Tratamientos

When formulating novel colloidal carriers/solubilisers for existing drugs, both the pharmacokinetics of the drug and the pharmacokinetic distribution of the carrier itself must be considered. Ideally, the drug pharmacokinetics should be identical to the original product in clinical use. If it differs, it should not adversely affect the efficacy or safety of the product, i.e. it should not accumulate in sites where drug activity could be deleterious. Secondly, the liposome pharmacokinetics have to be cautiously evaluated. It is generally not desirable for the liposomes to accumulate in the tissues such as the MPS. Therefore, phospholipids should be carefully selected to form liposomes which are rapidly destroyed and cleared in vivo. For toxicity reasons, liposomes should not circulate for prolonged periods if they are serving no purpose. Ideally, it is better for them to be destroyed rapidly before they even reach the MPS, where they could potentially cause difficulties. Particulate overload of MPS has been associated with reduced immune activity, which may lead to complications such as infection (Allen et al., 1984). Chronic liposome administration has also been implicated with histological changes occurring in the liver (Allen and Smuckler, 1985).

1.3.4.1 Pharmacokinetic distribution of lipophilic hydrophobes

Elegant work carried out by Fahr et al. (1995) used cyclosporin A (cyA) as a model hydrophobic drug to demonstrate that targeting o f most hydrophobes could not be achieved using liposomes. A series of experiments using liposomes with a variety of lipid compositions showed the pharmacokinetic distribution of the hydrophobe to be independant of the liposome fate. Irrespective of the type of liposome employed; saturated, charged, or PEG-ylated, it was demonstrated that in vivo., the drug rapidly equilibrated itself in the body as if it were administered in a micelle formulation. The reason for this is due to the ability of most hydrophobes to leave the liposome bilayer. Although these hydrophobes are defined as water insoluble by the Pharmacopoeias, they possess a degree of aqueous solubility, even if it is to a minimal extent. Therefore, when added to a large volume of water with lipophilic compartments, e.g. the bloodstream, the hydrophobe rapidly partitions out of the liposome via the aqueous environment. It redistributes itself between the liposome and other lipophilic compartments, e.g. fatty tissues, red blood cells and lipophilic plasma proteins, as if it were solubilised in

micelles. Most hydrophobes will behave in this manner unless the hydrophobe is chemically derivatised to encourage intercalation and anchorage to the liposome bilayer. The findings described above were contrary to the reports of some workers, who reported that the drug pharmacokinetic profile of liposome cyA was altered. Fahr (1995) put forward suggestions to explain these anomalies: although hydrophobes can not be targeted using liposomes, it is possible to modify the half life of cyA by controlling the amount of lipid injected. Drastically increasing the lipid level by introducing large levels o f phospholipid into the bloodstream, could possibly alter the pharmacokinetic distribution of the hydrophobe. Injecting large doses of lipid, effectively increases the fat compartment in the bloodstream and the drug partitions into this phospholipid as if it were excess fat. Additionally, differences in blood lipid profiles between animal models may account for the differing pharmacokinetic profiles of the drug between the different animal species. Similar pharmacokinetic behaviour of paclitaxel in animal models has been observed (Sparreboom and Beijnen, 1996). It seemed that the large amount of polyethoxylated castor oil contributed to the non-linear kinetics of the drug by increasing the lipid content of the blood, in the form of the polyethoxylated castor oil. 1.3.4.2 In vivo distribution of classical liposomes

The distribution o f the liposome depends largely upon the phospholipid composition. Addition of cholesterol and other membrane stabilising components (Muramatsu et al., 1994 and 1995; Qi et al., 1995) may maintain the integrity of the liposome and direct it towards the MPS. Incorporation of charge is believed to reduce circulation time of liposomes compared to neutral liposomes (Hemandez-Caselles et al., 1993). In this context classical liposomes with lipid compositions using unsaturated PC and unsaturated PL will mainly be considered.

One major concern using liposomes is the passive accumulation of liposomes in the cells o f the MPS. High doses of liposomes may lead to saturation of the system and possible reduction in the efficacy of the immune system (Allen, 1988). Originally, this saturation of the MPS was the rationale for pre-administering a high dose of blank liposomes: the objective being to transiently block the MPS activity to enable non-MPS tissues to be imaged/targeted (Proffitt et al., 1983). However, if high levels of cholesterol are omitted fi*om the bilayer and the phospholipids are predominantly unsaturated, the liposomes are likely to be destroyed rapidly, even before they can reach

Chapter one- Introduction

the MPS. Indeed this destruction seemed to be occurring when the original “targeting” experiments attempted to target liposomes containing hydrophilic materials. These initial experiments yielded disappointing results in animals, because the liposomes did not remain intact in vivo. It was soon realised that classical liposomes composed solely of phosphatidylcholine were both leaky and short lived in vivo. These phosphatidylcholine vesicles were predominantly destroyed by the lipophilic plasma proteins (Scherphof et al., 1978; Scherphof and Morselt, 1984; Bonté and Juliano,

1986). This property is desirable for liposomes if they are to be used as solubilisers. 1.3.5 Studies reporting the use of liposomes as solubilisers

There are relatively few studies reporting the use o f liposomes as solubilisers (Lidgate et al., 1988; Thoma and Schmid, 1992). The main classes of drugs which have been studied are the corticosteroids (Arrowsmith et al., 1983), hydrophobic antifungals (Lopez-Berestein and Juliano, 1987) and hydrophobic cytotoxics. Examples o f two clinically used cytotoxics include paclitaxel and teniposide, both hydrophobes are currently formulated in polyethoxylated castor oil. Paclitaxel, a natural diterpenoid extracted from yew bark (Wani et al., 1971), was solubilised in PL/ bile salts micelles which formed liposomes upon dilution. This carrier appeared to have reduced toxicity compared to the non-ionic carrier (Alkan-Onyuksul et al., 1994). In mice, the mixed micelle vehicle had a median lethal dose, LD50, which was 1.4 times less toxic than the polyethoxylated castor oil surfactant. A similar study by Sharma and Straubinger (1994) demonstrated that PL liposomes could dramatically reduce the toxicity of the formulation. In this study, paclitaxel could be completely solubilised, if the paclitaxel content was kept < 3 mol% with specific lipid compositions.

Teniposide, a semi-synthetic podophyllotoxin cytotoxic, has been associated with liposomes generated from bile mixed micelles (Alkan-Onyuksul and Son, 1992). However, a large amount o f phospholipid relative to teniposide (approximately 50:1 w/w) was required to fully solubilise this hydrophobe.

Examples of novel compounds solubilised in liposomes include some photo dynamic therapy drugs (Richter et al., 1993; Segalla et al., 1994) and tacrolimus (Lee et al.,

1995). Photo dynamic therapy drugs are used in cancer therapy, because they have a tendency to selectively accumulate in malignant tissue. Subsequent illumination activates the drug and results in the destruction of the tissue. A specific example of a

photosensitiser incorporated into liposomes is zinc (TV) phthalocyanine, this hydrophobe was manufactured in a liposome formulation for pilot scale production by Isele et al. (1994). Liposomes produced by film hydration and extrusion have been used to study the solubilisation of tacrolimus (Lee et al., 1995), a low solubility immunosuppressant.