and oral bioavailability for poorly water-soluble piroxicam.     

Effects of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone

Entacapone is a new catechol‐O‐methyltransferase (COMT) inhibitor used clinically in a triple combination therapy for Parkinson's disease (PD). The bioavailability of entacapone after oral administration is low and subject to large interindividual variation. The purpose of this study was to evaluate aqueous solubility/dissolution profiles of entacapone in vitro, and to evaluate their role in the poor oral bioavailability of entacapone in rats. The effect of the novel pharmaceutical excipient hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) on the aqueous solubility and dissolution of entacapone, and on entacapone bioavailability in rats, was also studied. The aqueous solubility of entacapone determined in this study is below 80 μg/ml at pH ≤5.0 and increases with increased pH. Due to its poor aqueous solubility, the dissolution of entacapone in an acidic environment is very slow. Complexation of entacapone with HP‐β‐CD (10% [w/v]) increases the aqueous solubility of entacapone 12‐fold and 85‐fold at pH 3.0 and at pH 5.0, respectively, and improves its bioavailability at the former pH about 2‐fold, compared to an entacapone suspension at that pH. The administration of entacapone as a pH 7.4 solution further increases the absolute bioavailability of entacapone, which is 1.8 and 3.3 times higher compared to the inclusion complex or suspension, respectively. In conclusion, it is possible to increase entacapone's bioavailability by improving its solubility and dissolution properties. However, the solubility and dissolution properties of entacapone do not fully explain its erratic bioavailability. Drug Dev. Res. 49:238–244, 2000. © 2000 Wiley‐Liss, Inc.     

Selecting oral bioavailability enhancing formulations during drug discovery and development

Introduction: The role of chemical structure, lipophilicity, physico-chemical, absorption, distribution, metabolism, excretion, toxicity (ADMET) and biopharmaceutical properties of compounds including bioavailability are critical in drug discovery and drug dosage forms design.

Areas covered: The authors discuss a number of parameters including computational approaches used for selected chemical structures with biological activity for lead optimization and chemogenomics and preclinical studies for ADMET process development of ligand properties. The authors also look at a number of other parameters including: early drug product formulations with method selection based on the biopharmaceutical classification system (BCS); in vitro–in vivo correlation (IVIVC) and different formulation strategies to enhance solubility; dissolution rate and permeability; bioavailability evaluation and quality by design as an opportunity to develop ‘safe space' regions, where bioavailability is unaffected by pharmaceutical variations.

Expert opinion: The biopharmaceutical requirements for absorption are solubility and permeability. Both are influenced by lipophilicity, but in the opposite way. The genomic methodology, coupled with combinatorial chemistry, high-throughput screening, structure-based design and in silico ADMET would yield parameters as a starting point for the biopharmaceutical properties determination in further preclinical and clinical studies. Consecutive stages in drug discovery and development are irreplaceable, but pharmacokinetics is the critical step. Selection of drug formulations based on the BCS, IVIVC are the principal aspects to enhance the solubility and dissolution rate, while a rationale management of pharmaceutical and technological factors will enhance the bioavailability.     

Strategies to improve oral drug bioavailability

Efforts to improve oral drug bioavailability have grown in parallel with the pharmaceutical industry. As the number and chemical diversity of drugs has increased, new strategies have been required to develop orally active therapeutics. The past two decades have been characterised by an increased understanding of the causes of low bioavailability and a great deal of innovation in oral drug delivery technologies, marked by an unprecedented growth of the drug delivery industry. The advent of biotechnology and consequent proliferation of biopharmaceuticals have brought new challenges to the drug delivery field. In spite of the difficulties associated with developing oral forms of this type of therapeutics, significant progress has been made in the past few years, with some oral proteins, peptides and other macromolecules currently advancing through clinical trials. This article reviews the approaches that have been successfully applied to improve oral drug bioavailability, primarily, prodrug strategies, lead optimisation through medicinal chemistry and formulation design. Specific strategies to improve the oral bioavailability of biopharmaceuticals are also discussed.     

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-β-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy

Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 μg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8–12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving ¹H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-β-cyclodextrin (G₂-β-CD-Frax). Notably, G₂-β-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G₂-β-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G₂-β-CD-Frax (5 mg/kg) efficiently inhibited CCl₄-induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.     

阿苯达唑-盐酸盐的制备、表征及口服生物利用度的评价

目的 制备阿苯达唑（ABZ）-盐酸（HCl）盐（ABZ-HCl）,并对盐的固态性质、体外溶出行为、稳定性和生物利用度进行评价。方法 溶剂蒸发法制备结晶的ABZ-HCl,使用核磁共振氢谱（¹H-NMR）对制备的ABZ-HCl进行验证,通过粉末X射线衍射（PXRD）、动态水吸附（DVS）、热重分析（TGA）和差示扫描量热法（DSC）进行固态性质的表征;对药物盐进行表观溶解度和固有溶出速率（IDR）的测定以观察其在不同pH条件下溶解度和溶出速率;进行了ABZ-HCl在强光照射（4 500±500 lx）、高湿（92.5%±5% RH）和高温条件（50±2）℃,以及加速试验条件（40℃、75%±5% RH）的稳定性研究;评价ABZ、ABZ-HCl （25 mg·kg^-1）在大鼠体内的药动学行为差异。结果 通过¹H-NMR证实了ABZ-HCl的形成;ABZ和ABZ-HCl的PXRD图谱出现显著差异;DVS实验结果表明,ABZ原药的吸水性差,在90%相对湿度（RH）时吸水量仅为3.86%,且吸附与解吸附曲线基本重合,而ABZ-HCl在开始的0~20% RH范围内迅速吸收水分,随后质量缓慢增加,在RH达到90%时吸水量为37.65%,在解吸过程中,ABZ-HCl的吸附曲线和解吸曲线不一致,存在滞后现象;TGA和DSC实验结果表明,2种物质均无吸附水,ABZ-HCl较ABZ熔点降低;体外溶出实验结果显示ABZ-HCl的表观溶解度和IDR分别为ABZ的11.8、10.3倍;ABZ-HCl表现出良好的物理稳定性。体内药动学结果显示,与ig ABZ原料相比,ABZ-HCl的AUC_{0~24 h}和C_max均显著提高,分别提高了8.8和6.9倍。结论 所制备的ABZ-HCl可改善ABZ的溶解性能和口服生物利用度,且具有良好的物理稳定性。     

Development of cyclosporin A-loaded hyaluronic microsphere with enhanced oral bioavailability

To develop a hyaluronic microsphere with the improved oral bioavailability of poorly water-soluble cyclosporin A (CsA), the microspheres were prepared with varying ratios of sodium hyaluronate (HA)/sodium lauryl sulfate (SLS)/CsA using a spray-drying technique. The effects of HA and SLS on the dissolution and solubility of CsA in microspheres were investigated. The CsA-microsphere prepared with HA/SLS/CsA at the ratio of 4/2/1 gave the highest solubility and dissolution rate of CsA among those formulae tested. As solubility and dissolution rate of CsA were increased about 17- and 2-fold compared to CsA powder, respectively, this CsA-microsphere was selected as an optimal formula for oral delivery in rats. The CsA-microsphere and Sandimmun neoral sol gave significantly higher blood levels compared with CsA powder alone. Moreover, the AUC, T(max) and C(max) values of CsA in CsA-microsphere were not significantly different from those in Sandimmun neoral sol in rats, indicating that CsA-microsphere was bioequivalent to the commercial product in rats. Our results demonstrated that the CsA-microsphere prepared with HA and SLS, with improved bioavailability of CsA, might have been useful to deliver a poorly water-soluble CsA.     

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, C_max, and lower T_max than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.     

Highly water-soluble mast cell stabiliser-encapsulated solid lipid nanoparticles with enhanced oral bioavailability

Cromolyn sodium (CS), a mast cell stabiliser, is widely employed for the prevention and treatment of allergic conditions. However, high hydrophilicity and poor oral permeability hinder its oral clinical translation. Here, solid lipid nanoparticles (SLNs) have been developed for the purpose of oral bioavailability enhancement. The CS–SLNs were engineered by double emulsification method (W₁/O/W₂) and optimised by using Box–Behnken experimental design. The surface and solid-state characterisations revealed the presence of CS in an amorphous form without any interactions inside the spherical-shaped SLNs. The in-vitro release study showed an extended release up to 24?hr by diffusion controlled process. Ex-vivo and in-vivo intestinal permeation study showed ～2.96-fold increase in permeability of CS by presentation as SLNs (p?<?0.05). Further, in-vivo pharmacokinetic study exhibited ～2.86-fold enhancements in oral bioavailability of CS by encapsulating inside SLNs, which clearly indicate that SLNs can serve as the potential therapeutic carrier system for oral delivery of CS.     

基于甘草酸为载体的紫杉醇-甘草酸纳米胶束的构建和口服生物利用度的评价

目的：构建紫杉醇-甘草酸纳米胶束（paclitaxel-loaded glycyrrhizic acid micelles）并对其理化性质及口服生物利用度进行考察。方法：所制备纳米胶束的包封率和载药量通过高效液相色谱法检测并计算;采用动态光散射仪测定其粒径分布;以紫杉醇溶液作为对照组,考察纳米胶束口服给药后药动学的变化;采用在体in-situ肠封闭法考察不同肠道对紫杉醇的吸收差异。结果：采用超声分散法制备载紫杉醇-甘草酸纳米胶束大小均匀,平均粒径为（245.42±5.62） nm;药物胶束的包封率为90.22%±0.27% （n=3）,载药量为7.90%±0.10%（n=3）;与对照组相比,纳米胶束口服生物利用度提高约6倍,很大程度上是由于紫杉醇在空肠以及结肠上吸收的增加引起。结论：该方法所制备的纳米胶束制剂能有效提高紫杉醇口服生物利用度,发挥甘草酸药物载体的特点以及药用安全性的优点,该纳米胶束可作为紫杉醇新的药物传递系统,具有临床应用前景。     

Solid lipid nanoparticles: an oral bioavailability enhancer vehicle

Introduction: The therapeutic efficacy of perorally administered drugs is often obscured by their poor oral bioavailability (BA) and low metabolic stability in the gastrointestinal tract (GIT). Solid lipid nanoparticles (SLNs) have emerged as potential BA enhancer vehicles for various Class II, III and IV drug molecules.

Area covered: This review examines the recent advancements in SLN technology, with regards to oral drug delivery. The discussion critically examines the effect of various key constituents on SLN absorption and their applications in oral drug delivery. The relationship between the complexity of absorption (and various factors involved during absorption, including particle size), stability and the self-emulsifying ability of the lipids used has been explored.

Expert opinion: The protective effect of SLNs, coupled with their sustained/controlled release properties, prevents drugs/macromolecules from premature degradation and improves their stability in the GIT. An extensive literature survey reveals that direct peroral administration of SLNs improves the BA of drugs by 2- to 25-fold. Overall, the ease of large-scale production, avoidance of organic solvents and improvement of oral BA make SLNs a potential BA enhancer vehicle for various Class II, III and IV drugs.     

乳腺康口服液相对生物利用度及生物等效性研究

目的:评价乳腺康口服液和注射液在家兔体内生物等效性。方法:采用紫外分光光度法测定血药浓度。结果:乳腺康口服液和注射液的Tmax分别为(3.8065±1.009)h和(1.0809±0.59)h,Cmax为(0.5333±0.03)和(0.5328±0.16)mg/ml,AUC为(3.1095±0.9)和(2.8938±0.14)mg/ml,t1/2为(3.1035±1.0143)和(2.8720±0.93)h,乳腺康口服液相对生物利用度为106.1%。结论:经统计学分析,乳腺康口服液和注射液具有生物等效性。     

Pharmaceutical particle technologies: An approach to improve drug solubility,dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.     

黄芩素自微乳的制备及大鼠体内生物利用度研究

目的:制备黄芩素自微乳化制剂(SMEDDS),考察其大鼠体内生物利用度。方法:采用伪三元相图法筛选自微乳的油相、表面活性剂及助表面活性剂;采用HPLC法测定大鼠血浆中药物浓度,与原料比较,对黄芩素自微乳进行大鼠体内生物利用度评价。结果:通过使用混合油相、混合表面活性剂及助表面活性剂,可获得较为理想的黄芩素自微乳。大鼠体内血药浓度-时间曲线结果表明,黄芩素自微乳的AUC是原料的3.77倍,且药时曲线的形状发生一定的改变。结论:自微乳系统可显著增加黄芩素的溶解度,有利于提高口服生物利用度,且自微乳可能改变其胃肠道吸收行为。     

Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin

Introduction: Curcumin is a safe, affordable and natural bioactive molecule of turmeric (Curcuma longa). It has gained considerable attention in recent years for its multiple pharmacological activities. However, its optimum pharmaceutical potential has been limited by its lack of aqueous solubility and poor bioavailability. To mitigate the above limitations, recently various nanostructured water-soluble delivery systems were developed to increase the solubility and bioavailability of curcumin.

Areas covered: Major reasons contributing to the low bioavailability of curcumin appear to be owing to its poor solubility, low absorption, rapid metabolism and rapid systemic elimination. The present review summarizes the strategies using curcumin in various nanocarrier delivery systems to overcome poor solubility and inconsistent bioavailability of curcumin and describes the current status and challenges for the future.

Expert opinion: The development of various drug delivery systems to deliver curcumin will certainly provide a step up towards augmenting the therapeutic activity of curcumin thereby increasing the solubility and bioavailability of curcumin. However, the future of such delivery technology will be highly dependent on the development of safe, non-toxic and non-immunogenic nanocarriers.