MXPA97008934A - Self-emulsifying formulations of lipofili drugs - Google Patents

Abstract

Self-emulsifying pharmaceutical pre-concentrated compositions comprising: (a) a lipophilic medicinal compound, (b) polyethylene glycol succinate of d-alpha-tocopheryl 1000 (TPGS), and (c) a lipophilic phase, as well as pharmaceutical compositions comprising to these pre-concentrates in combination with a sufficient amount of water to produce a stable emulsion.

Description

SELF-EMULSIFYING FORMULATIONS OF LIPOFILIC DRUGS Caamo Technique This invention relates to pharmaceutical compositions of medicinal compounds, and in particular, to spontaneously self-emulsifying pre-concentrates of lipophilic compounds, whose uses include (but are not limited to (the preparation of liquid oral formulations, soft elastic formulations or other capsule formulations for oral application, local formulations for local application, suppository formulations, and eye and ear drop formulations.

BACKGROUND OF THE INVENTION Pharmaceutical compounds that are highly lipophilic present considerable formulation challenges.

Due to their low solubility in aqueous media (including the digestive tract content of mammals), they often suffer from poor or irregular bioavailability when given orally or by other routes that require transmembrane absorption. One method to formulate lipophilic compounds is to combine them with glyceride vehicles that form emulsions when mixed with water. Emulsions are described, for example, in the United States Patent issued to Cavanak on June 14, 1983 (Patent Number 4,388,307), a commercial example of which is the oral product containing cyclosporin SANDIMMUNE. This product comprises the emulsifier LABRAFIL (transesterified triglyceride), olive oil, and alcohol in a ratio of approximately 36:52:12, the drug being cyclosporin A present in a concentration of 100 milligrams / milliliter. It is suggested, in the Cavanak patent, that these glyceride vehicles can assist in alleviating problems of physical instability (eg, drug precipitation from the solution), and can also make possible higher plasma concentrations. More recently, it has been proposed that a preferred vehicle for lipophilic compounds is the so-called self-emulsifying drug application system which, when exposed to an aqueous medium, forms a fine emulsion of oil in water with little or no agitation. The self-emulsification property allows these formulations to be administered as "pre-concentrates" (ie, in a concentrated form, such as, for example, in a soft elastic or gelatin capsule), with the expectation that an emulsion forms fine in the digestive tract. Moreover, it has been suggested that self-emulsifying formulations, when given orally, may offer improvements in both the rate and degree of absorption of the medicinal compound, and also in the consistency of the resulting plasma concentration profiles. (See SA Charman et al., Pharmaceutical Research 9 (l): 87-93 (1992), and NH Shah et al., International Journal of Pharmaceutics 106: 15-23 (1994).) Additionally, emulsions that have been prepared by The combination of a self-emulsifying pre-concentrate with an aqueous medium seems to benefit from the best physical stability when compared to conventional emulsions. The self-emulsifying systems disclosed above include those in which a lipophilic drug is combined with mixtures of: (i) medium chain triglyceride oils and nonionic surfactants, (ii) vegetable oils and nonionic emulsifiers, such as glycerides polyglycolized or medium chain mono- and di-glycerides, or (iii) vegetable oils and non-ionic surfactants such as polysorbate 80 or glyceryl trioleate of PEG-25. Other formulations that have been characterized as self-emulsifiers, such as the above cyclosporin SANDIMMUNE formulation, additionally contain a substantial amount of ethanol as a solubilizing agent or solvent, however, these solvent-containing preparations are often unsuitable for certain uses , such as filling in gelatin capsules, from which the solvent can easily escape.

Improved self-emulsifying formulations are proposed, which seek to overcome this drawback, in the United States of America patent issued to Hauer et al. On August 30, 1994 (Patent Number 5,342,625); In these formulations, a "microemulsion pre-concentrate" of cyclosporin is formed, combining the drug with: (i) a hydrophilic phase, (ii) a lipophilic phase, and (iii) a surfactant, as well as thickeners, antioxidants, or other optional excipients. Despite this, there remains a need for better formulations of lipophilic drugs that: (i) are self-emulsifying, and therefore, have the advantage of simplicity of use, and (ii) involve excipients that are physiologically well tolerated. There remains also a need for self-emulsifying pharmaceutical compositions containing little or no alcohol, which can tolerate a wide range of temperatures and other conditions, and which consequently can be administered orally in a pre-concentrated form by means of capsules of gelatin or other capsules, or parenterally in cases where the alcohols may be unduly irritating or incompatible with other vehicles of the formulation.

SUMMARY OF THE INVENTION It has now been discovered that the dietary supplement of polyethylene glycol succinate of d-alpha-tocopheryl 1000 (TPGS), a water-miscible form of vitamin E, can be used to prepare pre-concentrates that self-regulate. spontaneously emulsify on the addition of water or other aqueous medium. These pre-concentrates allow the oral application of lipophilic drugs in a form which, presumably due to the stability and homogeneity of the resulting aqueous emulsion, provides a good and unexpectedly consistent bioavailability. Previously, TPGS has been used as an emulsifier for lipophilic compounds, a solubilizer of hydrophilic compounds in fats and oils, and as an oral bioavailability enhancer (when coadministered with, for example, vitamin D or cyclosporin), - however, these previous uses gave no indication that formulations containing TPGS could: (i) self-emulsify, or (ii) be capable of forming stable emulsions of small particle size. Accordingly, the present discovery that TPGS imparts these properties to highly lipophilic drug formulations is unexpected. Moreover, these formulations have the additional advantage that TPGS is easily tolerated, or even beneficial, when given orally or locally. In accordance with the foregoing, in one aspect of the present invention, spontaneously self-emulsifying pharmaceutical pre-concentrated compositions comprising: (a) a lipophilic medicinal compound, (b) d-alpha polyethylene glycol succinate are disclosed. -tocopheryl 1000 (TPGS), and (c) a lipophilic phase. Preferred pre-concentrates are those in which the TPGS is present in an amount of between about 0.1 percent and about 50 percent by weight, - more preferably those where the TPGS is present in an amount of between about 0.5 percent and approximately 15 percent by weight; and more preferred are those where the TPGS is present in an amount of between about 1 percent and about 5 percent by weight. The components of the lipophilic phase which are suitable for use in the above pre-concentrates include: (a) glycerol fatty acid esters, (b) propylene glycol fatty acid esters, and (c) vegetable oil. Preferably, the weight ratio between these components of the lipophilic phase and the TPGS is between about 1: 1 and about 999: 1; more preferably, the weight ratio between the lipophilic phase and the TPGS is between about 9: 1 and about 99: 1. The particular lipophilic phase component that can be used in the pre-concentrates of the present invention includes, but is not limited to, propylene glycol laurate (PGL), caprylic / capric triglyceride (such as NEOBEE M-5 oil, a widely used commercial product), propylene glycol dicaprylate / dicaprate, corn oil, oil sesame, and cottonseed oil, either alone or in combination. When PGL is used, a weight ratio between the PGL and the TPGS is about 15: 1. Alternatively, when the lipophilic phase comprises propylene glycol laurate and caprylic / capric triglyceride together, a weight ratio between the lipophilic phase and the TPGS of between about 20: 1 and about 85: 1 is preferred.; Particularly preferred embodiments of these pre-concentrates include those which, when the weight ratio between PGL and caprylic / capric triglyceride is about 2: 1, have a weight ratio between the lipophilic phase and the TPGS of about 25: 1, or approximately 80: 1. As a further alternative, when the lipophilic phase comprises propylene glycol dicaprylate / dicaprate, a weight ratio between the lipophilic phase and the TPGS of between about 1: 1 and about 99: 1 is preferred. The pre-concentrates of the present invention may optionally comprise ethanol as well. When present, the ethanol is preferably used in an amount of between about 1 percent and about 9 percent by weight, with an amount of about 5 percent by weight being especially preferred. With respect to any of the above pre-concentrates, a preferred medicinal compound for use therein is cyclosporin. Preferred cyclosporin-containing compositions are those wherein the drug is present in an amount of between about 0.5 percent and 25 percent by weight; more preferred are those in which the drug is present in an amount of between about 10 percent and about 15 percent, with a cyclosporin concentration of about 10 percent being especially preferred. In another aspect of the present invention, pharmaceutical compositions are disclosed, which comprise one of the above self-emulsifying pre-concentrates of the invention, in combination with a sufficient amount of water, to produce a stable emulsion. Stable emulsions, where the particle size of the emulsion is relatively independent of the proportions of the internal (lipophilic) and external (aqueous) phases, can be obtained with proportions of the lipophilic phase to the aqueous phase up to 1:10 or even higher.

Detailed Description of the Invention As used throughout this specification, and in the appended claims, the following terms have the specified meanings: The term "cyclosporin" as used herein, refers to one or more of the cyclosporins, and especially cyclosporin A, as described in the United States of America patent issued to Harri et al. (Patent Number 4,117,118), and incorporated herein by reference. The term "emulsion", as used herein, refers to a dispersion of fine droplets of a lipophilic phase in an aqueous phase, which droplets are stabilized at their interface to the lipophilic phase / aqueous phase by TPGS. The term "pre-concentrate" as used herein, refers to pharmaceutical compositions or formulations of a sufficiently high concentration, so that they can be administered directly (as, for example, when filled in gelatin capsules), or used as a "pre-mix" for the preparation of a more dilute formulation (as, for example, in the form of an emulsion suitable for oral administration). The term "self-emulsifier", as used herein, refers to pre-concentrates that spontaneously or only with minimal agitation form a stable emulsion or dispersion upon addition to an aqueous medium. The term "stable", as used herein in connection with emulsions, refers to emulsions that do not exhibit phase separation when stored, without agitation, at room temperature for 1 hour or more. The compositions of the present invention can be administered orally, parenterally (or by injection or infusion intravenously, intramuscularly, intraperitoneally, intrasternally, subcutaneously, and intraauricularly), or locally (as by ointments, drops, or transdermal patches), as know in the pharmaceutical technique. Oral formulations include gelatin capsules which have been directly filled with the pre-concentrates of the invention, as well as the emulsions of the invention which are formed by a combination of this pre-concentrate with a suitable aqueous medium such as water. As necessary, oral formulations may also include auxiliaries, such as viscosity inducers (e.g., microcrystalline cellulose or beeswax); wetting, sweetening, flavoring, and / or perfuming agents; and other inert and pharmaceutically acceptable excipients that may be desired. Solvents may also be included to facilitate dissolution of the drug in the lipophilic phase, and / or to prevent freezing of the drug. pre-concentrated; These solvents include, but are not limited to, ethanol, propylene glycol, and dimethylisosorbide, and their pharmaceutically acceptable alternatives.

Parenteral formulations may be prepared from the emulsions of the present invention, and may contain conventional adjuvants such as to regulate or control tonicity. Local formulations, which are intended to be administered to the skin or mucosa (such as to the surfaces of the lung and the eye), can be prepared from both the pre-concentrates and the emulsions of the invention, and can also contain excipients, such as those that modify the consistency and absorption speed. Any of the above formulations, when prepared using the pre-concentrates or emulsions of the present invention, may additionally include antibacterial or antifungal agents, such as, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. When used in the treatment of diseases, the pre-concentrates and emulsions of the present invention can be administered in a sufficient amount, and for a sufficient period of time, as necessary to provide the desired therapeutic effect. The specific therapeutically effective dosage level for any particular patient, which will be determined by the physician attending, will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the medicinal compound used, - the specific composition used; age, body weight, general health, sex, and the patient's diet; the time of administration, the route of administration, and the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincident with the specific compound employed, and similar factors well known in the medical art. The pre-concentrates of the invention can be prepared using readily available materials and equipment. Typically, the lipophilic phase (such as propylene glycol laurate, or PGL, and caprylic / capric triglyceride in combination) is heated to about 40-45 ° C, with mixing if necessary, before the addition of the appropriate amount of TPGS. The combined materials are mixed until dissolved, and the resulting mixture is cooled to room temperature. Depending on its stability and its solubility in the lipophilic phase, the medicinal agent may be added before or after cooling, followed by mixing until the drug is completely dissolved. If any PGL or component of the lipophilic phase has been reserved, then it is added with mixture until it is uniform. The resulting pre-concentrate, which at room temperature can have a consistency from a solution to a soft, waxy, homogeneous solid, can then be stored as is, can be filled into soft gelatin capsules or other capsules, or can be processing in an aqueous pharmaceutical composition of the present invention by mixing with water or another aqueous liquid. The formulations of the present invention will be better understood in connection with the following examples, which are intended as an illustration of, and not a limitation on, the scope of the invention. Both later and throughout the descriptive memory, it is intended that the citations of the literature be expressly incorporated as a reference.

EXAMPLE 1 Preparation of Pre-Concentrates and Placebo Emulsions The ability of TPGS to facilitate the self-emulsification of a lipophilic phase in water was tested by preparing a number of pre-concentrates of the present invention, mixing each with • water and observing the resulting physical behavior (such as dispersibility and particle size). The specific pre-concentrates were prepared as follows: (A) Propylene glycol laurate (Gattefossé, Westwood, New Jersey; from 71.0 to 99.9 percent by weight) was heated to about 40-45 ° C, and a corresponding amount of TPGS (Eastman Kodak, Tennessee, -from 29.0 to 0.1 weight percent) was added with mixing until dissolved. The solutions were allowed to cool to room temperature. 100 milligrams of each pre-concentrate was added to 10 milliliters of distilled and filtered water, and the resulting mixtures were observed. (B) Propylene glycol laurate (from 80.0 to 92. 0 percent by weight) was heated to about 40-45 ° C, and a variable amount of TPGS (from 13.3 to 1.3 weight percent) was added with mixing until dissolved. The solutions were allowed to cool to room temperature, ethanol (6.7 weight percent) was added, and the solution was mixed until uniform. 100 milligrams of each pre-concentrate was added to 10 milliliters of distilled and filtered water, and the resulting mixtures were observed. (C) Propylene glycol laurate (53.3 to 80.0 weight percent) was combined with caprylic / capric triglyceride (brand NEOBEE M-5, 45.3 to 6.7 weight percent). The mixture was heated to about 40-45 ° C, and a variable amount of TPGS (from 1.3 to 13.3 weight percent) was added with mixing until dissolved. The solutions were allowed to cool to room temperature. 100 milligrams of each pre-concentrate was added to 10 milliliters of distilled and filtered water, and the resulting mixtures were observed. (D) The propylene glycol laurate (46.7 weight percent) was combined with caprylic / capric triglyceride (brand NEOBEE M-5, 33.3 weight percent). The mixture was heated to about 40-45 ° C, and TPGS (13.3 weight percent) was added with mixture until dissolved. The solution was allowed to cool to room temperature, ethanol (6.7 weight percent) was added, and the solution was mixed until uniform. 100 milligrams of the pre-concentrate was added to 10 milliliters of distilled and filtered water, and the resulting mixture was observed. (E) Caprylic / capric triglyceride (trademark NEOBEE M-5: 80.0 to 99.9 weight percent) was heated to about 40-45 ° C, and a corresponding amount of TPGS was added (from 20.0 to 0.1 percent by weight). weight) with mixture until dissolved. The solutions were allowed to cool to room temperature. 100 milligrams of each pre-concentrate was added to 10 milliliters of distilled and filtered water, and the resulting mixtures were observed. (F) Caprylic / capric triglyceride (NEOBEE M-5 brand: 75.0 to 94.9 weight percent) was heated to about 40-45 ° C, and a variable amount of TPGS was added (from 20.0 to 0.1 percent by weight). weight) with mixture until dissolved. The solutions were allowed to cool to room temperature, ethanol was added (at 5.0 or 6.3 weight percent), and the solutions were mixed until uniform. 100 milligrams of each pre-concentrate was added to 10 milliliters of distilled and filtered water, and the resulting mixtures were observed. (G) Corn oil, sesame oil, and cottonseed oil (Arista Industries, Inc., Darien, CT: 85.0 to 94.0 weight percent) were heated to about 40-45 ° C, and added variable amounts of TPGS (from 10.0 to 0.1 percent by weight) with mixing until dissolved. The solutions were allowed to cool to room temperature, ethanol (5.0 weight percent) was added, and the solution was mixed until uniform. 100 milligrams of each pre-concentrate was added to 10 milliliters of distilled and filtered water, and the resulting mixtures were observed. In each case (A) to (G), the resulting pre-concentrates easily formed stable aqueous emulsions without the need for vigorous agitation, microfluidization, or other management commonly associated with the preparation of oil-in-water emulsions. Moreover, particle size distributions were measured for several of the above emulsions. The results, shown below in Table 1, demonstrate that aqueous emulsions formed from pre-concentrates of the present invention have particle sizes that are compatible with the oral application of lipophilic drugs.

Table 1 Particle Sizes of Emulsions Formed from Placebo Pre-Concentrates Proportion (% by weight) PGL TPGS CCT EtOH Average size (microns) 90 10 7.7 53. 3 13. 3 33.3 --- 2.8 46. 7 13. 3 33.3 6.7 8.8 PGL = Propylene glycol laurate. TPGS = polyethylene glycol succinate of d-alpha-tocopheryl 100 CCT = caprylic / capric triglyceride EtOH = Ethanol EXAMPLE Preparation of Pre-Concentrates and Cyclosporin Containing Cyclosporin A The propylene glycol laurate (65.0 to 74.0 weight percent) was heated to about 40-45 ° C, and a variable amount of TPGS ( 10.0 to 1.0 percent by weight) with mixing until dissolved. The solutions were allowed to cool to room temperature, and cyclosporin A USP (25.0 weight percent) was added, and mixed until dissolved. 100 milligrams of each pre-concentrate was added to 10 milliliters of distilled and filtered water, and the physical stabilities and particle size distributions of the resulting mixtures were observed. In each case, the pre-concentrates easily formed stable emulsions comparable to those described in the previous Example.

E-example 3 Oral Bioavailability of Pre-Concentrates Containing Cyclosporine The oral bioavailability of two pre-concentrates of the present invention was evaluated in beagle dogs fasted as follows: To prepare the first pre-concentrate containing 100 milligrams / milliliter of cyclosporin, approximately 1.5 milliliters of propylene glycol laurate (PGL) was added to 1.25 milliliters of caprylic / capric triglyceride (CCT). After heating the mixture to 40-45 ° C, 0.25 grams of TPGS were added, and dissolved with stirring, and the mixture was cooled to room temperature. Then 0.50 grams of cyclosporin A were added, and they were dissolved with stirring, after which additional PGL (approximately 1.5 milliliters) was added, and mixed until uniform, to produce a solution containing 25 percent CCT, 5 percent TPGS and 10 percent ciclosporin by weight; the resulting pre-concentrate was designated as "Formula 1." To prepare the second pre-concentrate, which also contained 100 milligrams / milliliter of cyclosporin, about 1500 milliliters of PGL was poured into a container, and heated to 40-45 ° C. Then 100 grams of TPGS were added, and they were dissolved with stirring, and the mixture was cooled to room temperature. 200 grams of cyclosporin A were added, and they were dissolved with stirring, after which, additional PGL (approximately 200 milliliters) was added, and mixed until uniform, to produce a solution containing 5 percent TPGS and the 10 percent cyclosporine by weight, - the resulting pre-concentrate was designated as "Formula 2". The above pre-concentrates, and the control samples that consisted of the commercial cyclosporine product SANDIMMUNE, were then filled into soft elastic capsules in amounts that, when applied to the subjects, delivered 5 milligrams / kilogram of cyclosporin to each dog. The capsules were heat sealed and inspected to confirm the absence of leaks. Three groups of six dogs each, were fasted overnight, and then, at time 0, they were given one of the pre-encapsulated pre-concentrates. Blood samples were taken at 15, 30, 60, and 90 minutes, and at 2, 4, 6, 9, 12, 15, and 24 hours after dosing, and analyzed by the blood concentration of cyclosporin. (Food was made available after the blood had been taken at the 12-hour mark). From these data, the maximum serum concentration (Cmax), the time from dosing to the maximum concentration (Tmax), and the total presence (area under the curve, or AUC), as well as the standard deviations were calculated. These are shown in Table 2. Table 2 Concentrations in Sanare of Cyclosporine After Oral Dosing of 5 Milligrams / Kilogram to Dogs Formulation Cmax_in / ml_l T, ^ (hours) AUC (ng »hour / mL) Formula 1 405 ± 43 1.7 ± 0.4 2723 + 587 Formula 2 631 ± 121 1.4 + 0.4 3532 ± 899 Control 672 ± 157 1.2 + 0.3 2808 + 656 These results demonstrate that cyclosporin formulated as a pre-concentrate of the present invention is readily available, and has a pharmacokinetic profile substantially similar to that of the commercial cyclosporin product. Furthermore, the variability (standard deviation) of the maximum serum concentration obtained with the pre-concentrates of the present invention can be seen to be lower in each case than that observed using the commercial control.

EXAMPLE 4 PREPARATION OF PRE-CONCENTRATED SOLES CONTAINED CYCLOSPORIN A v ETHANOL Four additional pre-concentrates of the present invention were prepared for further study in clinical trials, in accordance with the following formulations (wherein the percentages indicated are by weight): (A ) 75% propylene glycol laurate 5% TPGS 5% ethanol 15% cyclosporin (B) 54% propylene glycol laurate 25% caprylic / capric triglycerides 1% TPGS 5% ethanol 15% cyclosporin (C) 52% propylene glycol laurate 25% caprylic / capric triglycerides 3% TPGS 5% ethanol 15% cyclosporin (D) 50% propylene glycol laurate 25% caprylic / capric triglycerides 5 % TPGS 5% ethanol 15% cyclosporine In each case (A) through (D) above, the pre-concentrates were prepared as described in the previous Examples, and were found to have satisfactory physical characteristics both before and after the addition to water. It is understood that the foregoing detailed description and the accompanying Examples are merely illustrative, and should not be construed as limitations on the scope of the invention, which is defined solely by the appended claims and their equivalents. It is expected that experts in this field will be able to see different changes and modifications to the modalities given to know, and can be done without departing from the spirit and scope of it.

Claims (16)

1. A self-emulsifying pharmaceutical pre-concentrated composition, which comprises: (a) a lipophilic medicinal compound, (b) a polyethylene glycol succinate of d-alpha-tocopheryl 1000 (TPGS), and (c) a lipophilic phase.

2. A self-emulsifying pre-concentrate according to claim 1, wherein the TPGS is present in an amount of between 0.1 percent and 50 percent by weight.

3. A self-emulsifying pre-concentrate according to claim 2, wherein the TPGS is present in an amount of between 1 percent and 5 percent by weight.

4. A self-emulsifying pre-concentrate according to claim 1, wherein the lipophilic phase comprises at least one component selected from the group consisting of: (a) fatty acid esters of glycerol, (b) esters of propylene glycol fatty acid, and (c) vegetable oil.

5. A self-emulsifying pre-concentrate according to claim 4, wherein the weight ratio between the lipophilic phase and the TPGS is between 1: 1 and 999: 1.

6. A self-emulsifying pre-concentrate according to claim 5, wherein the weight ratio between the lipophilic phase and the TPGS is between 9: 1 and 99: 1.

7. A self-emulsifying pre-concentrate according to claim 4, wherein the lipophilic phase comprises propylene glycol laurate, and wherein the weight ratio between the propylene glycol laurate and the TPGS is about 15: 1.

8. A self-emulsifying pre-concentrate according to claim 4, wherein the lipophilic phase comprises propylene glycol laurate and caprylic / capric triglyceride, and wherein the weight ratio between the lipophilic phase and the TPGS is between 20 and 20. : 1 and 85: 1.

9. A self-emulsifying pre-concentrate according to claim 8, wherein the weight ratio between the propylene glycol laurate and the caprylic / capric triglyceride is about 2: 1.

10. A self-emulsifying pre-concentrate according to claim 9, wherein the weight ratio between the lipophilic phase and the TPGS is between 25: 1 and 80: 1.

11. A self-emulsifying pre-concentrate according to claim 4, wherein the lipophilic phase comprises propylene glycol dicaprylate / dicaprate, and the weight ratio between the lipophilic phase and TPGS is between 1: 1 and 99: 1.

12. A self-emulsifying pre-concentrate according to any of claims 4 to 11, which additionally comprises ethanol in an amount of between 1 percent and 9 percent by weight.

13. A self-emulsifying pre-concentrate according to any of claims 1 to 13, wherein the medicinal compound is cyclosporin, and wherein the cyclosporin is present in an amount of between about 0.5 percent and about 25 percent. cent in weight.

14. A self-emulsifying pre-concentrate according to claim 13, wherein the cyclosporin is present in an amount of between about 10 percent and about 15 percent by weight.

15. A pharmaceutical composition comprising a self-emulsifying pre-concentrate according to claim 13, in combination with a sufficient amount of water to produce a stable emulsion.

16. A pharmaceutical composition comprising a self-emulsifying pre-concentrate according to any of claims 1 to 12, in combination with a sufficient amount of water to produce a stable emulsion.