Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts

Lipid-based dose forms, which encompass a wide variety of compositional and functional characteristics, can be advantageously utilized for the formulation of lipophilic drugs. There has been a traditional reluctance to develop lipid-based dose forms due to potential problems of chemical and physical instability, and a paucity of knowledge regarding formulation design algorithms and technology transfer issues. However, there is a current resurgence of interest in lipid-based dose forms due to potential commercial and pharmaceutical benefits, and the industry trend towards the discovery/development of increasingly hydrophobic (and potent) new chemical entities. This mini-review describes some emerging formulation and biopharmaceutic strategies that hold promise for better understanding how to design and evaluate lipid-based dose forms.     

Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs.

The main purpose of this review is to provide a current and general overview of the existing self-dispersing formulations resulting from dilution into emulsions, microemulsions and surfactant dispersions. The systematic approach used and the presentation of the various physico-chemical and biopharmaceutical aspects should facilitate the comprehension of this interesting field and clarify the main considerations involved in designing and characterizing a specific self-dispersing drug delivery system. Studies have shown that the self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. It was suggested that the ease of emulsification could be associated with the ease by which water penetrates into the various liquid crystalline (LC) or gel phases formed on the surface of the droplet. Numerous bioavailability studies carried out in animals and humans, reviewed in the present study, suggest that hydrophobic drugs are better absorbed when administered in self-dispersing lipid formulations (SDLFs). Examples which illustrate the beneficial use of SDLFs for drug absorption enhancement are presented. This review outlines SDLFs as one of the most promising approaches to overcome the formulation difficulties of these hydrophobic/lipophilic drugs.     

Effects of lipophilic components on the compatibility of lipid-based formulations with hard gelatin capsules

The present study investigated the effect of lipophilic components on the compatibility of propylene glycol (PG)-containing lipid-based drug delivery system (LBDDS) formulations with hard gelatin capsules. The presence of a lipophilic active pharmaceutical ingredient (API) (log P ～6.1) and an additional lipophilic excipient (Capmul MCM) significantly affected the activity of PG in the fills and the equilibrium of PG between capsule shells and fills. These changes in activity and equilibrium of PG were furthermore correlated to the mechanical and thermal properties of the liquid-filled capsules and subsequently linked to the shelf-life of the capsules on stability with respect to capsule deformation. The present study also investigated the mechanism by which lipophilic component(s) might affect the activity of PG in the fill formulations and the equilibrium of PG between capsule shells and fills. The activities of PG in two series of “binary” mixtures with Capmul MCM and with Cremophor EL were measured, respectively. The mixtures of PG containing Capmul MCM were found to be more nearly ideal than those containing Cremophor EL. The observed negative deviation from Rauolt's law indicates that the excess free energies of mixing are less then zero indicating favorable interaction between PG and the other component. It is speculated that enhanced hydrogen bonding opportunities with Cremophor EL are responsible for the decreased excess free energy of mixing. Replacement of Cremophor EL with lipophilic API also reduces the hydrogen bonding opportunities for PG in the mixtures. This hypothesis may further explain the increased activity of PG in the fills and the shifted equilibrium of PG toward the capsule shells. Activity determination utilizing headspace gas chromatography (GC) using short 30 min incubation time seems to be a time-efficient approach for assessing capsule-fill compatibility. Direct measurements of PG migration and other physical properties of the capsules took much longer time (7 weeks) for ranking the predicted capsule deformation at 40°C. Asides from the time savings, activity determination can be considered to be material sparing by offering capsule-fill compatibility assessment even without the need for preparing liquid-filled capsules once appropriate positive and negative references are established. With further optimization, this approach should enable high throughput screening of LBDDS for capsule-fill compatibility in liquid-filled capsule development. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:128–141, 2010     

Opportunities and challenges for oral delivery of hydrophobic versus hydrophilic peptide and protein-like drugs using lipid-based technologies

Peptide and protein-like drugs are macromolecules currently produced in increasing numbers by the pharmaceutical biotechnology industry. The physicochemical properties of these molecules posebarriers to oral administration. Lipid-based drug-delivery systems have the potential to overcome these barriers and may be utilized to formulate safe, stable and efficacious oral medicines. This review outlines the design of such lipid-based technologies. The mechanisms whereby these formulations enhance the absorption of lipophilic versus hydrophilic peptide and protein-like drugs are discussed. In the case of lipophilic compounds, the advantages of lipid-based drug-delivery systems including increased solubilization, decreased intestinal efflux, decreased intracellular metabolism and possible lymphatic transport are well established as is evident from the success of Neoral and other drug products on the market. In contrast, with respect to hydrophilic compounds, the situation is more complex and, while promising formulation approaches have been studied, issues including reproducibility of response, intersubject variability and duration of response require further optimization before commercially viable products are possible.     

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs

Introduction: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently.

Areas covered: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials.

Expert opinion: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.     

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations

Purpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 g·cm^–2·h^–1 and 3.2 g·cm^–2·h^–1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.     

Emulsion forming drug delivery system for lipophilic drugs

In the recent years, there is a growing interest in the lipid-based formulations for delivery of lipophilic drugs. Due to their potential as therapeutic agents, preferably these lipid soluble drugs are incorporated into inert lipid carriers such as oils, surfactant dispersions, emulsions, liposomes etc. Among them, emulsion forming drug delivery systems appear to be a unique and industrially feasible approach to overcome the problem of low oral bioavailability associated with the BCS class II drugs. Self-emulsifying formulations are ideally isotropic mixtures of oils, surfactants and co-solvents that emulsify to form fine oil in water emulsions when introduced in aqueous media. Fine oil droplets would pass rapidly from stomach and promote wide distribution of drug throughout the GI tract, thereby overcome the slow dissolution step typically observed with solid dosage forms. Recent advances in drug carrier technologies have promulgated the development of novel drug carriers such as control release self-emulsifying pellets, microspheres, tablets, capsules etc. that have boosted the use of "self-emulsification" in drug delivery. This article reviews the different types of formulations and excipients used in emulsion forming drug delivery system to enhance the bioavailability of lipophilic drugs.     

Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies

Oral lipid-based drug delivery systems may include a broad range of oils, surfactants, and cosolvents. This diversity makes comparison of lipid-based formulations difficult. Although the relationship between formulation and drug absorption is understood at a conceptual level, performance in vivo cannot be predicted with confidence at present. The Lipid Formulation Classification System (LFCS) identifies the factors which are likely to affect performance in vivo. There is now a need to establish performance criteria which will facilitate in vitro-in vivo correlation studies. In this review we discuss the properties of excipients, and identify criteria for selection of excipients for lipid-based formulations. Excipients are discussed in the context of the LFCS, our existing knowledge of the fate of these materials during dispersion and digestion, and the likely consequences of their use in formulations. We outline the formulation strategies that can be used for each type of lipid formulation, and suggest a framework for the in vitro testing of each type. Finally we address the choice of lipid formulations in relation to the physicochemical properties of the drug.     

Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs

Oncology pharmacists face a constant challenge with patients who cannot swallow oral anticancer drugs, making extemporaneous oral liquid preparation a requirement. Improper extemporaneous preparation of these agents, especially with the traditional chemotherapy with a narrow therapeutic index, may increase the risk of over- or underdosing. In community pharmacies, multiple barriers exist that prevent these pharmacies from preparing extemporaneous oral anticancer drug formulations for a patient's use at home. In a home setting, patients or caregivers without proper counseling and education on how to safely handle chemotherapy are at increased risk for exposure to these drugs. Based on a review of the literature, compounding recipes are available for 46% of oral anticancer agents. A paucity of data exists on dose uniformity, bioequivalence, and stability of extemporaneous oral liquid formulations of anticancer drugs. Pharmacists must have an understanding of the basic scientific principles that are an essential foundation for the proper preparation of extemporaneous oral anticancer liquid formulations. The collaborative effort of a multidisciplinary team can also help identify different barriers in the community setting, especially in areas where community pharmacies may lack resources for the extemporaneous compounding of oral chemotherapy, and to find ways to coordinate better pharmaceutical care. There are great opportunities for oncology pharmacists, as well as community pharmacists, as a resource for educating and monitoring patients receiving oral chemotherapy to ensure dosing accuracy, safe administration, and proper disposal of hazardous drugs. Development of national guidelines to promote standards of practice in the community and/or home setting is urgently needed to help improve the safety of dispensing and handling oral chemotherapeutic agents, including extemporaneously compounded oral liquid formulations of these drugs.     

Oil-based formulations for oral delivery of insulin

Several oil-based solution formulations of insulin were prepared, in which insulin was solubilized in the form of anhydrous reverse micelles. The preparation process involved micellar dissolution of insulin followed by freeze drying, then reconstitution of lyophilized product with an oil phase. These formulations were stable at room temperature for up to 12 months. No significant changes in the appearance were observed and no degradation products of insulin were detected during the course of the stability study. The efficacy of these formulations was evaluated in-vivo using diabetic Wistar rat as an animal model and then a specific formulation was chosen for further study in non-diabetic New Zealand rabbits. It was found that the efficacy of insulin oil solution was dose dependent and insulin oil solution had the same efficacy as insulin emulsion with the same formulation composition. If ethylene-diaminetetraacetic acid (EDTA) was pre-delivered 40 min before the delivery of insulin oil solution, the hypoglycaemic effect of insulin oil solution was greatly enhanced, with an AUC (% glucose reduced) value increase from 28.5 +/- 14.7 to 167.1 +/- 72.3. The improvement of oral absorption induced by predelivery of EDTA might be attributed to enzyme inhibition, reduced gut mobility and the opening of paracellular routes.     

Beads made of cyclodextrin and oil for the oral delivery of lipophilic drugs: in vitro studies in simulated gastro-intestinal fluids

The aim of this work was to investigate the stability in vitro, in simulated gastro-intestinal fluids, of beads, made of α-cyclodextrin and soybean oil, and to study the release of progesterone, a model of lipophilic drug. This was evaluated over time by the monitoring of the proportion of intact beads, their volume and the percentage of progesterone dissolved. Their incubation in the simulated gastric fluid provoked a moderate reduction of their number (20%) and a decrease of their volume (50%) after 55 min. Whatever the intestinal medium subsequently introduced, bead number and volume decreased more until bead disintegration that appeared faster in sodium taurocholate rich-medium. In such fluid, the amount of progesterone dissolved increased rapidly between 65 and 180 min, with both beads and emulsion to be equal after 85 min. With soft capsules, the increase was more gradual. In sodium taurocholate free-medium, more progesterone was dissolved from the emulsion than from beads or soft capsules. The release of progesterone from beads resulted from the erosion of their matrix and its partition equilibrium between oily micro-droplets and aqueous phase. The original structure of beads confers to this multiparticulate system interesting properties for the oral delivery of lipophilic drugs.     

Hydrogel-thickened nanoemulsion system for topical delivery of lipophilic drugs

In this work, a hydrogel-thickened nanoemulsion system (HTN) with powerful permeation ability, good stability and suitable viscosity was investigated for topical delivery of active molecules. HTN was prepared to deliver an oily mixture of 5% camphor, 5% menthol and 5% methyl salicylate for topical therapy of arthritis, minor joint and muscle pain using soybean oil as the oil phase, soybean lecithin, Tween 80 and poloxamer 407 as the surfactants, propylene glycol as the cosurfactant, carbomer 940 as a thickening agent. The HTN system was found to combine the o/w microstructure of nanoemulsion with the gel network of hydrogel and had a suitable viscosity of 133.2PaS. The system had small average diameters and good long-term stability. The abilities of HTN to deliver the high amounts of camphor, menthol and methyl salicylate were evaluated using the in vitro permeation studies. The permeation rates of camphor, menthol and methyl salicylate from the optimal HTN formulation were 138.0+/-6.5, 63.6+/-3.3, 53.8+/-3.2 microg cm(-2) h(-1) and showed the significant advantages over the control gel. The HTN with good stability and powerful permeation enhancing ability and suitable viscosity might be a promising prospective carrier for topical delivery of lipophilic drugs.     

Biopharmaceutical challenges associated with drugs with low aqueous solubility--the potential impact of lipid-based formulations

The percentage of new chemical entities synthesised with low aqueous solubility and high therapeutic efficacy is growing, this presents major challenges for the drug delivery scientists. The role of physicochemical properties in identification of suitable drug candidates for oral lipid-based delivery systems is discussed. A knowledge of the interplay of physicochemical and biopharmaceutical drug properties with the physiological environment of the gastro-intestinal tract (GIT), as a prerequisite to successful formulation design, is reviewed. The importance of excipient selection with an emphasis on bioactive excipients is stressed. The need for more examples of in vitro-in vivo correlations as a means of maximizing the development potential and commercial future for lipid-based formulations, and, promoting confidence within the industry for these delivery systems is highlighted.     

Development of supersaturatable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs

The supersaturatable self-emulsifying drug delivery system (S-SEDDS) represents a new thermodynamically stable formulation approach wherein it is designed to contain a reduced amount of a surfactant and a water-soluble cellulosic polymer (or other polymers) to prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo. The S-SEDDS formulations can result in enhanced oral absorption as compared with the related self-emulsifying drug delivery systems (SEDDS) formulation and the reduced surfactant levels may minimise gastrointestinal surfactant side effects.     

Pharmacosomes: the lipid-based new drug delivery system

Lipid-based drug delivery systems have been investigated in various studies and shown their potential in controlled and targeted drug delivery. Pharmacosomes are amphiphilic phospholipid complexes of drugs bearing active hydrogen that bind to phospholipids. Pharmacosomes impart better biopharmaceutical properties to the drug, resulting in improved bioavailability. Pharmacosomes have been prepared for various non-steroidal anti-inflammatory drugs, proteins, cardiovascular and antineoplastic drugs. Developing the pharmacosomes of the drugs has been found to improve the absorption and minimize the gastrointestinal toxicity. This article reviews the potential of pharmacosomes as a controlled and targeted drug delivery system and highlights the methods of preparation and characterization.     

Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine

By using a rational formulation approach, we have tried to find the general characteristics for promising self-emulsifying drug delivery systems (SEDDS) based on natural lipid components, for the oral delivery of lipophilic drugs. Galactolipids, which are polar lipids commonly found in the chloroplast membranes of green plants, and a natural part of the human diet, were the main surfactants in these formulations. This was done in three clinical studies: a screening study, followed by a prediction study and, finally, a confirmatory study; in all 17 experimental formulations were investigated. The clinical trials were performed in healthy volunteers. Cyclosporine, a well-known lipophilic peptide, was incorporated in different SEDDS, and administered orally, followed by the measurement of the blood concentration of the drug over time. The pharmacokinetic parameters, which describe the rate and extent of absorption, were estimated. We found that fractionated oat oil (FOO) and medium chain monoglycerides (60:30:10 mono-, di- and tri-glycerides) promoted absorption, and resulted in a formulation with absorption characteristics nearly equal to the commercial formulation of cyclosporine, Sandimmun Neoral^®.     

Recent approaches of lipid-based delivery system for lymphatic targeting via oral route

Abstract

Lymphatic system is a key target in research field due to its distinctive makeup and huge contributing functions within the body. Intestinal lymphatic drug transport (chylomicron pathway) is intensely described in research field till date because it is considered to be the best for improving oral drug delivery by avoiding first pass metabolism. The lymphatic imaging techniques and potential therapeutic candidates are engaged for evaluating disease states and overcoming these conditions. The novel drug delivery systems such as self-microemulsifying drug delivery system, nanoparticles, liposomes, nano-lipid carriers, solid lipid carriers are employed for delivering drugs through lymphatic system via various routes such as subcutaneous route, intraperitoneal route, pulmonary route, gastric sub-mucosal injection, intrapleural and intradermal. Among these colloidal particles, lipid-based delivery system is considered to be the best for lymphatic delivery. From the last few decades, mesenteric lymph duct cannulation and thoracic lymph duct cannulation are followed to assess lymphatic uptake of drugs. Due to their limitations, chylomicrons inhibitors and in-vitro models are employed, i.e. lipolysis model and permeability model. Currently, research on this topic still continues and drainage system used to deliver the drugs against lymphatic disease as well as targeting other organs by modulating the chylomicron pathway.     

Enteric microsphere formulations of papain for oral delivery

Enteric microspheres formulations of papain were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP), Eudragit L 100 and Eudragit S 100, to avoid gastric inactivation of papain. Smaller internal and external aqueous phase volume provided maximum encapsulation efficiency (74.49-79.76%), least particle size (52.4-60.2 μm) and 21-26% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastro-resistance of formulations. The anionic microspheres, zeta potential between -18.21 and -20.06 mV, aggregated in 0.1 N HCl (i.e., gastric pH 1.2), due to protonation of carboxylic groups of enteric polymer and loss of surface charge with subsequent change in zeta potential. The aggregates being <500 μm size would not impede gastric emptying. However, at pH>5.0 (duodenal pH) the microspheres showed de-aggregation due to restoration of surface charge. HPMCP and Eudragit L 100 microspheres facilitated almost complete release of papain within an hour at pH 6.0 and 6.8, respectively while Eudragit S 100 microspheres released 84.56% papain at pH 7.4, following Higuchi kinetics. FTIR spectroscopy revealed entrapment of enzyme; PXRD & DSC indicated amorphous character and SEM showed spherical shape of microspheres. In simulated gastro-intestinal pH condition, HPMCP, Eudragit L 100 and Eudragit S 100 microspheres showed good digestion of paneer and milk protein. Thus, enteric microspheres formulations could serve as potential carrier for oral enzyme delivery. Stability studies indicated the formulations with around 5% overage would ensure 2 years shelf life at room temperature.