Oral Bioavailability Of Hydrophobic Drugs Research Articles

Computation Design: Nanostructured Lipid Carrier Formula of Pinostrobin

Nano lipid carriers (NLC) function by increasing the solubility and oral bioavailability of hydrophobic drugs. This study was conducted to estimate the solubility of pinostrobin in various types of solid and liquid lipid carriers through computational design and to select the optimal NLC formula with the best candidate lipid carriers. Pinostrobin and all lipid carriers were determined for their interactions with the AutoDockTools program. The values of the free energy binding (ΔG), the inhibition constant (Ki), and the type of interaction visibility were recorded as a result of the molecular docking. The interaction type of visualization was determined by the BIOVIA Discovery Studio program. The results showed that apocarotenal was the best liquid lipid carrier with a ΔG value of -3.57 kcal/mol and a Ki value of 2.40 mM. Cetosteryl alcohol was the best carrier for solid lipids, with a ΔG value of -2.18 kcal/mol and a Ki value of 25.35 mM. Apocarotenal and cetostearyl alcohol as lipid carrier candidates for the NLC formula of pinostrobin.

Self-microemulsifying system of an ethanolic extract of Heliopsis longipes root for enhanced solubility and release of affinin

Self-microemulsifying or self-nanoemulsifying drug delivery systems (SMEDDS/SNEDDS) are well known to improve the dissolution and increase the oral bioavailability of hydrophobic drugs, including herbal extracts. Organic extracts of Heliopsis longipes root and affinin, its main component, induce a vasodilator effect; however, they are poorly water soluble and therefore are difficult to administer and dose by the oral route. This research aimed to develop, through pseudo-ternary phase diagrams, a self-microemulsifying system prepared from an ethanolic extract of H. longipes root (HL-SMDS). In addition, the optimized lipid-based formulation was characterized and its in vitro gastrointestinal simulated dissolution was determined. The formulation composed of Transcutol, 55% (solubilizer); Tween80/PG, 10% (surfactant/co-solvent); Labrasol, 35% (surfactant); and the herbal extract was selected as optimal and identified as a SMEDDS, since when coming into contact with water, it forms a micro-emulsion with droplet sizes less than 100 nm. The stability tests showed that HL-SMDS remained stable over time under extreme conditions. Furthermore, the amount of affinin released from HL-SMDS at pH 1 and 6.8 was higher than that of the ethanolic extract from H. longipes root. These results indicate that HL-SMDS is a novel alternative to improve the aqueous solubility and therefore the oral bioavailability of the ethanolic extract of H. longipes root.

Enhanced bioavailability and biosafety of cannabidiol nanomicelles for effective anti-inflammatory therapy

Cannabidiol (CBD) shows great anti-inflammatory potential; however, the hydrophobicity and strong first-pass effect of CBD leads to its extremely low oral bioavailability. Poloxamer 407 (P407) is a triblock copolymer composed of (poly)ethylene oxide (PEO) and (poly)propylene oxide (PPO) sections. It has a PEO-PPO-PEO structure, which is widely used in the preparation of drug delivery systems that are highly biocompatible. When it reaches a certain concentration in water, P407 can self-assemble into a micelle structure containing a hydrophobic core and a hydrophilic shell. A potential approach to enhancing the oral bioavailability of hydrophobic drugs incorporating them into the hydrophilic carrier. We prepared CBD nanomicelles with a drug loading of 14.29% by a cosolvent evaporation method using P407 with appropriate antioxidants. Cell experiments indicated that anti-inflammatory markers (IL-4 and IL-10) increased, while inflammatory markers (TNF-α and IL-6) decreased. Moreover, animal experiments showed that inflammatory cells were inhibited by CBD nanomicelles, and the anti-inflammatory effect of micelles was better than that of CBD, while no obvious evidence indicated toxicity to the liver and kidney.

Preparation, In Vivo and In Vitro Evaluation, and Pharmacodynamic Study of DMY‐Loaded Self‐Microemulsifying Drug Delivery System

AbstractHyperlipidemia has become a common disease in modern society with its prevalence becoming relatively high in the world. A series of complications that accompany hyperlipidemia are seriously threatening individuals’ health. Dihydromyricetin (DMY) is a kind of polyphenol hydroxy (OH) dihydroflavonol extracted from the stems and leaves of Ampelopsis grossedentata. It has a variety of pharmacological activities. This study aims to develop a self‐microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of DMY, and to evaluate its hypolipidemic activity. The self‐microemulsion drug delivery system is composed of medium chain triglyceride (MCT, oil phase), Tween 80 (emulsifier), and PEG 200 (coemulsifier). The prepared DMY‐SMEDDS has stable physical and chemical properties, small droplet size (15.49 ±0.15 nm), good polydispersity index (PDI = 0.160 ± 0.010), negative zeta potential (−17.37 ± 0.09 mV), and high encapsulation efficiency (98.04 ± 0.25%). The results of in vitro dissolution and in vivo pharmacokinetics show that the prepared DMY‐SMEDDS significantly improve the solubility of DMY in aqueous medium, while its oral bioavailability is 2.34 times higher than that of free drug. In conclusion, the DMY‐SMEDDS prepared in this study prospectively improves the solubility and oral bioavailability of DMY also enhance the therapeutic effect.Practical Applications: This study is relevant in the sense that SMEDDS may be used as a new strategy to improve the oral bioavailability of hydrophobic drugs. This novel nanocarrier could increase (by 2.34 times) the relative bioavailability of oral DMY‐SMEDDS in rats comparative to dihydromyricetin (DMY) suspension. Thus, DMY‐SMEDDS may prospectively be applied in food, nutraceutical, and pharmaceutical industries in view of its biocompatible excipients and good stability.

Advances in drug delivery systems: Work in progress still needed?

A new era of science and technology has emerged in pharmaceutical research with focus on developing novel drug delivery systems for oral administration. Conventional dosage forms like tablets and capsules are associated with a low bioavailability, frequent application, side effects and hence patient noncompliance. By developing novel strategies for drug delivery, researchers embraced an alternative to traditional drug delivery systems. Out of those, fast dissolving drug delivery systems are very eminent among pediatrics and geriatrics. Orally disintegrating films are superior over fast dissolving tablets as the latter are assigned with the risk of suffocation. Due to their ability of bypassing the dissolution and the first pass effect after oral administration, self-emulsifying formulations have also become increasingly popular in improving oral bioavailability of hydrophobic drugs. Osmotic devices enable a controlled drug delivery independent upon gastrointestinal conditions using osmosis as driving force. The advances in nanotechnology and the variety of possible materials and formulation factors enable a targeted delivery and triggered release. Vesicular systems can be easily modified as required and provide a controlled and sustained drug delivery to a specific site. This work provides an insight of the novel approaches in drug delivery covering the critical comparison between traditional and novel "advanced-designed" systems.

Development and characterisation of ibuprofen-loaded nanoemulsion with enhanced oral bioavailability

Lipophilic compounds constitute a majority of therapeutics in the pipeline of drug discovery. Despite possessing enhanced efficacy and permeability, some of these drugs suffer poor solubility necessitating the need of a suitable drug delivery system. Nanoemulsion is a drug delivery system that provides enhanced solubility for poorly soluble drugs in an attempt to improve the oral bioavailability. The purpose of this study is to develop a nanoemulsion system using ibuprofen as a model drug in order to investigate the potential of this colloidal system to enhance the absorption of poorly water-soluble drugs. Ibuprofen loaded-nanoemulsion with different drug concentrations (1.5, 3 and 6% w/w) were formulated from olive oil, sucrose ester L-1695 and glycerol using D-phase emulsification technique. A pseudoternary phase diagram was utilised to identify the optimal excipient composition to formulate the nanoemulsion system. In vitro diffusion chamber studies using rodent intestinal linings highlighted improved absorption profile when ibuprofen was delivered as nanoemulsion in comparison to microemulsions and drug-in-oil systems. This was further corroborated by in vivo studies using rat model that highlighted a two-fold increase in ibuprofen absorption when the drug was administered as a nanoemulsion relative to drug-in-oil system. On the other hand, when ibuprofen was administered as microemulsions, only a 1.5-fold increase in absorption was observed relative to drug-in-oil system. Thus, this study highlights the potential of using nanoemulsion as a drug delivery system to enhance the oral bioavailability of hydrophobic drugs.

WITHDRAWN: Advances in drug delivery systems: Work in progress still needed?

A new era of science and technology has emerged in pharmaceutical research with focus on developing novel drug delivery systems for oral administration. Conventional dosage forms like tablets and capsules are associated with a low bioavailability, frequent application, side effects and hence patient noncompliance. By developing novel strategies for drug delivery, researchers embraced an alternative to traditional drug delivery systems. Out of those, fast dissolving drug delivery systems are very eminent among pediatrics and geriatrics. Orally disintegrating films are superior over fast dissolving tablets as the latter are assigned with the risk of suffocation. Due to their ability of bypassing the dissolution and the first pass effect after oral administration, self-emulsifying formulations have also become increasingly popular in improving oral bioavailability of hydrophobic drugs. Osmotic devices enable a controlled drug delivery independent upon gastrointestinal conditions using osmosis as driving force. The advances in nanotechnology and the variety of possible materials and formulation factors enable a targeted delivery and triggered release. Vesicular systems can be easily modified as required and provide a controlled and sustained drug delivery to a specific site.This work provides an insight of the novel approaches in drug delivery covering the critical comparison between traditional and novel “advanced-designed” systems.

Development of self nanoemulsifying drug delivery system for black seed oil (Nigella sativa L.)

One strategy to improve oral bioavailability of hydrophobic drugs like black seed oil with formulate them into self nanoemulsifying drug delivery system (SNEDDS). The aim of this study is to develop black seed oil into liquid SNEDDS formulation to enhance oral bioavailability. The optimization of SNEDDS was carried out using various comparison between oil, surfactant and cosurfactant. The formulated SNEDDS were evaluated for transmittance percentage, emulsification time, dispersebility, robustness, thermodynamics stability and globul size determination. The best formulation of SNEDDS obtained from tween 80 as surfactan and PEG 400 as cosurfactant (2:1) with ratio of oil and mix surfactant-cosurfactant 1:8. The formulation of SNEDDS met the requirement of transmittance percentage (97.80%), emulsification time (35.00 second), grade A of dispersibility, stable of robustness and thermodynamic stability tests and the average of globul size was 65.4 nm. The SNEDDS formulation containing black seed oil has good physical characteristic and stability.

6]-Shogaol/β-CDs inclusion complex: preparation, characterisation, in vivo pharmacokinetics, and in situ intestinal perfusion study

Aims: The aim was to improve the absorption and bioavailability of [6]-shogaol with β-cyclodextrin (β-CD) prior to in vitro and in vivo evaluation.Methods: [6]-Shogaol/β-CDs inclusion complexes (6-S-β-CDs) were developed using saturated aqueous solution method and characterised with appropriate techniques. The absorption and bioavailability potential of [6]-shogaol was evaluated via in vivo pharmacokinetics and in situ intestinal perfusion.Results: The results of characterisation showed that 6-S-β-CDs (drug loading, 7.15%) were successfully formulated. In vitro release study indicated significantly improved [6]-shogaol release. Pharmacokinetic parameters such as Cmax, AUC0–36 h, and oral relative bioavailability (about 685.36%) were substantially enhanced. The in situ intestinal perfusion study revealed that [6]-shogaol was markedly absorbed via passive diffusion in the intestinal segments, and duodenum followed by ileum and jejunum.Conclusions: Cyclodextrin inclusion technology could enhance the intestinal absorption and oral bioavailability of hydrophobic drugs like [6]-shogaol.

Stabilizing supersaturated drug-delivery system through mechanism of nucleation and crystal growth inhibition of drugs.

A supersaturated drug-delivery system is capable of enhancing oral bioavailability of hydrophobic drugs. Maintenance of the supersaturated system both in vitro and in vivo is one of the most challenging parts, for that it is required to keenly understand the nucleation and crystal growth behavior. Polymers are widely used to stabilize supersaturated solutions; screening of polymers is done on the basis of their interaction with drug. Nucleation and crystal growth inhibition and drug-polymer interactions can be investigated by using various spectroscopic methods. Various formulations are prepared as supersaturated systems using different drug-delivery systems utilizing different polymers, which illustrates that supersaturation is worthwhile toincrease the solubility and hence oral bioavailability of poorly soluble drugs.

Self-emulsifying drug delivery formulations

As a consequence of modern drug discovery techniques, lipid-based drug delivery systems are the most popular approaches usually used to improve the dissolution and oral bioavailability of hydrophobic drugs. Self-emulsifying drug delivery systems (SEDDS), as one class of these lipid-based systems, are isotropic mixtures of oil, surfactants and co-surfactants where the drug is usually better soluble than in oil alone. The principal characteristic of SEDDS is their ability to form fine oil in water micro-emulsifying drug delivery systems (MEDDS) upon dilution by an aqueous phase through the gastrointestinal tract. SEDDS are considered promising strategy to improve the rate and extent of oral absorption of drugs. However conventional liquid SEDDS have some limitations, solid SEDDS are prepared by solidification of liquid self-emulsifying ingredients into powders or nanoparticles. This overview gives a particular emphasis on the solidification techniques and applications of liquid SEDDS in the pharmaceutical dosage forms to meet a wide range of the formulation requirements achieving reasonable routes of administration with efficient oral bioavailability.

Review on the formulation considerations needed to produce a stable Self micro Emulsifying Drug Delivery System (SMEDDS)

Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modifications and lipid based delivery systems finding increased appliance with the apparent increase in absorption of drug. Among lipid based formulations, self-micro emulsifying formulations (droplet size < 100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented. Various components that are used to formulate these dosage forms like surfactants and lipids contribute to the overall improvement in oral bioavailability via promoting the lymphatic transport; thereby hepatic first pass metabolism can be surmounted. The present article gives exhaustive information on the formulation design and characterization of SMEDDS by which the bioavailability can be improved. In this review article, the various aspects of pharmaceutical SMEDDS where compiled together and target audience are specifically the B. Pharm and M. Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publication.

Lecithin-gold hybrid nanocarriers as efficient and pH selective vehicles for oral delivery of diacerein—In-vitro and in-vivo study

We report the synthesis and evaluation of lecithin-gold hybrid nanocarriers for the oral delivery of drugs with improved pharmacokinetics, Au-drug interactive bioactivity and controlled drug releasing behavior at physiological pH inside human body. For this purpose, diacerein, a hydrophobic anti-arthritic drug, was loaded in lecithin NPs (LD NPs), which were further coated by Au NPs either by in-situ production of Au NPs on LD NPs or by employing pre-synthesized Au NPs. All LDAu NPs were found to release drug selectively at the physiological pH of 7.4 and showed 2.5 times increase in the oral bioavailability of diacerein. Pharmacological efficacy was significantly improved i.e., greater than the additive effect of diacerein and Au NPs alone. LDAu NPs started suppressing inflammation at first phase, whereas LD NPs showed activity in the second phase of inflammation. These results indicate the interaction of Au NPs with prostaglandins and histaminic mediators of first phase of carrageenan induced inflammation. Acute toxicity study showed no hepatic damage but the renal toxicity parameters were close to the upper safety limits. Toxicity parameters were dependent on surface engineering of LDAu NPs. Apart from enhancing the oral bioavailability of hydrophobic drugs and improving their anti-inflammatory activity, these hybrid nanocarriers may have potential applications in gold-based photothermal therapy and the tracing of inflammation at atherosclerotic and arthritic site.

A Review on Self-Micro Emulsifying Drug Delivery System: Evident to improve the oral bioavailability of hydrophobic drugs

The SMEDDS are the isotropic mixture of oil, surfactant and co-surfactant. SMEDDS solve the problem of all BCS class of drug such as solubility, high molecular weight, pre systemic first pass effect, enzymatic degradation, gastric irritation and also increase the bioavailability and stability of drug. Currently a number of technologies are available to deal with the poor solubility, dissolution rate and bioavailability of insoluble drugs one of them is Self-Micro Emulsifying Drug Delivery Systems (SMEDDS). lipid based formulations, self-microemulsifying formulations (droplet size <100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented.

Self-Microemulsifying Drug Delivery Systems: An Attractive Strategy for Enhanced Therapeutic Profile.

Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modification, and cocrystals exist, lipid based delivery systems finding increased appliance with the apparent increase in absorption of drug. Among lipid based formulations, self-microemulsifying formulations (droplet size < 100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented. Various components that are used to formulate these dosage forms like surfactants and lipids contribute to the overall improvement in oral bioavailability via promoting the lymphatic transport; thereby hepatic first pass metabolism can be surmounted. The present paper gives exhaustive information on the formulation design and characterization of SMEDDS along with the probable mechanisms by which the bioavailability can be improved with SMEDDS.

Chitosan amphiphiles provide new drug delivery opportunities

Chitosan, an acid soluble and renewable biopolymer, was first studied as a drug delivery agent in 1990. This review focuses on the relatively newer self‐assembling chitosan amphiphiles and their use as drug delivery agents. Chitosan amphiphiles, first introduced in the late 1990s, are prepared by conjugating hydrophobic and sometimes additional hydrophilic units to chitosan. These amphiphiles self‐assemble in aqueous media at neutral pH to form micelles, with critical micellar concentrations (CMCs) ranging from 0.09 to 700 µg mL−1. The CMCs depend on the actual molecular architecture, molecular weight and hydrophobic character, but are typically lower than the values reported for block copolymer amphiphiles. As well as linear amphiphiles in which chitosan is derivatised with hydrophobic pendant groups, new claw amphiphiles have been prepared in which chitosan amphiphiles radiate geometrically from a dendrimer core. These chitosan amphiphiles (linear and claw) have been exploited as drug delivery agents and they increase the oral bioavailability of hydrophobic drugs up to sixfold, deliver hydrophobic drugs to tumours, genes to the liver via the intravenous route, genes to the muscle via the intramuscular routes and small interfering RNAs to tumours via the intratumoural route. Chitosan amphiphile nanoparticles also deliver peptides to the brain via the intravenous and oral routes. © 2014 Society of Chemical Industry

Development of Lipid-Based Nanoparticles for Enhancing the Oral Bioavailability of Paclitaxel

The current research work investigates the potential of solid lipid nanoparticles (SLNs) in improving the oral bioavailability of paclitaxel. Paclitaxel-loaded SLNs (PTX-SLNs) were prepared by modified solvent injection method using stearylamine as lipid, soya lecithin and poloxamer 188 as emulsifiers. SLNs were characterized in terms of surface morphology, size and size distribution, surface chemistry and encapsulation efficiency. Pharmacokinetics and bioavailability studies were conducted in male Swiss albino mice after oral administration of PTX-SLNs. SLNs exhibited spherical shape with smooth surface as analyzed by transmission electron microscopy (TEM). The mean particle size of SLNs was 96 ± 4.4 nm with a low polydispersity index of 0.162 ± 0.04 and zeta potential of 39.1 ± 0.8 mV. The drug entrapment efficiency was found to be 75.42 ± 1.5% with a loading capacity of 31.5 ± 2.1% (w/w). Paclitaxel showed a slow and sustained in vitro release profile and followed Higuchi kinetic equations. After oral administration of the PTX-SLNs, drug exposure in plasma and tissues was ten- and twofold higher, respectively, when compared with free paclitaxel solution. PTX-SLNs produced a high mean C (max) (10,274 ng/ml) compared with that of free paclitaxel solution (3,087 ng/ml). The absorbed drug was found to be distributed in liver, lungs, kidneys, spleen, and brain. The results suggested that PTX-SLNs dispersed in an aqueous environment are promising novel formulations that enhanced the oral bioavailability of hydrophobic drugs, like paclitaxel and were quite safe for oral delivery of paclitaxel as observed by in vivo toxicity studies.

Self-Nanoemulsifying Drug Delivery Systems: Formulation Insights, Applications and Advances

There has been a resurgence of interest in nanoemulsions for various pharmaceutical applications since low-energy emulsification methods, such as spontaneous or self-nanoemulsification, have been described. Self-nanoemulsifying drug delivery systems (SNEDDS) are anhydrous homogenous liquid mixtures consisting of oil, surfactant, drug and coemulsifier or solubilizer, which spontaneously form oil-in-water nanoemulsion of approximately 200 nm or less in size upon dilution with water under gentle stirring. The physicochemical properties, drug solubilization capacity and physiological fate considerably govern the selection of the SNEDDS components. The composition of the SNEDDS can be optimized with the help of phase diagrams, whereas statistical experimental design can be used to further optimize SNEDDS. SNEDDS can improve oral bioavailability of hydrophobic drugs by several mechanisms. The conversion of liquid SNEDDS to solid oral dosage forms or solid SNEDDS has also been achieved by researchers. Solid SNEDDS can offer better patient compliance and minimize problems associated with capsules filled with liquid SNEDDS.

Molecular Dynamics Study of Non-nucleoside Reverse Transcriptase Inhibitor 4-[[4-[[4-[(E)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (TMC278/Rilpivirine) Aggregates: Correlation between Amphiphilic Properties of the Drug and Oral Bioavailability

The non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278/rilpivirine is an anti-AIDS therapeutic agent with high oral bioavailability despite its high hydrophobicity. Previous studies established a correlation between ability of the drug molecule to form stable, homogeneous populations of spherical nanoparticles (approximately 100-120 nm in diameter) at low pH in surfactant-independent fashion and good oral bioavailability. Here, we hypothesize that the drug is able to assume surfactant-like properties under physiologically relevant conditions, thus facilitating formation of nanostructures in the absence of other surfactants. The results of all-atom molecular dynamics simulations indeed show that protonated drug molecules behave as surfactants at the water/aggregate interface while neutral drug molecules assist aggregate packing via conformational variability. Our simulation results suggest that amphiphilic behavior at low pH and intrinsic flexibility influence drug aggregation and are believed to play critical roles in the favorable oral bioavailability of hydrophobic drugs.

Influence of bile on the oral bioavailability of vitamin K-loaded polymeric micelles

Enhancing the oral bioavailability of hydrophobic drugs is an important topic, especially for patients lacking bile production (cholestasis). Polymeric micelles have been suggested as possible oral delivery systems. Using a cholestatic animal model, we showed that uptake of vitamin K formulated in thermosensitive polymeric micelles is not possible without bile acids. Bile acids are required to extract the drug from the micelles and to deliver it to the endothelial lining.