An update on polymer-lipid hybrid systems for improving oral drug delivery

Introduction: A promising approach that has recently emerged to overcome the complex biobarriers and interrelated challenges associated with oral drug absorption is to combine the benefits of polymeric and lipid-based nanocarriers within one hybrid system. This multifaceted formulation strategy has given rise to a plethora of polymer-lipid hybrid (PLH) systems with varying nanostructures and biological activities, all of which have demonstrated the ability to improve the biopharmaceutical performance of a wide range of challenging therapeutics.

Areas covered: The multitude of polymers that can be combined with lipids to exert a synergistic effect for oral drug delivery have been identified, reviewed and critically evaluated. Specific focus is attributed to preclinical studies performed within the past 5 years that have elucidated the role and mechanism of the polymer phase in altering the oral absorption of encapsulated therapeutics.

Expert opinion: The potential of PLH systems has been clearly identified; however, improved understanding of the structure–activity relationship between PLH systems and oral absorption is fundamental for translating this promising delivery approach into a clinically relevant formulation. Advancing research within this field to identify optimal polymer, lipid combinations and engineering conditions for specific therapeutics are therefore encouraged.     

含功能性油的水飞蓟宾超饱和自纳米乳的制备与体外评价

目的制备含功能性油的水飞蓟宾超饱和自纳米乳(SLB-S-SNEDDS),并对其进行表征及体外评价研究,以提高难溶性药物水飞蓟宾的生物利用度。方法铁氢化钾还原力与1,1-二苯基-2-苦肼基(DPPH)自由基清除实验筛选功能性油脂;伪三元相图考察乳化剂乳化能力;测定粒径、多分散指数(PDI)、Zeta电位等考察混合油相比例与载药量;相容性与溶出度实验筛选促过饱和物质并考察其质量浓度;从外观、粒径分布、自乳化效率、形态学等方面表征SLB-S-SNEDDS,并进行溶出度、抗氧化能力、细胞毒性等体外评价。结果所得SLB-S-SNEDDS处方为(1)小麦胚芽油/Capryol 90-Cremophor ELP-Transcutol HP与(2)沙棘籽油/Capryol 90-Cremophor ELP-Transcutol HP,1 g基质(包含0.043 g小麦胚芽油或沙棘籽油、0.387 g Capryol 90、0.380 g Cremophor ELP、0.190 g Transcutol HP),水飞蓟宾的添加量为各组分平衡溶解度之和的20%,Soluplus的添加量为上述总质量的0.1%。小麦胚芽油、沙棘籽油体系分别为淡黄色、亮黄色透明状均一液体,2种体系自乳化分散后均呈近球形白色扁平乳滴,粒径约为50 nm,乳化时间均为65 s。与药物原料及SLB-SNEDDS相比,SLB-S-SNEDDS中水飞蓟宾的累积溶出率8h内均维持在85%～110%,表明该体系能够显著提高药物的溶出度。SLB-S-SNEDDS与铁氰化钾反应后的吸光度(A值0.452～0.782,0.488～0.765)以及DPPH自由基清除率(39.09%～96.02%,30.54%～89.20%)均高于相应质量浓度下水飞蓟宾原料的A值与清除率(0.411～0.760,22.89%～63.21%),表明2种处方体系均能提高水飞蓟宾的抗氧化能力。细胞毒性实验结果显示,在5、10μmol/L药物浓度下,水飞蓟宾原料组、水飞蓟宾S-SNEDDS组及其相应的空白S-SNEDDS组细胞生存率均90%,说明SLB-S-SNEDDS及其所用辅料对人克隆结肠腺癌细胞(Caco-2)毒性较小、安全性较好。结论制备的含功能性油SLB-S-SNEDDS在提高水飞蓟宾累积溶出率的同时,增强了其抗氧化能力,为将超饱和自纳米乳(S-SNEDDS)用于改善难溶性药物水溶性及其生物活性提供有益参考。     

Dose proportionality and pharmacokinetics of dronedarone following intravenous and oral administration to rat

1. The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats.

2. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1?mg/kg) and orally (5, 10 and 40?mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24?h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS.

3. The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUC_inf increased in a dose-proportional manner, whereas AUC_24h and C_max exhibited a lack of dose proportionality over the dose range between 5 and 40?mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay.

4. These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.

     

Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo

The purpose of this study was to develop and characterize levosulpiride loaded liquid suppository with improved bioavailability. The content of levosulpiride-loaded liquid suppositories were optimized in a series of experiments using various weight ratios of P188, P407, Tween 80, and drug. The suppositories were liquid at room temperature, however, when rectally administered, they became gel at body temperature. Their rheological properties and release characteristics were determined in vitro while pharmacokinetic study was performed after its rectal administration in rats and compared with drug suspension. Poloxamer 188 and Twee 80 decreased the gelation temperature and gelation time, but increased the gel strength and mucoadhesive force of liquid suppositories. Liquid suppository composed of [Levosulpiride/P 188/P 407/Tween 80 (1/15/17/3%)] with a gelation temperature of about 30.7?°C remained liquid at 25?°C, but converted to gel at 30–36.5?°C, resulting in easy administration and rapid gelation inside the body. This liquid suppository gave a considerably increased dissolution rate reflected in a meaningfully higher plasma concentration and 7.1-fold AUC values of levosulpiride in rats as compared to the drug suspension. Hence, liquid suppository system could be used for enhanced bioavailability of levosulpiride-loaded pharmaceutical products.     

The bioavailability of ingested 26Al-labelled aluminium and aluminium compounds in the rat

The fractional uptake of ingested aluminium and aluminium compounds (aluminium citrate, aluminium nitrate, aluminium chloride, aluminium sulphate, aluminium hydroxide, aluminium oxide, aluminium metal, powdered aluminium pot electrolyte, acidic sodium aluminium phosphate (SALP), basic sodium aluminium phosphate (Kasal), sodium aluminium silicate and FD&C red 40 aluminium lake) from the gastro-intestinal tract of adult female rats was measured. This was determined by comparing retained body burden of ²⁶Al at seven days post-admistration of an i.v. injection of ²⁶Al-labelled aluminium citrate with that retained following the gastric admistration of ²⁶Al-labelled test compounds as either solutions or suspended solid. The calculated percentage uptake of ²⁶Al for all the aluminium solutions was similar: aluminium citrate 0.08%, aluminium chloride 0.05%, aluminium nitrate 0.05% and aluminium sulphate 0.21%. The uptake of ²⁶Al administered as insoluble particulates was lower: 0.03% for aluminium hydroxide; 0.02% for aluminium oxide; 0.04% for powdered pot electrolyte; 0.12% for sodium aluminium silicate; and 0.09% for FD&C red 40 aluminium lake. For aluminium metal, SALP and Kasal the amount of ²⁶Al present in the rats was insufficient to determine uptake and was less than 0.03%. The results produced for aluminium citrate, aluminium hydroxide and aluminium sulphate are close to those published for man.     

Effect of Food on the Pharmacokinetic and Pharmacodynamic Profiles of Hetrombopag in Healthy Volunteers

PurposeHetrombopag, a novel, oral small molecule thrombopoietin receptor agonist, exhibits an obvious thrombocytopoietic effect with good safety. Hetrombopag is currently under clinical development for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). The objectives of this study were to assess the effect of high-fat and high-calorie food on the pharmacokinetic and pharmacodynamic (PK/PD) profiles of hetrombopag in healthy volunteers.MethodsAn independent, single-dose, open-label, randomized-sequence, crossover trial was conducted. Healthy volunteers received hetrombopag 7.5-mg tablets in the fasted state or with a high-fat, high-calorie breakfast. The effects of the high-fat and high-calorie food on the PK/PD profiles of hetrombopag were evaluated by using a noncompartmental analysis and a semi-physiological model.FindingsTwelve Chinese healthy volunteers were enrolled. Mean plasma AUC_0–t and C_max decreased by 98.7% and 95.0%, respectively, when hetrombopag was administered with high-fat and high-calorie food. The semi-physiological PK/PD model analysis showed that the absorption rate constant at the first absorption site was almost halved at the fed condition. The change in platelet counts in the fed condition was not sufficiently as sensitive as that in the fasted condition.ImplicationsHigh-fat and high-calorie food were associated with significantly reduced systemic exposure and platelet count sensitivity. Thus, hetrombopag should be taken in a fasted state to avoid the impact of food on bioavailability and platelet counts. ClinicalTrials.gov identifier: NCT02409394.     

Oral Dispersible System: A New Approach in Drug Delivery System

Dosage form is a mean used for the delivery of drug to a living body. In order to get the desired effect the drug should be delivered to its site of action at such rate and concentration to achieve the maximum therapeutic effect and minimum adverse effect. Since oral route is still widely accepted route but having a common drawback of difficulty in swallowing of tablets and capsules. Therefore a lot of research has been done on novel drug delivery systems. This review is about oral dispersible tablets a novel approach in drug delivery systems that are now a day''s more focused in formulation world, and laid a new path that, helped the patients to build their compliance level with the therapy, also reduced the cost and ease the administration especially in case of pediatrics and geriatrics. Quick absorption, rapid onset of action and reduction in drug loss properties are the basic advantages of this dosage form.     

Comparative pharmacokinetics and tissue distribution of cryptotanshinone,tanshinone IIA,dihydrotanshinone I,and tanshinone I after oral administration of pure tanshinones and liposoluble extract of Salvia miltiorrhiza to rats

Salvia miltiorrhiza is one of the most commonly used traditional Chinese medicines in the treatment of cardiovascular and cerebrovascular diseases. Cryptotanshinone (CTS), tanshinone IIA (Tan IIA), dihydrotanshinone I (diTan I), and tanshinone I (Tan I) are the main active compounds in the liposoluble extract of Salvia miltiorrhiza. The differences in the pharmacokinetic and tissue distribution behaviors of the four tanshinones after oral administration of the liposoluble extract of Salvia miltiorrhiza and pure compounds are not clear. This study aims to compare the pharmacokinetics and tissue distribution of the four tanshinones after oral administration of pure tanshinone monomers and the liposoluble extract of Salvia miltiorrhiza. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) analysis method was developed for the determination of the four tanshinones. The results showed that the AUC and C_max of tanshinones in rats receiving the extract of Salvia miltiorrhiza were significantly increased compared with those receiving the pure tanshinones. In the tissue distribution experiments, the AUC of the four tanshinones in the extract was much greater than the AUC of the monomers in the lung, heart, kidney, liver, and brain, and the coexisting constituents particularly promoted the distribution of tanshinones into tissues that the drug cannot sufficiently penetrate. These findings suggested that the coexisting constituents in the liposoluble extract of Salvia miltiorrhiza play an important role in the alteration of plasma concentration and tissue distribution of the four tanshinones. Understanding these differences could be of significance for the development and application of Salvia miltiorrhiza extract and tanshinone components.