HK1089951B - Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids - Google Patents

Description

Self-emulsifying and self-microemulsifying formulations for oral administration of taxanes

The present invention relates to oral formulations of taxanes (taxoids).

The taxanes used in the formulations of the present invention preferably have the general formula (I):

wherein the content of the first and second substances,

R₁is H, acyl (C)₂-C₄) Alkyl (C)₁-C₃)，

R₂Is OH, alkoxy, or R₂And R₃Is a methylene group, and is a linear or branched chain,

R₃is CH₃Or R is₂And R₃Is a methylene group, and is a linear or branched chain,

R₄is OCOCH₃Or OCOOCH₃，

R is phenyl or alkoxy (C)₃-C₄) Or alkenyloxy (C)₃-C₄) Preferably phenyl or tert-butoxy, R' is aryl, preferably phenyl, optionally substituted, or is alkyl (C)₂-C₄) Or alkenyl (C)₂-C₄)。

The taxanes used in the formulations of the invention are, for example, the taxanes of formulae (Ia) to (If) below:

formula Ia: (docetaxel)

Formula Ib:

formula Ic:

formula Id: (Taxol)

Formula Ie:

formula If:

taxanes of the general formulae (Ia) to (If) and their use are known. These taxanes have unique advantages as chemotherapeutic agents. Unfortunately, taxanes are poorly water soluble compounds. These molecules are slightly lipophilic and have relatively large molecular weights. To date, taxanes have been administered intravenously, particularly using formulations containing high levels of PS80 or Cremopor. It is an object of the present invention to develop taxane formulations for oral administration.

In animals such as dogs, oral administration of PS80 or Cremophor formulations of taxanes results in very low bioavailability, which may be caused by high metabolic rates. In addition, formulations containing high levels of PS80 (e.g., less than 40mg taxane/g PS80) are not desirable for oral administration because of the potential toxicity of PS80 to the intestinal mucosa. Furthermore, due to solubility limitations and the resulting limited ability of PS80 to solubilize taxanes in gastrointestinal fluids, a dose escalation test would not be possible to achieve the desired dose. Finally, pharmaceutical development of pharmaceutical dosage forms will become a major problem: in fact, immediate dilution of PS80 solution with an aqueous medium for oral administration of cytotoxic agents is not feasible.

A large number of documents describe systems suitable for solubilizing hydrophobic active ingredients and/or improving bioavailability. However, to date, these systems have been tested and proven ineffective for preparing pharmaceutical compositions containing stable and bioavailable taxanes wherein the taxane can be administered orally at effective concentrations.

WO 95/24893 describes a delivery system for hydrophobic drugs. This application describes compositions comprising digestible oils, lipophilic surfactants and hydrophilic surfactants intended for formulating hydrophobic active ingredients and for increasing their bioavailability.

WO 99/49848 describes pharmaceutical dosage forms of anticancer drugs such as paclitaxel in which the active drug is formulated as a stable self-emulsifying preconcentrate. WO 99/49848 describes a composition comprising an anti-cancer drug in a carrier system comprising at least one hydrophobic component selected from a tri-, di-or monoglyceride, a free fatty acid, a fatty acid ester or derivatives thereof and one hydrophilic component selected from a hydroxy alkane, a dihydroxy alkane or a polyethylene glycol (PEG), and at least one surfactant.

EP 0152945B 1 describes a pharmaceutically acceptable transparent multi-component system containing one or several active ingredients in a system consisting of an oily component, a surfactant, a co-surfactant and optionally water.

EP 0670715B 1 describes a pharmaceutical, intended to be digested, composition capable of forming a microemulsion comprising at least the active ingredient, lipophilic phase, surfactant, co-surfactant and hydrophilic phase of the specific composition.

EP 0334777B 1 describes pharmaceutical microemulsions comprising a water-soluble phase and a lipid phase, which comprise at least one polyethylene glycol-based surfactant and at least one polyglycerol-based co-surfactant.

It has now been found that it is possible to prepare formulations for oral administration of taxanes which are stable in physicochemical properties, which form the subject of the present invention. The present invention relates to self-emulsifying formulations of taxanes for oral administration comprising at least one taxane and at least one amphiphilic surfactant with hydrophilic properties, preferably said amphiphilic surfactant is(glycerides of PEG and saturated fatty acids).

In a preferred embodiment of the invention, the formulation contains up to 200mg taxane/mlFor example 150mg taxane/mlPreferably 5-100mg taxane/mlFor example, 5mg/ml, 10mg/ml, 20mg/ml, 30mg/ml, 40mg/ml, 50mg/ml, 60mg/ml, 70mg/ml, 80mg/ml, 90mg/ml or 100 mg/ml.

Taxane(s) are/isThe formulation may further comprise certain other additives which may be stabilizers, preservatives, agents possibly regulating viscosity or agents capable of modifying, for example, the organoleptic properties.

Another aspect of the invention relates to self-microemulsifying (SMES) formulations for oral administration of taxanes comprising at least one taxane,(POE hydrogenated castor oil), at least one co-surfactant and at least one oil.

The co-surfactant is an amphiphilic surfactant having lipophilic character and an HLB (HLB represents the hydrophilic-lipophilic balance) of less than 10. The cosurfactant is preferably selected from(glyceryl oleate), Lauroglioco(PG laurate), Capryol(polyethylene glycol monocaprylate), Maisine 35-(caprylic acid monoglyceride) and Imwitor(caprylic acid mono-diglyceride).

The oil is preferably a medium chain triglyceride. The medium chain triglyceride is preferably Miglyol

The amount of co-surfactant is preferably less than 50% (weight percent), more preferably less than 40%, for example 35%, 30%, 25%, 20%, 15%, 10% or 5%. The concentration of oil is preferably below 40%, more preferably below 30%, e.g. 25%, 20%, 15%, 10% or 5%. In a preferred embodiment of the invention, the ratio of surfactant to co-surfactant is 3: 1 or higher (e.g. 5: 1 or 6: 1) and the oil concentration is 20%.

In a preferred embodiment of the invention, the SMES formulation contains 5 to 50mg/g, preferably close to 50mg/g, of taxane.

In a preferred embodiment of the invention, the formulation comprises one of the following compositions: -Cremophor EL/Maisine/Miglyol 812N, or-Cremophor EL/Lauroglycol 90/Miglyol 812N, or-Cremophor EL/captyol 90/Miglyol 812N, or-Cremophor EL/Peceol/Miglyol 812N, or-Cremophor EL/imwittor 988/Miglyol 812N.

In a preferred embodiment of the invention, the formulation comprises one of the following compositions: -Cremophor EL/Maisine/Miglyol 812N, 50mg/g, or-Cremophor EL/Lauroglycol 90/Miglyol 812N, 50mg/g, or-Cremophor EL/caplyol 90/Miglyol 812N, 50mg/g, or-Cremophor EL/Peceol/Miglyol 812N, 50mg/g, or-Cremophor EL/Imwitor 988/Miglyol 812N, 50mg/g, SMES (5).

In a preferred embodiment of the invention, the SMES contains 50mg of taxane per g of formulation, wherein the formulation comprises 60% Cremophor EL, 20% Imwitor 988 and 20% Miglyol 812N (weight percent).

The taxane/SMES formulation may also contain certain other additives which may be stabilizers, preservatives, agents which may adjust viscosity or agents which modify, for example, organoleptic properties.

Another aspect of the invention relates to a process for preparing the self-emulsifying formulation, wherein a mixture of the main excipients, when solid or semi-solid excipients, if desired after heating, is prepared as appropriate; then, if necessary, preparing a mixture with other additives; then the taxane was added and stirring was continued to obtain a homogeneous mixture.

This approach has been used to obtain formulations capable of enhancing the solubility of taxanes in aqueous media by employing amphiphilic and lipid-based formulations capable of forming colloidal systems (fine latex or micellar solutions) in vivo.

Among the amphiphilic and lipid-based formulations, 3 types were identified:

amphiphilic polymers (micelle or latex formation),

phospholipids (lipid vesicle formation),

SMES (self-microemulsifying system): oil + surfactant + co-surfactant (microemulsion formation).

After first selecting the appropriate excipient (for safety and developability), the solubility of the taxanes in the excipient is the first screening step in selecting the excipient and selecting the prototype. These prototypes (liquid or semi-solid) were then produced and characterized to simulate in vitro behavior and chemical stability in gastrointestinal media. Finally, the physical properties and stability of the semi-solid prototype were studied.

Different classes of excipients described in the literature as components of amphiphilic and lipid based formulations have been tested for the solubility of taxanes:

1. oil (medium chain triglycerides, fatty acids);

2. amphiphilic surfactants with hydrophilic character (HLB > 10) (PEO sorbitan fatty acids, castor oil ethoxylates, fatty acid ethoxylates);

3. amphiphilic surfactants with lipophilic character (HLB < 10) (fatty acid glycerides: oleic/linoleic glycerides, oleyl polyglycolyglycerides; propylene glycol derivatives: PG octanoate/linoleate);

4. phospholipids (lecithins);

5. a hydrophilic solvent (PEG 400).

All selected excipients are described as safe for oral administration, and they may be developed (alone or as a mixture) as pharmaceutical dosage forms (soft or hard capsules).

The chemical composition of the selected excipients in liquid form at room temperature and the solubility of the taxane of formula Ib are reported in table 1 below.

Table 1: solubility data for Ib taxanes in liquid vehicles

Table 2 below reports the chemical composition of selected excipients in semi-solid form at room temperature and the solubility of the taxane of formula Ib. The excipient has been melted by preheating to 70 deg.C to dissolve the drug.

Table 2: solubility data in semi-solid excipients (molten state) and solid excipients

The solubility of the taxane of formula Ib at room temperature has been determined by X-ray diffraction.

In view of the solubility of the taxane of formula Ib, the following excipients were reserved for the three types of drug delivery systems:

-for lipid vesicle formation, phosphoal 75SA and Phospholipon 90H;

for emulsion formation, Labrasol;

-for microemulsion formation: as surfactants, Myrj 45, PS80, Cremophor EL, Labrasol; maisine, Capryol 90, Peceol, Lauroglycol 90, Imwitor 988 as co-surfactants; miglyol 812N, Edenor as oil.

For the first two types, the excipients and drug were formulated as a binary system at the following concentrations:

phosal 75SA (solution): 100mg/g of formulation;

phospholipon 90H (solid powder): 50. 100mg/g of formulation;

labrasol (solution): 50. 100 and 200mg/g preparation.

For SMES type (3-component system), first screening of excipients as oil, surfactant (HLB > 10) and co-surfactant (HLB < 10) mixed in varying proportions in the presence of inactive drug was necessary to identify formulations that could form microemulsions (droplet size < 30nm) upon infinite dilution with water. The following SMES were identified by this screen:

-Cremophor EL/Maisine/Miglyol 812N，50mg/g

-Cremophor EL/Lauroglycol 90/Miglyol 812N，50mg/g

-Cremophor EL/Capryol 90/Miglyol 812N，50mg/g

-Cremophor EL/Peceol/Miglyol 812N，50mg/g

-Cremophor EL/Imwitor 988/Miglyol 812N，50mg/g。

the proportions of excipients in the retained formulation were as follows: the ratio of surfactant to co-surfactant was 3: 1 and the oil concentration was 20%.

It will be understood that the dosage will vary depending upon the degree or nature of the condition being treated. Thus, the amount of active in the composition of the invention will be determined to give a suitable dosage. As a result, the amount of taxanes varies as a function of their solubility in the mixture and also as a function of the appropriate dose for treating the patient. Preferably care should be taken to have the taxane drug loading not more than 10% w/w to avoid microemulsion instability.

It will be appreciated that in order to select the most appropriate daily dosage for a human, the weight of the patient, the general health, age and all factors which may affect the therapeutic effect should be considered. The compositions are preferably prepared as a unit dose of a composition containing from 0.1 to 50mg of active substance.

Alternatively, the composition may contain 0.2 to 50mg when the second active ingredient is introduced. However, this amount may optionally be lower and may vary between 0.2 and 10 mg.

When the composition also comprises certain other additives, the latter may be stabilizers, preservatives, agents possibly regulating the viscosity or agents capable of modifying, for example, the organoleptic properties.

The stabilizer may for example be an antioxidant, for example selected in particular from alpha-tocopherol, ascorbyl palmitate, BHT (butylhydroxytoluene), BHA (butylhydroxyanisole), propyl gallate or malic acid.

The preservative may for example be selected from sodium metabisulphite, propylene glycol, ethanol or glycerol.

Among the agents capable of regulating the viscosity, mention may be made, for example, of lecithin, phospholipids, propylene glycol alginate, sodium alginate or glycerol.

Examples of agents which modify the organoleptic properties of the composition are malic acid, fumaric acid, glycerol, vanillin or menthol.

When used, the additives described above constitute from 0.001% to 5% by weight of the total composition.

According to the invention, the pharmaceutical composition is obtainable as follows: mixing the primary excipients as appropriate (when solid or semi-solid excipients, if desired, after heating); then, if necessary, mixed with other additives; taxane was then added, with stirring, to obtain a homogeneous mixture.

The compositions of the present invention may be provided in a liquid state. They are particularly suitable for presentation in hard or soft gelatin capsules or in the form of oral liquids.

The compositions of the present invention are particularly advantageous due to their good physical and chemical stability and the increased bioavailability they provide for the oral administration of taxanes.

The following examples, given without limitation, illustrate the formulations of the present invention.

The attached drawings are as follows:

FIG. 1: the release profile of the taxane of formula Ib in simulated gastric media was varied at 100mg/g for the different formulations.

FIG. 2: 50mg/g of a self-microemulsifying system (SMES) was used to simulate the release profile of the taxane of formula Ib in gastric media.

FIG. 3: the particle size of the taxane formulation of formula Ib in simulated gastric media.

FIG. 4: such that the droplet size of the taxane formulation of formula Ib is < 50nm in simulated gastric media.

FIG. 5: PK profile for taxane-PS 80 formulation of formula Ib.

FIG. 6: PK profile for taxane-SMES formulation of formula Ib.

FIG. 7: PK profile of formula Ib taxane-formula Ib taxane nanocrystals.

FIG. 8: formula Ib taxane-PK profile of 3 formulations in dog No. 1.

FIG. 9: formula Ib taxane-PK profile of 3 formulations in dog No. 2.

FIG. 10: formula Ib taxane-PK profile of 3 formulations in dog No. 3.

FIG. 11: formula Ib taxane-comparison of plasma radioactivity Cmax of different formulations in Beagle dogs.

FIG. 12: formula Ib taxane-comparison of plasma radioactivity AUC of different formulations in Beagle dogs.

Examples

Example 1: prototype preparation

1.1 materials

A taxane of formula Ib

Miglyol 812N(Condea Vista Company，Cranford，NJ，USA)

Labrasol(Gattefossé，Saint Priest，F)

Cremophor EL(BASF AG，Ludwigshafen，DE)

Capryol 90(Gattefossé，Saint Priest，F)

Lauroglycol 90(Gattefossé，Saint Priest，F)

Peceol(Gattefossé，Saint Priest，F)

Maisine 35-1(Gattefossé，Saint Priest，F)

Imwitor 988(Condea Vista Company，Cranford，NJ，USA)

Phosal 75SA(Nattermann，Cologne，DE)

Phospholipon 90H(Nattermann，Cologne，DE)

PS80VG DF(Seppic，Paris，France)

1.2 preparation of the solution

The weighed drug was dispersed in the vehicle and then maintained under mechanical agitation until complete dissolution (about 3-5 hours). For SMES formulations, the drug is dissolved in a pre-homogenized mixture of 3 excipients.

1.3 preparation of the solid Dispersion

The drug and vehicle (Phospholipon 90H) were dispersed in absolute ethanol (0.1g drug, 0.9g vehicle, 6g ethanol) in a sphere reactor and then heated at 50 ℃ until dissolved. The solvent was evaporated by Rotavap (150-.

1.4 chemical stability

Chemical stability of the different formulations is a major parameter. The prototype batches were stored (glass vials) at +5 ℃ (± 3 ℃), 25 ℃ (± 2 ℃) and 30 ℃ (± 2 ℃) with 60% (± 5%) Relative Humidity (RH) and at 40 ℃ (± 2 ℃) and 75% (± 5%) RH for 3 months.

Stability was assessed by HPLC-determined titers and evaluation of related substances. Prototypes analyzed for drug dose and stability studies are shown in the table below.

Table 3: prototype taxane formulations of formula Ib for stability studies

Prototype	Pharmaceutical preparation with a concentration of mg/g
		PS 80	100
Capryol 90	250
		Labrasol	100
Labrasol	200
		Phosal 75SA	100
CremophorEL-Miglyol 812N-Peceol	50
		CremophorEL-Miglyol 812N-Maisine	50
CremophorEL-Miglyol 812N-Lauroglycol 90	50
		Cremophor EL-Miglyol 812N-Capryol 90	50
Cremophor EL-Miglyol 812N-Imwitor 988	50
		Phospholipon 90H	50
Phospholipon 90H	100

All formulations, except the SMES formulation, were stable at 40 ℃ and 75% RH for three months. In fact, SMES is stable for one month at 25 ℃ whereas impure taxanes of formula Ib (hydrolysis) appear at 40 ℃ (at t)_{1 month}And from 1.15 to 3.88% depending on the nature of the co-surfactant). Three month analysis of the samples can assess whether this impurity increase is critical: after three months, an increase in the impurity content of the taxane of formula Ib was observed. SMES was stable for 7 months at 5 ℃.

Example 2: in vitro behavior in simulated gastrointestinal media

Release profiles after incubation in simulated gastrointestinal media

Simulating the composition of a liquid

The following simulated media were selected for this experiment:

gastric Medium USP, pH 1.2

Fasted intestinal medium, PH 6.8 (see Dressman et al, pharm. res., 1998) fed intestinal medium, PH 5 (see Dressman et al, pharm. res., 1998).

Table 4: composition for simulating gastrointestinal medium

2.1 conditions of the experiment

In the first step of the experiment, the formulation (100mg drug/g formulation, 500mg of formulation per hard gelatin capsule) was diluted 1: 500 in gastric medium (1 capsule/250 ml) and incubated at 37 ℃ for 2 hours with stirring in a USP standard dissolution apparatus. The same experiment was performed in gastric media with two capsules containing a smaller concentration of formulation (50mg drug/g formulation) to investigate the effect of the drug/excipient and excipient/vehicle ratios on the release profile. In the second step of the experiment, the gastric media was first incubated for 1 hour and then either fasted or fed intestinal media for 2 hours to simulate the gastric emptying process.

Samples were taken after 5, 15, 30, 60 minutes and 2 hours. Drug concentrations were determined by HPLC after centrifugation (6000rpm, 10 min). The homogeneity of the medium was evaluated by sampling at the bottom, middle and top of the vessel.

2.2 results

The drug release profile in gastric media for the 100mg/g formulation is shown in figure 1.

The curves obtained from the formulation data of Phosal are not very representative, since these formulations form very heterogeneous mixtures after incubation. The Labrasol formulation resulted in the formation of a very homogeneous emulsion with the vehicle, despite very low drug recovery after centrifugation (see release curve), suggesting that centrifugation (determining emulsion breaking of the emulsion) underestimates its in vitro performance for the coarse emulsion (coarse emulsion). The Phospholipon 90 experiment was stopped (data not collected) because the powder flow did not form a uniform suspension.

The in vitro plots of 5 self-microemulsifying systems (SMES) tested all showed 100% "release" within a few minutes (fig. 2). However, the fact that centrifugation does not separate the aqueous and oil phases of SMES means that SMES is still finely dispersed in the aqueous phase (gastric medium). After centrifugation, the drug remains dissolved in the tiny microemulsion droplets. However, SMES systems are certainly of great interest, even though chemical stability may be an issue (the effect of hygroscopic surfactants or co-surfactants on the chemical stability of drugs has yet to be investigated).

Example 3: particle size analysis after incubation in gastric Medium (USP)

The objective of this study was to evaluate the colloidal stability and self-emulsifying properties of the emulsion/microemulsion/micellar solution formulation of taxane of formula Ib after incubation in gastric media by particle size measurement.

3.1 conditions of the experiment

The formulation (100mg drug/g formulation, 100mg formulation) was diluted 1: 500 in gastric medium (50ml) and incubated at 37 ℃ for 2 hours with mechanical stirring (300 rpm). The sample was immediately diluted with water to measure particle size or filtered through 2 μm as appropriate. Filtration allows retention of oil droplets > 2 μm and drug crystals > 2 μm, so that particle size can be determined by QELS (quasi elastic light scattering) (Nanosilzer N4+, Beckmann-Coulter)

3.2 results

As shown in FIGS. 3 and 4, particle sizes of < 50nm were only obtained in formulations with an active substance concentration of 50 mg/g: 5 microemulsions (regardless of their components). The results suggest that formulations that form small and monodisperse droplets in the gastric medium are used to have better in vivo performance. Further experiments in simulated intestinal media should be performed to evaluate the effect of bile salts on particle size and colloidal stability of the formulation.

3.3 preliminary conclusions on the evaluation of taxane formulations of formula Ib

The following table summarizes the in vitro behavior in simulated gastrointestinal fluids and the chemical stability under accelerated conditions for all orally administered formulations of the taxane of formula Ib.

Table 5: summary of in vitro behavior of 50mg/g formulation

Preparation	Chemical stability	In vitro droplet size (gastric medium, 37 ℃, 2 hours)	In vitro homogeneity (gastric medium, 37 ℃, 2 hours)	Drug release in vitro after 2 hours in gastric media%	Drug release in vitro after 1 hour in gastric media and 2 hours in Fassif%
						Labrasol	Not testing	Not testing	Good effect	2％	23％
SMES(5)	At 5 deg.C for 7 months	＜30nm	Good effect	＞90％	100％

Since the in vitro behavior of the 5 SMES species was almost identical, the SMES recommended for further evaluation was an SMES containing Imwitor 988 as a co-surfactant: indeed, such excipients are described as being able to prevent lipolysis inhibition that normally occurs with the use of hydrophilic surfactants (e.g. Cremophor) and should allow the lipids (Miglyol) to be digested for drug release and absorption. Since absorption of the taxane of formula Ib is not a critical step, it is undesirable that lipolysis be delayed (to improve uptake of intact droplets via the lymphatic pathway).

Table 6: overview of the in vitro behavior of the 100mg/g formulation

Preparation	Chemical stability	In vitro droplet size (gastric medium, 37 ℃, 2 hours)	In vitro homogeneity (gastric medium, 37 ℃, 2 hours)	Drug release in vitro after 2 hours in gastric media%	Drug release in vitro after 1 hour in gastric media and 2 hours in Fassif%
						Labrasol	At 40 ℃/75% RH > 3 months	＞1μm	Good effect	1-11％	5-14％
SMES(5)	Not testing	Greater than 1 μm (without microemulsion)	Not testing	Not testing	Not testing

At 100mg/g, only Labrasol formulations showed promising behavior (in terms of release profile and droplet size).

4. Conclusion and further study

Table 7: comparing the properties of the recommended formulations according to selected criteria

Example 5: taxane of the formula Ib-

Comparison of different dosage forms in Beagle dogs:

three male Beagle dogs were tested at a dose of 0.5mg/kg using the following formulation: polysorbate 80; 50mg/g self-microemulsifying system (SMES) (composition: Cremophor EL 60% Imwitor 98820% and Miglyol 812N 20%); a 14C-taxane nanocrystal suspension of formula Ib. Plasma emission curves were determined by LSC.

As a result:

the plasma radioactivity concentration was determined after a single oral administration of the C-14-taxane PS80 formulation of formula Ib at 0.5mg/kg to Beagle dogs (FIG. 5).

The plasma radioactivity concentration was determined after a single oral administration of the C-14-taxane SMES formulation of formula Ib at 0.5mg/kg to Beagle dogs (FIG. 6).

The plasma radioactivity concentration was determined after a single oral administration of the C-14-taxane nanocrystal formulation of formula Ib at 0.5mg/kg to Beagle dogs (FIG. 7).

The plasma radioactivity concentration after a single oral administration of the C-14-taxane of formula Ib at 0.5mg/kg was determined for Beagle dog No. 1 (FIG. 8).

The plasma radioactivity concentration after a single oral administration of the C-14-taxane of formula Ib at 0.5mg/kg was determined for Beagle dog No. 2 (FIG. 9).

The plasma radioactivity concentration after a single oral administration of the C-14-taxane of formula Ib at 0.5mg/kg was determined in Beagle dog numbered 3 (FIG. 10).

The maximum plasma radioactivity concentration (Cmax) was determined following a single oral administration of the C-14-taxane of formula Ib at 0.5mg/kg to Beagle dogs (FIG. 11). PS80 and SMES formulations demonstrated no difference in plasma radioactivity Cmax. PS80 or SMES proved to be significantly different from the nanocrystal formulation.

Plasma radioactivity exposure (AUC (0-48 hours)) following a single oral administration of the C-14-taxane of formula Ib at 0.5mg/kg was determined for Beagle dogs (FIG. 12). The PS80 and SMES formulations demonstrated no difference in plasma radioactivity AUC. The AUC of PS80 or SMES was 16 times higher than that of the nanocrystals.

The results are summarized below:

for PS80 and self-microemulsifying formulations, a rapid absorption of radioactivity is observed (t)_{Maximum of}0.5-2 hours) and low variability in radioactive concentration (C.V < 11% for Cmax).

For nanocrystalline formulations, a rapid to slow absorption of radioactivity is observed (t)_{Maximum of}0.5-4 hours) and high variability in radioactive concentration (c.v.49% for Cmax).

The plasma radioactivity Cmax and AUC proved to be without difference for PS80 and self-microemulsifying formulations (320 + -25 Vs366 + -57 ng eq.h/mL, respectively).

Mean Cmax and AUC of plasma radioactivity for PS80 or self microemulsifying formulations were at least 1.6 times higher than for nanocrystals.

Claims (10)

1. Self-microemulsifying formulation for the oral administration of taxanes comprising at least one taxane, a co-surfactant selected from glycerol monooleate, PG monolaurate, polyethylene glycol monocaprylate, glycerol linoleate and mono-diglycerol caprylate, a medium chain triglyceride which is caprylic/capric triglyceride and a POE hydrogenated castor oil as surfactant.

2. Self-microemulsifying formulation for the oral administration of taxanes, comprising at least one taxane, a co-surfactant selected from glycerol monooleate, PG monolaurate, polyethylene glycol monocaprylate, glycerol linoleate and caprylic acid mono-diglyceride, a medium chain triglyceride which is caprylic/capric triglyceride, a medium chain triglyceride, POE hydrogenated castor oil as surfactant and at least one further additive selected from stabilizers, preservatives, agents capable of regulating viscosity or agents capable of modifying the organoleptic properties.

3. Self-microemulsifying formulation as claimed in claim 1, wherein the amount of cosurfactant is less than 50% by weight.

4. Self-microemulsifying formulation as claimed in claim 2, wherein the amount of co-surfactant is less than 50% by weight.

5. Self-microemulsifying formulation as claimed in claim 1, wherein the medium chain triglyceride concentration is less than 40%.

6. Self-microemulsifying formulation as claimed in claim 2, wherein the medium chain triglyceride concentration is less than 40%.

7. Self-microemulsifying formulation as claimed in claim 1, wherein the ratio of surfactant to co-surfactant is 3: 1 and the medium chain triglyceride concentration is 20%.

8. Self-microemulsifying formulation as claimed in claim 2, wherein the ratio of surfactant to co-surfactant is 3: 1 and the medium chain triglyceride concentration is 20%.

9. Self-microemulsifying formulation as claimed in any of claims 1 to 8, wherein the concentration of taxane does not exceed 10% w/w.

10. Self-microemulsifying formulation as claimed in claim 9, wherein the concentration of taxane is from 1 to 50 mg/g.