EP0999833A1

EP0999833A1 - Taxol emulsion

Info

Publication number: EP0999833A1
Application number: EP98935215A
Authority: EP
Inventors: Stanley Stewart Davis; Jihong Han
Original assignee: West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd
Current assignee: Kyowa Kirin Services Ltd
Priority date: 1997-07-26
Filing date: 1998-07-24
Publication date: 2000-05-17
Also published as: AU8456198A; GB9715759D0; ZA986645B; WO1999004787A1

Abstract

An emulsion composition having a lipid phase comprising a compound selected from tocopherol, tocotrienol and derivatives thereof, a phospholipid emulsifier and an ionic emulsifier is described. The emulsion may carry a drug compound such as a taxane or taxane derivative.

Description

TAXOL EMULSION

The present invention relates to an emulsion and particularly to an emulsion comprising a drug, such as a taxane or derivative thereof. More particularly, the present invention relates to an emulsion comprising paclitaxel.

Taxanes are a class of natural products that includes the anticancer compound paclitaxel (Taxol). This compound is very poorly soluble in water and, as a result, it has been extremely difficult to develop mjectable formulations for clinical use. Various emulsion, liposome, nanoparticle and solubilized systems are described in the prior art - see, for example, the review by Jonkman-de Vries et al. Drug Dev. Ind. Pharm. 22 475 (1996)). The marketed product Taxol, sold by Bristol-Myers Squibb Pharmaceuticals, is a solubilized system containing paclitaxel, polyoxyethylated castor oil (Cremophor EL) and dehydrated alcohol. This formulation has the disadvantage that it must be diluted using aseptic techniques prior to infusion. Furthermore, the component Cremophor EL is known to give rise to hypersensitivity reactions.

Lipid emulsion formulations containing paclitaxel have also been described by Lundberg in J. Pharm. Pharmacol. 1997 49 16. The oil phase used was triolein which was present at low concentration in the emulsion. The emulsifiers were non-ionic block copolymers such as the poloxamers and poloxamines either as single components or in admixture with phospholipid emulsifiers such as egg lecithin. The drug loading in the formulation was low. Moreover, Lundberg commented that most of the paclitaxel was situated in the surface layer of the emulsion droplet. Examples of emulsion formulations containing Vitamin E and a drug have been described in WO-97/03651. These emulsion formulations comprised a lipid vehicle, such as vegetable oil, a drug contained in the lipid vehicle and Vitamin E to enhance the solubility of the drug in the lipid vehicle.

We have now found that stable emulsions of Vitamin E (tocopherol) and derivatives thereof, such as tocopherol acetates, and tocotrienols which contain high loadings of taxanes such as paclitaxel can be produced without the need to use vegetable oils or non-ionic polymeric surfactants as co-emulsifiers. We have discovered that ionic co-emulsifiers such as bile salts and fatty acids, the latter at alkaline pH, can impart good stability to Vitamin E and tocotrienol emulsions.

According to a first aspect of the present invention there is provided an emulsion composition having a lipid phase comprising a compound selected from tocopherol, tocotrienol and derivatives thereof, a phospholipid emulsifier and an ionic emulsifier.

According to a second aspect of the present invention there is provided an emulsion composition having a lipid phase comprising a compound selected from tocopherol, tocotrienol and derivatives thereof, a phospholipid emulsifier, an ionic emulsifier and a drug compound, such as a taxane or a taxane derivative.

By the terms tocopherol (Vitamin E) and tocotrienol we include the α-, β-, γ- and δ-forms thereof that differ by the number and position of methyl groups on the chromanol ring as well as the various isomers of these compounds. By derivatives of tocopherol and tocotrienol we are referring to the pharmaceutically acceptable derivatives of these compounds such as the esters of tocopherol, e.g. the linoleate, nicotinate, acetate or acid succinate ester.

The nomenclature for Vitamin E and related compounds is not unequivocal in current practice and can vary when used by different compendia and organisations. This problem has been well addressed by Sheppard et al. in Vitamin E in Health and Disease, Editors Packer, L. and Fuchs, J. Dekker, New York 1993 p.9.

The United States Pharmacopoeia described Vitamm E as a form of α- tocopherol. This includes d- or d, 1 -α-tocopherol, d- or d, 1-α-tocopherol acetate and d- or d, 1 -α-tocopherol succinate. The term Vitamin E is also used as a generic description for all tocopherol and tocotrienol derivatives that exhibit Vitamin E activity. Thus, the term tocopherols is synonymous with Vitamin E, but also for methyl tocols.

In the present application, by the terms tocopherol, tocotrienol and derivatives thereof we include all compounds that exhibit the general physiological activity of Vitamin E.

In the present invention, a mixture of two or more compounds selected from tocopherol, tocotrienol and the derivatives thereof may be used.

A preferred compound for use in the emulsions of the present invention is α-tocopherol as described in the United States Pharmacopoeia, Volume 23, 1995 which is also known as all-rac-α-tocopherol. This material can be obtained from Roche Products Ltd., Heanor, UK. The content of the tocopherol or tocotrienol or derivative in the emulsion can be from 5 to 30% w/v based on the total emulsion, i.e. from 5 to 30 g of tocopherol, tocotrienol or derivative per 100 mis of emulsion.

In the present application, by the terms drug and drug compound we include all compounds which may be administered to a mammal and which are pharmaceutically, pharmacologically, therapeutically, diagnostically, cosmetically or prophylactically active or which are a prodrug for such a compound. Preferably, the drug is not a vitamin or dietary mineral such as zinc or iron.

The drug should have reasonable solubility in the tocopherol/tocotrienol lipid phase. Preferably, the drug has a solubility of at least 1 mg/ml, e.g. 1 to lOmg/ml, in the tocopherol, tocotrienol or derivative.

We have discovered that those drugs that are poorly soluble in chlorinated organic solvents such as chloroform tend to be poorly soluble in Vitamin E. In contrast drugs that have good solubility in chloroform have acceptable solubility in Vitamin E. Suitable drugs preferably have a solubility in chloroform of 6mg/ml or more, preferably lOmg/ml or more.

In contrast, if the molecule demonstrates good solubility in methanol (more than lOmg/ml) it will tend to demonstrate low solubility in Vitamin E (less than lmg/ml). Thus, a person skilled in the art will be able to decide whether a drug is a suitable candidate for the invention by reviewing published data on solubility in chloroform or methanol. The ratio of the solubility in chloroform (mg/ml) divided by the solubility in methanol (mg/ml) is preferably greater than 10, more preferably greater than 100.

To measure the solubility of a drug in chloroform and methanol, saturated solutions of the drug in these solvents are prepared. An appropriate means of preparing a saturated solution is to suspend approximately 60mg of drug in 3ml of the solvent and stir for 24 hours at room temperature. If all of the drug dissolves during this time, further 10 mg aliquots should be added until a suspension is again formed. After 24 hours, the suspension is centrifuged or filtered to separate drug in solution from undissolved particulate drug. The drug solutions are assayed for drug content by an appropriate means, e.g. high performance liquid chromatography, and the saturated solubility calculated.

The suitability of a drug may also be determined by measuring its solubility parameter.

The ability of solvents to mix well together or for solvents to dissolve in solvents can be estimated using the procedure of solubility parameters. This method, based upon concepts of cohesion density, was developed originally by Hildebrand and refined by others for a wide range of materials. The concepts of solubility parameters is well reviewed by Barton in CRC Handbook of Solubility Parameters and Other Cohesion Parameters, 2nd Ed. CRC Press, 1991. Those skilled in the art often use this concept to estimate whether a particular drug (solute) will dissolve in a given solvent and the extent of such solubility. In order to do this the solubility parameter of the solute and solvent are required. While solubility parameter values are available for many solvents used in pharmaceutical formulations, solubility parameter values for drugs are not normally available. However, methods have been established wherein solubility parameter values can be calculated. The procedure described by Fedors is well known in this regard (Polym. Eng. Sci. 14 147, 1974).

It has been established previously that polar drug materials have solubility parameters greater than 13 and non-polar materials below 8. The solubility parameter for Vitamin E is estimated to be 9.7, similar to the value for chloroform (9.2). Methanol has a solubility parameter of 14.7. Those drugs that have solubility parameter values close to that of Vitamin E would be expected to show acceptable solubility in Vitamin E.

In the present invention we prefer drugs that have a solubility parameter value between 8 and 13 and more especially between 9 and 12. The same concepts can be applied to all the tocopherols, tocotrienols and derivatives.

Drugs that are suitable for the emulsion formulation are antifungal agents such as itraconazole, anticancer agents such as taxol, hexamethylmelamine, penclomedine and lipophilic porphyrin derivatives, steroids such as pregnanolone, anaesthetic agents such as propofol (diisopropyl phenol), retinoid compounds, cardiovascular agents such as S-emapomil, agents such as prostaglandins, lipophilic peptides such as cyclosporin, and protein kinase C inhibitors such as dihydrosphingasine.

Especially preferred drugs for the emulsion compositions of the invention are taxanes and taxane derivatives including diterpenoid molecules that have antitumour activities by acting on microtubule assemblies in cells (microtubule stabilizing activity). These molecules include taxatere derivatives such as baccatin. Full details of such derivatives have been given by Parness et al. Biochem. Biophys. Res. Commun. 105 1082 (1982), Burkhart et al. Cancer 54 5779 (1994), Kingston et al., Fortschr. Chem. Org. Naturst. 61 1-206 (1993). Paclitaxel is especially preferred.

The use of tocopherol and tocotrienols as carriers for the anti-tumour agent paclitaxel is expected to have the additional advantage in that tocopherols and especially tocotrienols have been shown to have anti- tumour activity (Kato et al. Abura Kajaku, 1985 24 375, Komiyama et al. Chem. Pharm. Bull. 1989 37 1369).

Oil in water emulsions of the present invention can contain up to 5 mg/ml, e.g. from 0.1 to 5 mg/ml and preferably from 1 to 5 mg/ml, of a taxane compound and still retain the desired stability. By desired stability we mean an emulsion in which the mean droplet diameter does not change by more than 20% over a storage period of 40 days and also that the taxane compound, which tends to dissolve in the lipid or oil phase provided by the Vitamin E or its derivative, does not precipitate as small crystals which would be hazardous on injection to a patient.

The phospholipid emulsifier which forms an essential component in the presently claimed emulsions can be any pharmaceutically acceptable material derived from soybeans or eggs, e.g. soy or egg lecithins. Egg lecithins, such as the material provided by Lipoid (Germany) known as Lipoid E80, are preferred, although other phospholipid materials could be used including phospholipid-polyethylene glycol (PEG) conjugates (PEGylated phospholipids) that have been described for use in liposome systems, e.g. by Litzinger et al, Biochem Biophys Acta, 1190 (1994) 99- 107. Modified phospholipids of this type may be able to provide the emulsion with good- in vitro stability and may also minimise the interactions of the particles with elements of the reticuloendothelial system (in particular the Kupffer cells in the liver) as well as minimising the particle flocculation on injection and the capture of particles in the lung by mechanical filtration. A suitable phospholipid-PEG conjugate is PEG- phosphatidyl ethanolamine. The PEG chains in such an emulsifier will preferably have a molecular weight in the range of from about 2000 to about 5000, e.g. from about 2000 to about 4000. A PEG chain having a molecular weight of about 2000 or about 5000 is especially preferred. Such materials can be obtained from Avanti Polar Lipids, Alabaster, Alabama (USA). Mixtures of phospholipid emulsifiers may also be used, such as a mixture of a PEGylated phospholipid and an unPEGylated phospholipid. A preferred ratio of PEGylated to unPEGylated phospholipid is 1: 10 on a weight basis.

The phospholipid can be used at a concentration of 1 to 10% w/v but preferably from 2-4% w/v based on the total emulsion. In other words, the phospholipid can be present in an amount of from 1 to 10 g, preferably in an amount of from 2 to 4 g per 100 mis of emulsion.

Suitable ionic emulsifiers for use in the emulsions of the present invention include the fatty acids and salts thereof and bile acid and salts thereof. Suitable fatty acids are those having greater than 8 carbon atoms in their structure with oleic acid being a preferred material. The preferred ionic emulsifiers are the bile salts and the preferred bile salt is a salt of deoxycholic acid. Suitable salts are the pharmaceutically acceptable salts such as the alkali metal, e.g. Na and K, salts. The ionic co-emulsifier can be added at a concentration of 0.1 to 5% w/v on the total emulsion, but a preferred concentration range is 0.5 to 2 % w/v on the total emulsion. In other words, the ionic -emulsifier can be present in an amount of from 0.1 to 5 g, preferably in an amount of from 0.5 to 2 g per 100 mis of emulsion.

It will be appreciated that a mixture of two or more different ionic emulsifiers may be used if desired.

The amount of the two emulsifier components may be increased with increase in the lipid or oil content of the emulsion. For an emulsion containing 30% w/v of tocopherol, tocotrienol or a derivative of these compounds, the emulsifiers could be used at twice the concentration used for an emulsion containing 10 % w/v of the tocopherol, tocotrienol or derivative.

When the ionic emulsifier is a fatty acid or a fatty acid salt, the pH of the final emulsion is preferably adjusted to a value equal to or greater than 8.5, e.g. in the range of from 8.5 to 9.5 in order to provide for improved stability.

The emulsions can be prepared by methods familiar to those skilled in the art including high pressure homogenisation and ultrasonics. We prefer to use a Microfluidizer system (Microfluidics Corporation, USA). Aseptic processing techniques can be used during the formation of the emulsion or, alternatively, the emulsion can be prepared and then terminally sterilized by heating in an autoclave. A rotating autoclave is preferred to mώimize instability in the emulsion system. The emulsions of the -present invention are suitable for parenteral, nasal and oral administration, but are particularly useful for parenteral administration.

The present invention is now illustrated but not limited with reference to the following examples.

Example 1 - Preparation of Paclitaxel Emulsions based on 10% Vitamin E in Water

Paclitaxel (Taxol) was obtained from Bristol Myers Squibb. Vitamin E was obtained from Sigma. The phospholipid emulsifier, Lipoid E 80, was obtained from Lipoid, Germany. Sodium deoxycholate was obtained from Sigma.

An emulsion composition comprising 10% w/v of Vitamin E (i.e. lOg of Vitamin E per lOOmls of the final emulsion), 2% w/v of E80 (i.e. 2g of E80 per lOOmls of the final emulsion), 1 % w/v of sodium deoxycholate (i.e. lg of sodium deoxycholate per lOOmls of the final emulsion) and 2 or 4 mg/ml of paclitaxel was prepared as follows.

The paclitaxel, Vitamin E and E80 were dissolved in methanol. The solvent was removed using a stream of nitrogen. The mixture was then vacuum desiccated at room temperature for 2-3 hours. The resulting oily paste was then emulsified in water containing the sodium deoxycholate by sonication using a Dawe soniprobe. The pulse cycle was fixed at 50% . The output levels varied from 30-70% (normally the output level was gradually increased during the sonication). The emulsions were examined for the growth of paclitaxel crystals under a light microscope at different storage times over 30 days. Details are provided in Table 1.

Table 1

Time (days) 0 2 10 17 25 30

Sample 1 (2 mg/ml) - - -

Sample 2 (4 mg/ml) - - + + + +

- = no crystals were detected + = crystals were detected

No crystals were detected in the emulsion containing 2 mg/ml of drug.

Example 2 - Preparation of Paclitaxel Emulsions based on 10 and 20% Vitamin E in Water

Emulsions were prepared as in Example 1 containing 10% w/v and 20% w/v Vitamin E, 2 % w/v E80 and 0.5 % w/v sodium deoxycholate and 0.5 % w/v deoxycholic acid. The drug content was varied from 2 to 8 mg/ml. The particle size of the emulsion was measured by Photon Correlation Spectroscopy using a Malvern Instruments' PCS. The particle size was monitored over a period of 30 days at room temperature. The results on particle size of the emulsion and crystal growth are given in Table 2. Table 2

Sample VE Taxol Size (nm)

Number Content

Sample 1 20% 4 mg/ml 193.4 4.1

Sample 2 20% 6 mg/ml 195.3 2.9 +

Sample 3 20% 8 mg/ml 197.0 3.0 + +

Sample 4 10% 2 mg/ml 155.1 2.3

Sample 5 10% 3 mg/ml 155.6 2.8 + +

Sample 6 10% 4 mg/ml 163.9 1.5 + + +

- = no crystals detected + = crystals detected VE = Vitamin E

Example 3 - Preparation of Emulsions Using Oleic Acid

In this example, oleic acid was chosen as an ionic fatty acid emulsifier to be used in combination with the phospholipid material egg lecithin. However, prior to preparing the emulsion the oleic acid was converted to its sodium salt by the addition of sodium hydroxide so that in the final emulsion itself the ionic emulsifier was sodium oleate.

Two emulsions (Formulations 1 and 2) containing Vitamin E, Lipoid E80 and the sodium oleate were prepared as follows.

The Vitamin E and Lipoid E80 were dissolved in methanol and the solvent was then removed under a nitrogen stream. After the methanol had been removed the residue was vacuum desiccated at room temperature and the resulting oily paste was then emulsified in water containing the sodium oleate by microfluidisation to provide an emulsion with a fine particle size. The emulsions had the following compositions.

Formulation 1 : Vitamin E 10 g (20%)

E80 - 1 g (2%)

Oleic acid - 0.5 g (l %)

NaOH 0.071 g x 80% water to 50 ml

Formulation 2: Vitamin E 10 g (20%)

E80 - 1 g (2%)

Oleic acid 0.25 g (0.5 %)

NaOH 0.035 g x 80% water to 50 ml

Each emulsion was divided into two samples and one sample of each emulsion was left unchanged while the other had its pH adjusted using hydrochloric acid. The stability of all the emulsions was then monitored by visual examination and, in particular, by looking for creaming of the oil particles to form a distinct layer at the top of the emulsion and the separation of free oil (a broken emulsion). If the emulsion was stable at the end of 43 days the particle size thereof was measured by Photon Correlation Spectroscopy using a Malvern Instruments' PCS. The results are given in Table 3 for Formulation 1 and in Table 4 for Formulation 2. It was found that stable emulsions could be produced using egg lecithin and sodium oleate as emulsifiers when the pH was greater than 8.5. Below this pH, the emulsions demonstrated poorer stability.

Table 3

PH O day 12 days 21 days 43 days

9.5 (not excellent excellent excellent 176.9^(b)+ 2.1 nm adjusted) 7.5 (HC1 broken^(a) added)

Table 4

pH O day 12 days 21 days 43 days

9.2 (not excellent excellent excellent 180.8^(b)+ 2.8 nm adjusted)

8.1 (HC1 satisfactory partly broken^(a) added) broken ^a)

(a) broken = separation of free oil

(b) particle size as measured on day 43 by Photon Correlation Spectroscopy using a Malvern Instruments' PCS.

The oleic acid can be added as sodium oleate if required, once again the pH should be adjusted to 8.5 or greater, e.g. about 9.0 to provide good emulsion stability. Example 4 - Preparation of Emulsions Using PEGylated Phospholipids

Three emulsions were prepared using a modified phospholipid emulsifier comprising the conjugate of a polyethylene glycol moiety having a molecular weight of about 5000 and phosphatidyl ethanolamine (PEG5000-PE; Avanti Polar Lipids, USA).

Emulsions containing Vitamin E, PEG5000-PE, Lipoid E80 and sodium deoxycholate or sodium oleate (derived from the reaction of oleic acid with sodium hydroxide) were prepared as follows.

The Vitamin E, PEG5000-PE and Lipoid E80 were dissolved in methanol and the solvent was then removed under a nitrogen stream. After the methanol had been removed the residue was vacuum desiccated at room temperamre and the resulting oily paste was then emulsified in water containing the sodium deoxycholate or sodium oleate by sonication using a Dawe soniprobe. The pulse cycle was fixed at 50% . The output levels varied from 30-70% (normally the output level was gradually increased during the sonication). A typical increase scale was as follows:

Output (%) Duration (seconds)

30 30

40 90

50 60

60 30

70 30

The aqueous emulsions had the following compositions. Formulation 3 : Vitamin E 20 % w/v

E80 1 % w/v

PEG5000-PE 1 % w/v

Sodium deoxycholate 1 % w/v

Formulation 4: Vitamin E 5 % w/v

E80 1 % w/v

PEG5000-PE 1 % w/v

Sodium oleate 1 % w/v

The particle size of the emulsions was measured by Photon Correlation Spectroscopy using a Malvern Instruments PCS. The results on the particle size and polydispersity after preparation are given in Table 5.

Table 5

Sample size (nm) polydispersity

Formulation 4 210.3 ± 16.7 0.413 ± 0.065 Formulation 3 413.1 + 34.2 0.578 + 0.020

Example 5 - Preparation of Emulsions Using PEGylated Phospholipids

Two aqueous emulsions (Formulation 5 and Formulation 6) containing Vitamin E, PEG5000-PE, Lipoid E80 and sodium deoxycholate or sodium oleate (derived from the reaction of oleic acid with sodium hydroxide) were prepared using exactly the same technique as described in Example 4 except that microfluidization (15 cycles through the microfluidizer) was used instead of sonication to prepare the emulsion. The aqueous emulsions had the following compositions.

Formulation 5 : Vitamin E 10 % w/v

E80 1 % w/v

PEG5000-PE 1 % w/v

Sodium deoxycholate 1 % w/v

Formulation 6: Vitamin E 10 % w/v

E80 1 % w/v

PEG5000-PE 1 % w/v

Sodium oleate 1 % w/v

The particle size for the emulsions stored at 4°C was measured by Photon Correlation Spectroscopy using a Malvern Instruments PCS. The results on the particle size and polydispersity at 0 days and 20 days are given in Table 6.

Table 6

Time Formulation 5 Formulation 6

Size (nm) 196.3 ± 2.5 165.6 + 1.2

0 days Polydispersity 0.253 ± 0.016 0.210 ± 0.024

Size (nm) 197.2 ± 2.0 171.8 ± 4.0

20 days polydispersity 0.258 ± 0.026 0.200 ± 0.042 The two emulsions looked excellent and did not show any creaming during the first 24 hours. Microscopic examination proved that both emulsions did not aggregate. By the twentieth day no change was observed.

Example 6 - Stability of Emulsions Prepared Using PEGylated Phospholipids

Aggregation of the emulsions prepared in Example 5 in plasma was examined. The emulsions were mixed with plasma (emulsio plasma weight ratio 1:2.5) and the mixmre was examined under a light microscope.

Formulation 1 + rat plasma Formulation 1 + mouse plasma Formulation 1 + sheep plasma

Formulation 2 + rat plasma +

Formulation 2 + mouse plasma Formulation 2 + sheep plasma + +

- = not aggregated

+ = slightly aggregated

+ + = aggregated a little more heavily.

An emulsion containing 20% w/v Vitamin E, and 1 % w/v sodium deoxycholate with no added phospholipid emulsifier was also examined as a control. The emulsion aggregated much more heavily than the PEG5000-PE containing emulsions. Example 7 - Taxane Loaded Emulsions Prepared using PEGylated Phospholipids

The emulsions described in Example 5 were also prepared containing a loading of 2.5 mg/ml of paclitaxel. The same method as described in Example 5 was used with the paclitaxel being dissolved in the methanol along with the Vitamin E, PEG5000-PE and Lipoid E80. The emulsions prepared were of good stability.

Claims

Claims:

1. An emulsion composition having a lipid phase comprising a compound selected from tocopherol, tocotrienol and derivatives thereof, a phospholipid emulsifier and an ionic emulsifier.

2. An emulsion composition having a lipid phase comprising a compound selected from tocopherol, tocotrienol and derivatives thereof, a phospholipid emulsifier, an ionic emulsifier and a drug compound.

3. An emulsion composition according to claim 2, wherein the drug compound is a taxane or a taxane derivative.

4. An emulsion composition according to claim 3, wherein the taxane is paclitaxel.

5. An emulsion composition according to claim 3 or 4, wherein the taxane content in the emulsion is from 1 to 5 mg/ml.

6. An emulsion composition according to any one of claims 1 to 5, wherein the ionic emulsifier is a bile acid or bile salt.

7. An emulsion composition according to claim 6, wherein the ionic emulsifier is deoxycholic acid or a salt thereof.

8 . An emulsion composition according to any one of claims 1 to 5, wherein the ionic emulsifier is a fatty acid having a chain length greater than 8 carbons or a salt thereof and the pH of the emulsion is adjusted to a value of 8.5 or above.

9. An emulsion composition according to claim 8, wherein the ionic emulsifier is oleic acid or a salt thereof.

10. An emulsion composition according to any one of claims 1 to 9, wherein the ionic emulsifier has a concentration of between 0.1 and 5% w/v of the final emulsion.

11. An emulsion composition according to any one of claims 1 to 10, wherein the phospholipid emulsifier is egg or soy lecithin.

12. An emulsion composition according to any one of claims 1 to 10, wherein the phospholipid emulsifier is modified by polyethylene glycol.

13. An emulsion composition according to any one of claims 1 to 10, wherein the phospholipid emulsifier is a mixture of egg or soy lecithin and a lecithin modified with polyethylene glycol.

14. An emulsion composition according to any one of claims 1 to 13, wherein the lipid phase comprises tocopherol and the tocopherol is all-rac- ╬▒-tocopherol.

15. An emulsion composition according to any one of claims 1 to 14 for use in medicine.

16. The use of an emulsion composition according to any one of claims 1 to 14 for the parenteral administration of a drug.

17. The use of an emulsion composition according to any one of claims 3 to 5 for the parenteral administration of a taxane.

18. A method of preparing a stable emulsion of tocopherol or tocotrienol using a fatty acid as a co-emulsifier where the pH of the resultant oil in water emulsion is above 8.5.

19. The use of an emulsion composition according to any one of claims 1 to 14 in the manufacture of a medicament for use in the treatment of a patient in need of treatment with a drug.

20. The use of an emulsion composition according to any one of claims 3 to 5 in the manufacture of a medicament for use in the treatment of a patient in need of treatment with a taxane.

21. A method of treatment of a patient requiring treatment with a drug which comprises the administration of an emulsion composition according to any one of claims 1 to 14 to such a patient.

22. A method of treatment of a patient requiring treatment with a taxane which comprises the administration of an emulsion composition according to any one of claims 3 to 5 to such a patient.

23. A process for the preparation of a composition according to any one of claims 1 to 14 which comprises the dissolution of the drug in a tocopherol or tocotrienol lipid phase, including a phospholipid emulsifier and an ionic emulsifier.