Room temperature ionic liquids and their mixtures: potential pharmaceutical solvents.

Room temperature ionic liquids (RTILs) are organic salts which are liquids at ambient temperature. Composed of relatively large asymmetric organic cations and inorganic or organic anions, they have generated interest as 'green' solvents. Here we report on the solvency of alkyl imidazolium salts (PF(6)(-)Br(-)Cl(-)) for poorly water-soluble model drugs, albendazole and danazol, indicating their potential application as pharmaceutical solvents/cosolvents. The solubility of albendazole, for example, is increased by more than 10,000 times by 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF(6)(-)). Ionic liquids can be water-miscible or water-immiscible. The aqueous miscibility of a poorly water-miscible RTIL such as of [bmim]PF(6)(-) can be improved by the inclusion of a second more miscible RTIL (e.g. 1-hexyl-3-methylimidazolium bromide ([hmim]Br(-))). The extent of improvement in water miscibility was found to correlate with the hydrophilicity of the second RTIL. This ability to modulate RTILs' aqueous miscibility increases their usefulness as pharmaceutical solvents.

Local controlled drug delivery to the brain: mathematical modeling of the underlying mass transport mechanisms.

The mass transport mechanisms involved in the controlled delivery of drugs to living brain tissue are complex and yet not fully understood. Often the drug is embedded within a polymeric or lipidic matrix, which is directly administered into the brain tissue, that is, intracranially. Different types of systems, including microparticles and disc- or rod-shaped implants are used to control the release rate and, thus, to optimize the drug concentrations at the site of action in the brain over prolonged periods of time. Most of these dosage forms are biodegradable to avoid the need for the removal of empty remnants after drug exhaustion. Various physical and chemical processes are involved in the control of drug release from these systems, including water penetration, drug dissolution, degradation of the matrix and drug diffusion. Once the drug has been released from the delivery system, it has to be transported through the living brain tissue to the target site(s). Again, a variety of phenomena, including diffusion, drug metabolism and degradation, passive or active uptake into CNS tissue and convection can be of importance for the fate of the drug. An overview is given of the current knowledge of the nature of barriers to free access of drug to tumour sites within the brain and the state of the art of: (i) mathematical modeling approaches describing the physical transport processes and chemical reactions which can occur in different types of intracranially administered drug delivery systems, and of (ii) theories quantifying the mass transport phenomena occurring after drug release in the living tissue. Both, simplified as well as complex mathematical models are presented and their major advantages and shortcomings discussed. Interestingly, there is a significant lack of mechanistically realistic, comprehensive theories describing both parts in detail, namely, drug transport in the dosage form and in the living brain tissue. High quality experimental data on drug concentrations in the brain tissue are difficult to obtain, hence this is itself an issue in testing mathematical approaches. As a future perspective, the potential benefits and limitations of these mathematical theories aiming to facilitate the design of advanced intracranial drug delivery systems and to improve the efficiency of the respective pharmacotherapies are discussed.

Transcytosis of nanoparticle and dendrimer delivery systems: evolving vistas.

The translocation of particulate matter across the gastrointestinal tract is now a well documented phenomenon offering new potential for the delivery of drugs with poor dissolution profiles and labile chemistries via encapsulation in biodegradable nanoparticles. The last few years have seen an acceleration in the number of publications describing the varying facets of this approach and the multidisciplinary nature of this field. This review delineates data from this rather fragmented area and from cognate fields to provide a physicochemical viewpoint of the importance of surface chemistries of oral drug delivery vehicles and their interactions in and with gut contents prior to uptake. The role of lymphoid and non-lymphoid tissues is examined, and the role of bioadhesion is discussed. The exciting potential of molecular encapsulation of drugs via dendrimers and star branched molecules is discussed in the context of nanotechnological applications for the oral route. Evolving vistas include a better understanding of the plasticity of the intestinal epithelium and M-cell induction as well as the influence of disease states on particulate uptake. In this review we address a number of issues deemed vital to an understanding of the subject including (i) some background knowledge on particulate uptake (the subject of several reviews), (ii) factors affecting uptake such as diameter and surface charge and character, (iii) the dynamic nature of particle interactions in the gut, (iv) the dynamic nature of the processes of capture, adhesion, uptake, transcytosis and translocation, and (v) the influence of surface ligands.

Liposomes in drug delivery. Clinical, diagnostic and ophthalmic potential.

Liposomes (phospholipid-based vesicles) have been investigated since 1970 as a system for the delivery or targeting of drugs to specific sites in the body. Because of their structural versatility in terms of size, composition, surface charge, bilayer fluidity and ability to incorporate almost any drug regardless of solubility, or to carry on their surface cell-specific ligands, liposomes have the potential to be tailored in a variety of ways to ensure the production of formulations that are optimal for clinical use. This includes controlled retention of entrapped drugs in the presence of biological fluids, controlled vesicle residence in the blood circulation or other compartments in the body, and enhanced vesicle uptake by target cells. Accumulated in vivo evidence, particularly in areas such as cancer chemotherapy, antimicrobial therapy, vaccines, diagnostic imaging and the treatment of ophthalmic disorders has indicated clearly that some liposome-entrapped drugs and vaccines exhibit superior pharmacological properties to those observed with conventional formulations. Such work has encouraged the application of liposomes in the treatment of diseases in humans. A large number of trials in patients with cancer or infections suggest that certain liposomal drug formulations are likely to prove clinically useful.

Adverse drug events related to dosage forms and delivery systems.

While some of the adverse events caused by the administration of medicines are specifically attributable to the drug molecule, a proportion arises because of the chemical, biological and physical nature of the formulation. The effects may be compounded by certain patient factors, an incomplete understanding of the behaviour of the formulation or the coadministration of other drugs. This review examines adverse drug reactions and other adverse events arising from the nature of the dosage form or formulation used. These adverse effects may be the result of local irritation/toxicity, hypersensitivity or allergic reactions, systemic effects from essentially local therapies, or idiosyncratic reactions in a small number of individuals. In certain cases where the exact nature of the formulation is unknown, adverse events cannot be attributed to any single ingredient. In addition, the total of all ingredients of a formulation, even where details of the formulation are clear, may give rise to abnormal behaviour of the formulation in vivo. Often the desired objective of a particular specialised formulation leads to an unforseen but related adverse effect, and in certain instances these events are completely unpredictable and at variance with the perceived objectives of the formulation.

Novel oral drug formulations. Their potential in modulating adverse effects.

The rationale for specialised oral formulations of drugs include prolongation of effect for increased patient convenience and reduction of adverse effects through lowered peak plasma concentrations. Local and systemic adverse effects due to high concentrations of drug can be minimised by the use of controlled release delivery systems. Local effects in the gastrointestinal (GI) tract from the release of irritant drug molecules can also be reduced, but the gastric damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is only partially relieved by formulation approaches because of the involvement of systemic factors in the aetiology of GI adverse events. The advantages for each drug class must be examined. Newer dosage forms include: (i) osmotic pumps and zero order kinetics systems to control the release rate of the drug; (ii) bioadhesive systems and gastric retention devices to control GI transit; (iii) bioerodible hydrogels; (iv) molecular carrier systems (e.g. cyclodextrin-encapsulated drugs) to modulate local toxicity in the GI tract; (v) externally activated systems; and (vi) colloidal systems such as liposomes and microspheres. There is evidence for improved tolerability for a variety of drugs administered in novel delivery systems. However, the evidence for improved tolerability is complicated by the potential bias in adverse reaction reporting systems, and a lack of studies directly comparing conventional and modified release preparations. The technology now available to produce delivery systems which not only release drugs in a controlled and predetermined fashion, but which can also target to regions of the GI tract such as the colon, should allow greater control of therapy and potentially might minimise patient variables. However, the problem of variable GI transit times still eludes solution. Systems which rely on time to release drug might be more vulnerable to patient-to-patient variability than those which respond to local environments. The effect of food intake is more apparent on single-unit, nondisintegrating dosage forms, although of course none so far are immune from influence. The risk of new adverse effects resulting from such positional therapy with novel delivery devices must be considered. Understanding the mechanisms of induction of individual adverse effects can lead to advances in modes of delivery to decrease the potential for adverse reactions and events while maintaining therapeutic efficacy. Increased compliance can led to increased therapeutic control and hence safety. Each system has to be considered on its merits. No generalisations can be made, although invariably the modulation of high peak plasma concentrations diminishes adverse effects due to rapid absorption.

A low density lipoprotein-methotrexate covalent complex and its activity against L1210 cells in vitro.

Low-density lipoprotein particles are potential drug carriers, but only lipophilic drug species partition into the core of the system. In this paper the polar drug methotrexate has been coupled to the exterior protein of low density lipoprotein (LDL) particles using the reagent 1-ethyl-3(3'-dimethylaminopropyl) carbodiimide HCl. The coupled system was sized by photon correlation spectroscopy and the in vitro activity of the complex determined against L1210 cells maintained in medium supplemented with fetal calf serum. The reaction between methotrexate and low density lipoprotein is variable but quantifiable, about ten drug molecules being attached to each LDL particle, resulting in an increase in the radius and polydispersity of the particles. The activity of the complex against L1210 murine leukaemia cells has been demonstrated in vitro, but it is 30 times less active than free drug.

The distribution and elimination of methotrexate in mouse blood and brain after concurrent administration of polysorbate 80.

This paper describes further exploration of the effect of polysorbate 80 on the absorption, distribution, and elimination of methotrexate (MTX). This study has confirmed the earlier finding that polysorbate 80 could increase the absorption of MTX from the mouse gastrointestinal tract and enhance the drugs uptake into the brain. The experiments reported here suggest that polysorbate 80 has a direct effect on the blood-brain barrier leading to the increased uptake of MTX, which is evident following IV administration. Measurements of MTX excreted in the urine and faeces confirmed the role of polysorbate 80 in facilitating the excretion of MTX into the bile and urine. Polysorbate 80 administered PO did not cause any reduction of plasma volume, thus excluding the possibility that the higher MTX concentrations measured in mice after concurrent administration of polysorbate PO might result from a reduction in blood volume due to osmotic effects. At the doses given, polysorbate 80 appeared not to have a damaging effect on the gastrointestinal mucosa.

Effects of polysorbate 80 on the absorption and distribution of oral methotrexate (MTX) in mice.

This study is part of a programme of work aimed at improving the bioavailability of oral methotrexate (MTX). In preliminary experiments no significant effect of non-ionic surfactant polysorbate 80 (Tween 80) on absorption of 0.5 mg MTX X kg-1 in NMRI mice was observed except when the drug was given together with 6% polysorbate 80 in solution. Absorption from a higher dose of 3 mg MTX X kg-1 was increased when the drug was administered with 2% or 6% polysorbate 80. Plasma MTX measurements confirmed the significantly higher levels of MTX with 6% polysorbate 80 PO. In subsequent experiments, when Porton mice were used and 4 mg MTX X kg-1 was administered PO, higher plasma and brain levels of MTX were measured in animals given the drug with 6% polysorbate 80, suggesting the enhancement of MTX uptake by this non-ionic surfactant. Although the amount of MTX in the liver and kidney of mice given MTX with polysorbate 80 were not significantly different from the amounts in mice given MTX alone, the lower observed levels suggested that polysorbate 80 perhaps facilitates the elimination of the drug from these organs. The amount of plasma MTX in mice measured 1 h after oral administration of various MTX doses in the presence of 6% polysorbate 80 were significantly higher than the levels in mice given the drug without surfactant, but the significantly higher amounts of MTX in the brain were only observed following the doses of 2 and 6 mg MTX X kg-1.

Extrusion of niosomes from capillaries: approaches to a pulsed delivery device.

We describe an early prototype of a pulsatile delivery system for drug containing vesicles. Nonionic surfactant vesicles (niosomes) of average diameter 4-30 microm are extruded from glass capillaries (exit diameter, 5-10 microm), using air pressures of 0.5-5 p.s.i. The formulation of the vesicles is vital. Extrusions were affected by the size, shape, and membrane composition of the niosomes used. Spherical or polyhedral niosomes, formed by polyoxyethylene alkyl ethers with and without cholesterol, respectively, with diameters larger than the exit diameter of the capillary do not retain their membrane integrity on extrusion and were sheared to form new ultrastructures. The expulsion of single or groups of intact polystyrene microspheres or tetradecyl-beta-D-maltoside niosomes with sizes smaller than the exit diameter can be achieved readily. The stepwise release profile of luteinizing hormone releasing hormone (LHRH) obtained after pulsatile expulsion of groups of niosomes entrapping LHRH indicates the feasibility of this system for pulsatile delivery of vesicles, although it requires miniaturization.

Oral uptake and translocation of a polylysine dendrimer with a lipid surface.

A series of lipidic peptide dendrimers based on lysine with 16 surface alkyl (C(12)) chains has been synthesised in our laboratories. One of the series, a fourth generation dendrimer with a diameter of 2.5 nm was chosen to study its absorption after oral administration to female Sprague-Dawley rats (180 g, 9 weeks old). It was synthesised as the tritiated derivative (all acetyl portions) and had a molecular weight of 6300 and log P (octanol/water) of 1.24. First a single oral dose 14 mg/kg was administered by gavage. Maximum levels of dendrimer observed were 15% in the small intestine, 5% in the large intestine and 3% in the blood at 6 h after administration, while 1.5% reached the liver, 0.1% the spleen and 0. 5% the kidneys. In a parallel study with a higher dose of 28 mg/kg, approximately 1% was absorbed via Peyer's patches of the small intestine at 3 h. The maximum uptake by small intestine enterocytes was 4% of the dose after 3 h. After 12 h, 0.3 and 4% dendrimer was measured respectively in Peyer's patches and enterocytes of the large intestine. When calculated on the basis of target tissue weight, the total percentage of the dose absorbed through Peyer's patches was greater than through normal enterocytes in the small intestine after 3 and 24 h, but the opposite was true in the large intestine. These levels of uptake and translocation are lower than those exhibited by polystyrene particles in the range from 50 to 3000 nm. This might suggest that there is an optimum size for nanoparticulate uptake by the gut.

Factors affecting the oral uptake and translocation of polystyrene nanoparticles: histological and analytical evidence.

Quantitative and qualitative evidence from our laboratories on the absorption and translocation of polystyrene latex nanoparticles both by histological (qualitative) and analytical measurement of levels of polystyrene (quantitative) is briefly reviewed in this paper. We have previously compared the uptake of nonionized polystyrene latex ranging in size from 50nm to 3 microns, and made some comparisons of uptake between carboxylated microspheres and nonionic systems, showing the lower uptake of the former through the lymphoid tissue of the gastrointestinal tract. Size is a key parameter, uptake increasing with decreasing particle diameter. Early evidence suggested that uptake is by way of the Peyer's patches and other elements of the gut associated lymphoid tissue (GALT). Adsorption of hydrophilic block-copolymers onto polystyrene markedly reduces the uptake by intestinal GALT. Modification of the surface with specific ligands such as by covalent attachment of tomato lectin molecules has indicated widespread uptake by non-GALT tissues, following their binding to and internalisation by enterocytes. The ability to decrease and increase uptake is clear evidence of a phenomenon which has the potential for further control to allow it to be exploited fully for drug or vaccine delivery. The evidence to date with nanoparticles as carriers systems for labile drugs such as proteins by the oral route remains to be substantiated.

Comparative, quantitative study of lymphoid and non-lymphoid uptake of 60 nm polystyrene particles.

Uptake by gut epithelial tissue of 60 nm polystyrene particles was studied in female Sprague-Dawley rats (180 g, 9 weeks old) after 5 days oral dosing by gavage (14 mg/kg). The gut was divided into lymphoid and non-lymphoid tissue of the small and large intestine, prior to analysis for polystyrene by gel permeation chromatography (GPC). Approximately 10% of the administered dose was recovered from the entire gastrointestinal tract. The total percentage of the administered dose taken up through lymphoid tissue was statistically much greater than through non-lymphoid tissue. It was estimated that 60% of the uptake in the small intestine occurred through the Peyer's patches, even though the patches comprised a small percentage of the total surface area of the small intestinal tissue. A significant amount of the total uptake was shown to occur in the large intestine, particularly in the lymphoid sections of this tissue. These results were confirmed by fluorescence microscopy.

A non-ionic surfactant vesicle-in-water-in-oil (v/w/o) system: potential uses in drug and vaccine delivery.

An aqueous dispersion of niosomes (non-ionic surfactant vesicles) emulsified in an external oil phase forms the vesicle-in-water-in-oil (v/w/o) system described in this paper. The properties of the surfactant used to form the vesicles, the surfactant or surfactant mixture used to stabilize the emulsion and the nature of the oil phase can be changed to provide systems of different capacities for drug or antigen and different release characteristics. The same nonionic surfactant is used as the principle amphipile to form the niosomes and to stabilize the w/o emulsion, thus promoting stability by decreasing transfer of surfactant between the stabilizing monolayers and the vesicle bilayers. The in vitro release of carboxyfluoroscein and 5-fluorouracil encapsulated within the niosomes of the v/w/o system has been investigated, the nature of the oil phase and surfactant-oil interactions being important in determining the rate of solute release. Initial studies of the system in vivo, as an adjuvant for tetanus toxoid, using cottonseed oil as the external oil phase, showed enhanced immunological activity over the free antigen or vesicles.

The activity of doxorubicin niosomes against an ovarian cancer cell line and three in vivo mouse tumour models.

Demonstration of the improved doxorubicin pharmacokinetics and tumoricidal activity, after a single intravenous dose of 10mg kg-1 doxorubicin sorbitan monostearate (Span 60) based niosomes in the mouse adenocarcinoma (MAC) tumour model (Uchegbu et al., 1995) preceded the present study in which the activity of doxorubicin C16G2 (a hexadecyl diglycerol ether) based niosomes was evaluated against naive and established MAC tumour models. C16G2 niosomes were equiactive with doxorubicin solution. It is concluded that while in some tumour models, niosomal formulations demonstrate some advantages over the free drug, caution is advocated in the extrapolation of these results. The activity of doxorubicin C16G2 and Span 60 niosomes was also studied against a human ovarian cancer cell line and its doxorubicin resistant subline. There was a slight reduction in the IC50 against the resistant cell line when the drug was encapsulated in Span 60 niosomes in comparison to the drug in solution. Taking into account the in-vitro release characteristics of the various niosomal formulations, it is concluded that the use of niosomal formulations against multidrug resistance shows sufficiently encouraging results to warrant further study.

Biliary excretion of polystyrene microspheres with covalently linked FITC fluorescence after oral and parenteral administration to male Wistar rats.

To further our understanding of microspheres as a drug delivery system, the biliary excretion of covalently linked FITC fluorescence polystyrene microspheres of various diameters was investigated after oral and parenteral administration to male Wistar rats. About 36%, 16% 3% and 1% of the dose was excreted into the bile after parenteral injection of 50 nm, 500 nm, 1 micron and 3 microns diameter microspheres, respectively, over 24 h. In addition, about 30%, 11%, 1%, and 1% of the dose, respectively, was found in the blood at 24 h. After oral administration of 50 nm, 500 nm, and 1 micron microspheres, the recovery was about 18%, 8% and 1% of the dose in the bile and about 9%, 1%, and 0% in the blood, respectively. No 3 microns microspheres were detected in the bile or blood after oral administration. Particles were not detected in the urine of any group tested. Thus, the present study demonstrated that biliary excretion plays an important role in the disposition of microspheres administered by the oral or parenteral routes, and there is a size-related excretion of microspheres into the bile.

Novel sorbitan monostearate organogels.

Sorbitan monostearate, a hydrophobic nonionic surfactant, gels a number of organic solvents such as hexadecane, isopropyl myristate, and a range of vegetable oils. Gelation is achieved by dissolving/dispersing the organogelator in hot solvent to produce an organic solution/dispersion, which, on cooling sets to the gel state. Cooling the solution/dispersion causes a decrease in the solvent-gelator affinities, such that at the gelation temperature, the surfactant molecules self-assemble into toroidal inverse vesicles. Further cooling results in the conversion of the toroids into rod-shaped tubules. Once formed, the tubules associate with others, and a three-dimensional network is formed which immobilizes the solvent. An organogel is thus formed. Sorbitan monostearate gels are opaque, thermoreversible semisolids, and they are stable at room temperature for weeks. The gels are affected by the presence of additives such as the hydrophilic surfactant, polysorbate 20, which improves gel stability and alters the gel microstructure from a network of individual tubules to star-shaped "clusters" of tubules in the liquid continuous phase. Another solid monoester in the sorbitan ester family, sorbitan monopalmitate, also gels organic solvents to give opaque, thermoreversible semisolids. Like sorbitan monostearate gels, the microstructure of the palmitate gels comprise an interconnected network of rodlike tubules. Unlike the stearate gels, however, the addition of small amounts of a polysorbate monoester causes a large increase in tubular length instead of the "clustering effect" seen in stearate gels. The sorbitan stearate and palmitate organogels may have potential applications as delivery vehicles for drugs and antigens.

Effects of hydrotropic agents on the solubility, precipitation, and protein binding of etoposide.

Etoposide, a commonly used anticancer agent, has an aqueous solubility of 0.2 mg/mL. It is formulated for intravenous use as a more concentrated solution (Vepesid; 20 mg/mL) with polysorbate 80 and with cosolvents. In this work, hydrotropic agents such as sodium benzoate, sodium o-hydroxybenzoate (sodium salicylate), sodium 2,5-dihydroxybenzoate (sodium gentisate), and the sodium salts of 2,4-dihydroxy- and 2,6-dihydroxybenzoic acid and of 2,4,6-trihydroxybenzoic acid have been used as alternative solubilizers of etoposide. The weakest and strongest interactants with etoposide were, respectively, sodium benzoate and sodium 2,4,6-trihydroxybenzoate. The effect of mono- and dihydroxybenzoates on etoposide solubility was intermediate. Although sodium 2,4,6-trihydroxybenzoate is the most efficient solubilizer, its use is limited by its own low aqueous solubility. The effect of sodium salicylate and other formulation ingredients on the in vitro protein binding and precipitation of etoposide upon dilution with normal saline and human plasma has been studied. Etoposide binds to the extent of 94% to human serum albumin (HSA) and human plasma, but only 24% to bovine serum albumin (BSA) in vitro. Sodium salicylate significantly decreased the binding of the drug to both HSA and human plasma, whereas the components of Vepesid did not. Dilution of Vepesid (1:2 and 1:3) with plasma in vitro resulted in immediate precipitation, while the corresponding dilutions of etoposide aqueous solution (20 mg/mL in 2 M sodium salicylate) produced no precipitate for the first hour.

Water-in-sorbitan monostearate organogels (water-in-oil gels).

Novel multicomponent organogels containing an aqueous phase are described, and some properties which influence their potential as delivery devices for hydrophilic drugs and vaccines are discussed. The gel is produced by preparing a hot water-in-oil (w/o) emulsion using sorbitan monostearate, a nonionic surfactant which is also the organogelator, as the principal emulsifying agent. On cooling at room temperature, the w/o emulsion sets to an opaque, semisolid, thermoreversible organic gel. Cooling the emulsion results in a reduced solubility of the sorbitan monostearate in the oil, with a corresponding decrease in solvent-surfactant affinities, causing surfactant self-assembly into aggregates. The microstructure of the w/o gel is seen by light microscopy to consist of a network of tubules and fibrils (containing the aqueous phase) dispersed in the organic medium. X-ray diffraction and freeze-fracture studies suggest that the tubular aggregates in the w/o gel are made up of surfactant molecules arranged in inverted bilayers and that the aqueous phase is accommodated within these inverted bilayers, bound by the polar headgroups of the surfactant molecules. The presence of water in the tubular skeleton of the organic gels results in the establishment of percolating electroconductive aqueous channels in the organogel. Increasing the water content of a w/o gel causes the surfactant tubules to swell with a corresponding increase in conductivity until the tubules are saturated. Further increase in the water content results in the excess water accumulating in droplets within the organic medium and a decrease in conductivity as the gel integrity is compromised. The w/o gels (containing a model antigen, radiolabeled bovine serum albumin, in the aqueous phase) have demonstrated depot properties after intramuscular administration to mice, entrapped antigen being released over a period of days.

Effect of formulation of intramuscular injections of phenothiazines on duration of activity.

Trifluoperazine and pericyazine were formulated using both the hydrochloride and embonate salts, and some comparisons were made with the activity of fluphenazine salt and ester formulations. Simple solutions in polyethylene glycol, gelled aqueous solutions, nonaqueous suspensions, multiple emulsions, and microencapsulated preparations were formulated, and their duration of activity was tested in dogs. While the multiple emulsion system showed some promise, a nylon microcapsule system produced significant prolonged activity of the drug after deep intramuscular injection.