Functions of lipids for enhancement of oral bioavailability of poorly water-soluble drugs

Lipid-based formulations encompass a diverse group of formulations with very different physical appearance, ranging from simple triglyceride vehicles to more sophisticated formulations such as self-emulsifying drug delivery systems (SEDDS). Lipid-based drug delivery systems may contain a broad range of oils, surfactants, and co-solvents. They represent one of the most popular approaches to overcome the absorption barriers and to improve the bioavailability of poorly water-soluble drugs. Diversity and versatility of pharmaceutical grade lipid excipients and drug formulations as well as their compatibility with liquid, semi-solid and solid dosage forms make lipid systems most complex. Digestion of triglyceride lipids, physicochemical characteristics and solubilisation of lipid digestion products as well as intestinal permeability are some of the variable parameters of such formulations. Furthermore, among the factors affecting the bioavailability of the drug from lipid-based formulations are the digestion of lipid, the mean emulsion droplet diameter, the lipophilicity of the drug and the type of lipids. The solubility of the Active Pharmaceutical Ingredient in the Lipid System, the desorption/sorption isotherm and the digestibility of lipid vehicle are important issues to be considered for formulations of isotropic lipid formulations. This review also describes the fate of lipid formulations in the gut and the factors influencing the bioavailability from lipid-based formulations. Novel formulation systems and currently marketed products conclude this review.     

Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs

Nanocrystals, a carrier-free colloidal delivery system in nano-sized range, is an interesting approach for poorly soluble drugs. Nanocrystals provide special features including enhancement of saturation solubility, dissolution velocity and adhesiveness to surface/cell membranes. Several strategies are applied for nanocrystals production including precipitation, milling, high pressure homogenization and combination methods such as NanoEdge™, SmartCrystal and Precipitation-lyophilization-homogenization (PLH) technology. For oral administration, many publications reported useful advantages of nanocrystals to improve in vivo performances i.e. pharmacokinetics, pharmacodynamics, safety and targeted delivery which were discussed in this review. Additionally, transformation of nanocrystals to final formulations and future trends of nanocrystals were also described.     

Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: Effects of lipid composition and formulation

This study has explored the use of lipid-based formulations to enhance the oral bioavailability of the poorly water-soluble drug anethol trithione (ATT), and compared the performance of different formulations. Two groups of lipid-based formulations, sub-microemulsion (SME) and oil solution, were prepared using short (SCT), medium (MCT) and long (LCT) chain triglycerides respectively; aqueous suspension was used as the reference formulation. In vitro and in vivo studies were conducted to investigate the impact of lipid composition and formulation on drug absorption. In vitro digestion was used to analyze lipid digestion rates and drug distribution/solubilization. After in vitro digestion, the performance rank order for drug solubilization was SCT < MCT < LCT. SME formulations were digested more rapidly in vitro than oil solutions. The bioavailability of the drug from different formulations was investigated in rats. All six lipid-based formulations enhanced drug absorption compared to the aqueous suspension. For the SMEs, which were rapidly digested, in vivo bioavailability increased in accordance with the increase of solubilization data obtained by in vitro digestion, with the rank order SCT-SME < MCT-SME < LCT-SME. For the oil solutions, which were digested more slowly, there was no significant difference in drug bioavailability for the different formulations. In conclusion, lipid-based formulations can enhance the oral bioavailability of ATT, and for this BCS class II drug, both the lipid composition and type of lipid formulation are likely to govern in vivo performance.     

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.     

Lipid-based nanoparticle formulations for small molecules and RNA drugs

ABSTRACT

Introduction: Liposomes and lipid-based nanoparticles (LNPs) effectively deliver cargo molecules to specific tissues, cells, and cellular compartments. Patients benefit from these nanoparticle formulations by altered pharmacokinetic properties, higher efficacy, or reduced side effects. While liposomes are an established delivery option for small molecules, Onpattro® (Sanofi Genzyme, Cambridge, MA) is the first commercially available LNP formulation of a small interfering ribonucleic acid (siRNA).

Areas covered: This review article summarizes key features of liposomal formulations for small molecule drugs and LNP formulations for RNA therapeutics. We describe liposomal formulations that are commercially available or in late-stage clinical development and the most promising LNP formulations for ASOs, siRNAs, saRNA, and mRNA therapeutics.

Expert opinion: Similar to liposomes, LNPs for RNA therapeutics have matured but still possess a niche application status. RNA therapeutics, however, bear an immense hope for difficult to treat diseases and fuel the imagination for further applications of RNA drugs. LNPs face similar challenges as liposomes including limitations in biodistribution, the risk to provoke immune responses, and other toxicities. However, since properties of RNA molecules within the same group are very similar, the entire class of therapeutic molecules would benefit from improvements in a few key parameters of the delivery technology.     

Lipid - An emerging platform for oral delivery of drugs with poor bioavailability

The sole objective of pharmaceutical science is to design successful dosage forms which fulfill the therapeutic needs of the patients effectively. Development of new drug entities is posing real challenge to formulators, particularly due to their poor aqueous solubility which in turn is also a major factor responsible for their poor oral bioavailability. Lipids as carriers, in their various forms, have the potential of providing endless opportunities in the area of drug delivery due to their ability to enhance gastrointestinal solubilization and absorption via selective lymphatic uptake of poorly bioavailable drugs. These properties can be harvested to improve the therapeutic efficacy of the drugs with low bioavailability, as well as to reduce their effective dose requirement. The present communication embodies an in-depth discussion on the role of lipids (both endogenous and exogenous) in bioavailability enhancement of poorly soluble drugs, mechanisms involved therein, approaches in the design of lipid-based oral drug delivery systems with particular emphasis on solid dosage forms, understanding of morphological characteristics of lipids upon digestion, in vitro lipid digestion models, in vivo studies and in vitro-in vivo correlation.     

A new self-emulsifying drug delivery system (SEDDS) for poorly soluble drugs: Characterization, dissolution, in vitro digestion and incorporation into solid pellets

The aim of the current study was the development of a new pellet based self-emulsifying (SE) drug delivery system for the oral delivery of poorly soluble drugs. Furthermore, we wanted to investigate the influence of physiological dilution media and enzymatic digestion on the solubilization capacity of the formulation for the model drug Progesterone.Lipid mixtures composed of Solutol^® HS 15 and medium chain glycerides were optimized with respect to their self-emulsifying properties. The liquid SE lipid was mixed with microcrystalline cellulose and transformed into pellets by extrusion/spheronization. The pellets were characterized for size, shape, surface characteristics and friability. In vitro dissolution and digestion experiments were carried out using physiological dissolution media.The droplet diameter of the dispersed SE mixtures was largely affected by changing the oil to Solutol^® HS 15 ratio. Moreover, digestion of SE mixtures changed the solubilization capacity for Progesterone. Pellets with good properties (size, shape and friability) have been produced through the incorporation of a selected SE mixture into MCC.In conclusion, extrusion/spheronization is a suitable process to produce solid self-emulsifying pellets with up to 40% load of a liquid SE mixture. Digestion induces a change in lipid composition which affects the solubilization capacity of the lipid phase.     

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.     

Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs

To evaluate the intestinal permeability of poorly water-soluble compounds, it is of importance to completely dissolve them in a medium and to avoid precipitation during experiments. This study was undertaken to find an agent possessing a high-solubilizing capacity and exhibiting minimal modulating impact on membrane integrity and absorption systems such as passive diffusion and carrier-mediated permeation. Phenytoin dissolution was compared in the presence of seven solubilizing agents at concentrations of 1, 2, or 5% using a centrifugation method. The capacity to dissolve phenytoin was great in β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin, followed by Tween 80. Those of methanol, dimethyl sulfoxide, dimethyl acetoamide, and polyethylene glycol 400 were much lower than expected. One percent β-CD did not alter the absorption of fluorescein isothiocyanate-dextran 4000 or the release of protein and lactate dehydrogenase into in situ loop contents, suggesting that 1% β-CD had no significant impact on the integrity of the intestinal membrane. One percent β-CD also did not alter the absorption of caffeine, ceftibuten, or rhodamine 123 from in situ jejunal loops, indicating no interference with passive diffusion and active transports mediated by a peptide transporter and P-glycoprotein. In conclusion, 1% β-CD is a suitable solubilizing agent for evaluating in situ intestinal absorption of poorly water-soluble compounds.     

Tocol modified glycol chitosan for the oral delivery of poorly soluble drugs

The aim of this study was to develop tocol derivatives of chitosan able (i) to self-assemble in the gastrointestinal tract and (ii) to enhance the solubility of poorly soluble drugs. Among the derivatives synthesized, tocopherol succinate glycol chitosan (GC-TOS) conjugates spontaneously formed micelles in aqueous solution with a critical micelle concentration of 2 μg mL⁻¹. AFM and TEM analysis showed that spherical micelles were formed. The GC-TOS increased water solubility of 2 model class II drugs. GC-TOS loading efficiency was 2.4% (w/w) for ketoconazole and 0.14% (w/w) for itraconazole, respectively. GC-TOS was non-cytotoxic at concentrations up to 10 mg mL⁻¹. A 3.4-fold increase of the apparent permeation coefficient of ketoconazole across a Caco-2 cell monolayer was demonstrated. Tocol polymer conjugates may be promising vehicles for the oral delivery of poorly soluble drugs.     

Carboxylated mesoporous carbon microparticles as new approach to improve the oral bioavailability of poorly water-soluble carvedilol

The main objective of this study was to develop carboxylated ordered mesoporous carbon microparticles (c-MCMs) loaded with a poorly water-soluble drug, intended to be orally administered, able to enhance the drug loading capacity and improve the oral bioavailability. A model drug, carvedilol (CAR), was loaded onto c-MCMs via a procedure involving a combination of adsorption equilibrium and solvent evaporation. The physicochemical properties of the drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and HPLC. It was found that c-MCM has a high drug loading level up to 41.6%, and higher than that of the mesoporous silica template. Incorporation of CAR in both drug carriers enhanced the solubility and dissolution rate of the drug, compared to the pure crystalline drug. After loading CAR into c-MCMs, its oral bioavailability was compared with the marketed product in dogs. The results showed that the bioavailability of CAR was improved 179.3% compared with that of the commercial product when c-MCM was used as the drug carrier. We believe that the present study will help in the design of oral drug delivery systems for enhanced oral bioavailability of poorly water-soluble drugs.     

Oral formulation strategies to improve solubility of poorly water-soluble drugs

Introduction: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug–receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends.

Areas covered: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends.

Expert opinion: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.     

Parallel screening approach to identify solubility-enhancing formulations for improved bioavailability of a poorly water-soluble compound using milligram quantities of material

In this article, we present a parallel experimentation approach to rapidly identify a solubility-enhancing formulation that improved the bioavailability of a poorly water-soluble compound using milligrams of material. The lead compound and a panel of excipients were dissolved in n-propanol and dispensed into the wells of a 96-well microtiter plate by a TECAN robot. Following solvent evaporation, the neat formulations were diluted with an aqueous buffer, and incubated for 24 h. The solubilization capacity of the excipients for the compound at 24 h (SC_24 h), was determined by HPLC, and compared with its solubility in the corresponding neat formulations determined by a bench-scale method. The ranking order of solubilization capacity of the five tested formulations for this compound by this microscreening assay is same as the ranking order of the compound solubility in the neat formulations. Several formulations that achieved the target aqueous solubility were identified using the screening method. One of the top formulations, an aqueous solution of the compound containing 20% Tween^® 80 by weight, increased the compound solubility from less than 2 μg/mL to at least 10 mg/mL. In a rat pharmacokinetic (PK) study, the Tween^® 80 formulation achieved 26.6% of bioavailability, a significant improvement over 3.4% of bioavailability for the aqueous Methocel^® formulation (p < 0.01). The results in the study suggest that this parallel screening assay can be potentially used to rapidly identify solubility-enhancing formulations for an improved bioavailability of poorly water-soluble compounds using milligram quantities of material.     

Development of a high-throughput in vitro intestinal lipolysis model for rapid screening of lipid-based drug delivery systems

PurposeTo develop a high-throughput in vitro intestinal lipolysis (HTP) model, without any means of pH-stat-titration, to enable a fast evaluation of lipid-based drug delivery systems (LbDDS).Material and methodThe HTP model was compared to the traditionally used dynamic in vitro lipolysis (DIVL) model with regard to the extent of lipid digestion and drug distribution of two poorly soluble model drugs (cinnarizine and danazol), during digestion of three LbDDS (LbDDS I–III).ResultThe HTP model was able to maintain pH around 6.5 during digestion, without the addition of NaOH to neutralize the free fatty acids (FFAs), due to an increased buffer capacity. Cinnarizine was primarily located in the aqueous phase during digestion of all three LbDDS and did not differ significantly between the two models. The distribution of danazol varied from formulation to formulation, but no significant difference between the models was observed. The triacylglycerides (TAG) in LbDDS III were digested to the same extent in both models, whereas the TAG present in LbDDS II was digested slightly less in the HTP model. No TAG was present in LbDDS I and digestion was therefore not analyzed.ConclusionThe HTP model is able to predict drug distribution during digestion of LbDDS containing poorly water soluble drugs in the same manner as the DIVL model. Thus the HTP model might prove applicable for high-throughput evaluation of LbDDS in e.g. 96 well plates or small scale dissolution equipment.     

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.     

Development of oil-in-water microemulsions for the oral delivery of amphotericin B

Amphotericin B (AmB) is a very efficient drug against serious diseases such as leishmaniasis and systemic fungal infections. However, its oral bioavailability is limited due to its poor solubility in water. Nevertheless, it is marketed as high-cost lipid parenteral formulations that may induce serious infusion-related side effects. In this study, oil-in-water (O/W) microemulsions (MEs) were developed and characterized with a view to their use as solubility enhancers and oral delivery systems for AmB. Therefore, different nonionic surfactants from the Tween^® and Span^® series were tested for their solubilization capacity in combination with several oils. Based on pseudoternary phase diagrams, AmB-loaded MEs with mean droplet sizes about 120 nm were successfully produced. They were able to improve the drug solubility up to 1000-fold. Rheological studies showed the MEs to be low-viscosity formulations with Newtonian behavior. Circular dichroism and absorption spectra revealed that part of the AmB in the MEs was aggregated as an AmB reservoir carrier. Cytotoxicity studies revealed limited toxicity to macrophage-like cells that may allow the formulations to be considered as suitable carriers for AmB.     

Development and validation of dissolution test for lopinavir, a poorly water-soluble drug, in soft gel capsules, based on in vivo data

The objective of the present study was to develop and validate a dissolution test for lopinavir soft gel capsules (Kaletra), using a simulated absorption profile based on in vivo data. Different conditions such as surfactant concentration, apparatus and rotation speed were evaluated. In vivo release profiles were obtained from the literature. The fraction (and percentage) of dose absorbed (FA) was calculated by using Wagner-Nelson method. The best in vitro dissolution profile was obtained using Apparatus 2 (paddle) at 25 rpm, 1000 ml of medium with 2.3% of sodium lauryl sulfate and pH 6.0. Under these conditions a level-A in vitro-in vivo correlation (IVIVC) was obtained (r = 0.997). The in vitro dissolution samples were analyzed using a HPLC method and the validation was performed according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. Both the HPLC method and the in vitro dissolution method were validated and could be used to evaluate the release profile of lopinavir soft gel capsules.     

Preparation and characterization of chitosan nanopores membranes for the transport of drugs

In this paper, a novel chitosan nanopores membrane was developed by selective dissolution of its composition. Polyethylene glycol (PEG) as the porogen was selected to generate the nanopores structure of chitosan membrane. As the observation with scanning electron microscopy (SEM), we could find that the PEG content was greatly influenced on the structure of chitosan membrane. As the PEG content was larger than 50%, the chitosan nanopores membrane could successfully developed. Differential scanning calorimeter (DSC) measurement revealed that the PEG component could not be completely dissolved from the membrane and there was presence the possible interaction (hydrogen bond) between two components. Water adsorption test suggested that the obtained membranes have the great capacity of water adsorption ranging from 162.4 ± 22.5% to 321.5 ± 6.5%. In vitro degradation experiment showed that the obtained chitosan membranes have good biodegradability in the lysozyme solution. The permeability test was performed with two model drugs: vitamin B12 (non-ionic water-soluble drug) and sodium sulfamerazine (ionic water-soluble drug). And the results showed that these two drugs have significant differences in the permeability, indicating that chitosan nanopores membranes can potentially be used to the transport of drugs with controlled diffusion manner.     

纳米给药系统在难溶性药物制剂研究中的应用

近年来,难溶性药物给药系统一直是制剂学研究的重点和难点之一。纳米载体由于其良好的生物相容性及可装载大量难溶性药物等特点而被广泛应用于难溶性药物给药系统的研究,该类载体主要包括纳米粒、脂质体、纳米乳、聚合物胶束、纳米混悬剂等。本文结合近几年国内外文献报道,对纳米给药系统在难溶性药物制剂研究中的最新进展进行概述。