IL119176A - Soluble coprecipitates for enhanced oral bioavailability of lipophilic substances - Google Patents

Description

SOLID COPRECIPITATES FOR ENHANCED ORAL BIOAVAILABILITY OF LIPOPHILIC SUBSTANCES FIELD OF THE INVENTION The present invention concerns compositions comprising solid coprecipitates for enhanced oral bioavailability of lipophilic substances, and to methods for the preparation and use of these compositions. More particularly, these compositions comprise tocopheryl polyethyleneglycol succinate powdered coprecipitates of lipophilic substances .

BACKGROUND OF THE INVENTION Lipophilic substances with low water solubility often have poor oral bioavailability. These compounds being hydrophobic by nature show wetting difficulties and dissolution obviously represents a rate-limiting step in drug absorption from solid, oral dosage forms with a subsequent reduction in bioavailability. These substances are usually administered in the form of liquid preparations dissolved in edible oils or formulated in oil-in-water emulsions or microemulsions, however the oral bioavailability of many of them is still very low.

Examples of lipophilic compounds that exhibit poor oral bioavailability include lipophilic drugs, vitamins, and hormones. These include the steroids, steroid antagonists, non-steroidal anti-inflammatory drugs, antifungal compounds, antibacterial compounds, antiviral compounds, anticancer drugs, anti-hypertensives, antioxidants, anti-epileptic and antidepressants among many others .

Many formulations have been suggested to overcome the poor bioavailability of these and other classes of lipophilic compounds. However, to date safe and useful formulations that provide enhanced oral bioavailability have proven generally to be an unmet need.

The cannabinoids are one example of a family of lipophilic substances with very poor water solubility.

Cannabinoids such as Δ1-tetrahydrocannabinol (A^THC) , A6-tetrahydrocannabinol (Δ6-ΤΗΟ , A9-tetrahydrocannabinol (Δ9-ΤΗΟ , cannabinol, cannabidiol, and their metabolites, are highly hydrophobic lipid soluble compounds and can be dissolved in aqueous solutions only in the range of a few micrograms/ml or less depending upon conditions (Garret and Hunt, J. Pharm. Sci., 63:1056-1064,1974).

In general, the systemic availability of cannabinoids after oral administration is low and mean estimates of the human bioavailability of tetrahydrocannabinol (THC) following oral ingestion range from 6 to 12% depending on the vehicle used, for example the maximal plasma levels after oral dosing of 20 mg THC in a sesame oil formulation were around 10 ng/ml (Wall et al., Clin. Pharmacol. Ther. 34:352-363, 1983).

Dexanabinol (also denoted HU-211), as disclosed in US Patents 4,876,276 and 5,521,215 is a synthetic non-psychoactive cannabinoid with neuroprotective activity as a novel, multiple-action treatment for brain damage associated with stroke, head trauma , and cardiac arrest. The chemical structure of dexanabinol, (+) - (3S, S) -7-hydroxy-A6-tetra hydrocannabinol-1, 1-dimetylheptyl, is shown in Scheme 1.

Scheme 1 Dexanabinol is a very lipophilic compound practically insoluble in water (less than 50 μg/ml) with poor oral bioavailability.

Coenzyme Q10 (also denoted Ubiquinone or Vitamin K) , a fat-soluble natural antioxidant with potential use as a dietary supplement to protect against age-related degeneration, and as adjuvant therapy in many disease states, is another example of a very lipophilic substance with very low water solubility. The formulation of this substance in a suitable form affording convenient and efficient oral bioavailability is another unmet need.

Coenzyme Q10 is a fat-soluble quinone and is an essential component of the mitochondrial respiratory chain constituting a redox-link between flavoproteins and cytochromes and acting as an electron shuttle controlling the efficiency of oxidative phosphorylation.

Supplementary Coenzyme Q10 has reportedly shown beneficial influences in a variety of conditions or diseases, including periodontal disease, certain blood circulation diseases, impaired memory, tiredness, irregular heartbeat, high blood pressure, immune system impairment, and the aging process.

The recommended daily allowance for coenzyme Q10 has not been determined. Most experts agree however, that the daily requirement lies somewhere between 30 and 60 milligrams. When treating illnesses, dosages of 100 to 300 milligrams are commonly used.

The chemical name of CoQIO as 2, 3-dimethoxy-5-methyl-6-decaprenyl-1, 4-benzoquinone, is a very lipophilic compound and practically insoluble in water due to its long side chain of 10 isoprenoid units.

The oral bioavailability of CoQIO is generally very low and was found to be related to the dissolution rate of the formulation. Formulations of Coenzyme Q10 using lipids, in the form of emulsions, liposomes, microparticles and nanoparticles, have previously been disclosed. These known lipid formulations have been used as particles dispersed in an aqueous medium, and are suitable for various routes of administration including primarily for intravenous administration, as disclosed in WO 95/05164, which discloses microparticles and nanoparticles in aqueous suspension; in US Patent 4,824669, which discloses fatty emulsions; US Patent 4,636,381, which discloses liposomes; and US Patent 4,483,873, which discloses aqueous dispersions or solutions.

The neurohormone melatonin is synthesized in the pineal gland with a nocturnal circadian rhythm. Sleep disorders, seasonal depression, mood disorders, migraine, and jet lag are some of the disorders that have been correlated to a disruption of normal, physiological melatonin secretion. There are reports on the beneficial effect of exogenous melatonin administration to reestablish the synchronization of circadian rhythm. However, these studies have shown large variations in oral melatonin absorption, as well as the inconvenience of continuos intravenous delivery. Therefore an oral formulation of melatonin with good bioavailability is needed. A melatonin buccal mucoadhesive sustained release delivery patch has already been shown to deliver melatonin mimicking endogenous secretion (Benes et al., Proceed.

Intl. Symp. Control. Rel. Bioact. Mater., 21:551-552, 1994) .

Additional examples of lipophilic drugs with very poor water solubility and low oral bioavailability which could benefit from oral dosage forms are the antifungal agent amphothericin B, the anticancer drug etoposide and the tamoxifen and tamoxifen analogs.

Water-dispersible vitamin preparations were disclosed in US Patent 3,102,078, wherein the vitamin E derivative tocopheryl polyethyleneglycol succinate (TPGS) was shown to have useful properties as a solubilizing agent. Oily compositions of anti-tumor drugs utilizing TPGS as a solubilizing adjuvant have also been disclosed for instance in US 4578391. Further uses of TPGS as a surface active substance (US 4,668,513), as a cryoprotectant (US 5,198,432) or to improve the bioavailability of vitamin E (US patents 5,179,122 and 5,223,268). A powder formulation of water dispersible vitamin E compositions for use as a vitamin E supplement has also been disclosed in US 5,234,695.

The structure of TPGS is shown in scheme 2.

COO(CH 2CH20)nH Scheme 2 Nowhere in the art is it taught or suggested that this vitamin E derivative is useful as a general vehicle for the preparation of solid dosage forms of other lipophilic substances. Moreover, none of the background art teaches or suggests the novel advantages of tocopheryl polyethylene glycol succinate solid powdered coprecipitates.

SUMMARY OF THE INVENTION This invention is directed to compositions comprising tocopheryl polyethyleneglycol succinate (TPGS) solid coprecipitates useful for the oral delivery of lipophilic substances with low oral bioavailability, and to methods for preparing and using such compositions.

The solid coprecipitates of the present invention comprise three essential ingredients: a lipophilic substance, tocopheryl polyethyleneglycol succinate, and at least one dispersion agent or dispersion adjuvant to facilitate the homogeneous dispersion of the lipophilic substance in the mixture.

According to a preferred embodiment of the present invention, the solid TPGS coprecipitates of the present invention, comprise a dispersion adjuvant selected from the group consisting of polyvinylpyrrolidone, a medium chain triglyceride, a long chain triglyceride, tocopherol acetate, and polyethyleneglycol.

According to a more preferred embodiment, the solid TPGS coprecipitates of the present invention, comprise polyvinylpyrrolidone (PVP) as the dispersion adjuvant to help the lipophilic substance dissolve or disperse in the TPGS.

According to a most preferred embodiment of the present invention, the solid TPGS coprecipitates of the present invention, may advantageously further comprise a known free-flow imparting agent, such as fumed silica or the like. This embodiment provides powdered TPGS coprecipitates particularly useful in the preparation of solid dosage forms for oral administration.

Lipophilic substances incorporated in the powdered TPGS coprecipitates of the present invention have shown unexpectedly improved drug release in simulated gastric fluid in vitro and enhanced oral bioavailability in vivo. The present invention further relates to methods for producing the powdered TPGS coprecipitate compositions, comprising: co-melting TPGS, and the lipophilic^ substance at 40-60C; adding a dispersion adjuvant to the melted mixture and shaking; adding a fumed silica to the mixture and shaking; drying the resultant mixture at 100 C to get a dry coprecipitate .

The dispersion adjuvant used in accordance with this method may be added as an aqueous solution, an organic cosolvent solution, or an oil.

According to yet another embodiment the solid TPGS coprecipitate compositions according to the present invention may be prepared by freeze-drying of the TPGS/lipophilic substance/dispersing adjuvant mixture.

According to yet another embodiment the solid TPGS coprecipitates compositions according to the present invention may be prepared by spray-drying of the TPGS/ lipophilic substance/dispersing agent mixture.

According to a more preferred embodiment, the TPGS/ lipophilic substance/dispersing adjuvant coprecipitate formulations can be spray dried or freeze-dried to obtain dry powdered compositions suitable for the preparation of solid-dosage forms such as hard gelatin capsules or tablets.

According to a still more preferred embodiments these solid dosage TPGS coprecipitate compositions are advantageous for the oral delivery of "'Coenzyme Q10 as a dietary nutrient supplement, melatonin, dexanabinol, amphothericin B, etoposide, tamoxifen quaternary amine analogs, or for any appropriate lipophilic substance.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows the in vitro release of Dexanabinol in simulated gastric fluid from a powdered TPGS/PVP coprecipitate compositions packed in hard gelatin capsules.

FIG. 2 shows the Dexanabinol human plasma levels after oral administration of a solid TPGS coprecipitate composition compared to a MCT oil solution of the drug.

FIG. 3 shows the oral pharmacokinetics in rats of Dexanabinol formulated in a solid TPGS coprecipitate at three different dosages.

FIG. 4 shows the in vitro release of CoQIO in simulated gastric fluid from commercial CoQIO gelatin capsules and from a solid TPGS/PVP powdered coprecipitate formulation packed in gelatin capsule.

DETAILED DESCRIPTION OF THE INVENTION This invention is directed to compositions comprising tocopheryl polyethyleneglycol succinate solid coprecipitates useful for the oral delivery of lipophilic substances, and to methods for preparing and using such compositions.

Examples of lipophilic compounds that exhibit poor oral bioavailability include lipophilic drugs, vitamins, and hormones. These include the steroids, steroid antagonists, non-steroidal anti-inflammatory drugs, antifungal compounds, antibacterial compounds, antiviral compounds, anticancer drugs, anti-hypertensives, anti-oxidants, anti-epileptic and anti-depressants among many others.

The present invention discloses a novel way to increase the oral bioavailability of a lipophilic substance, being solid coprecipitates comprising the lipophilic substance and a surfactant vehicle having a melting point close to human body temperature. After mixing with body fluids such as gastric fluid, these compositions undergo quick dissolution with resultant micelles formation or emulsification. A good example of such a surfactant to obtain quickly dispersible drug coprecipitates is alpha-tocopheryl polyethylene glycol succinate (TPGS) , first disclosed in US patent 3,102,078). TPGS is an amphipathic molecule, prepared by esterification of hydrophilic polyethylene glycol molecule (usually with a mean molecular weight 1000, and about 20-25 ethylene oxide chains) with the carboxylic group of hydrophobic d-alpha-tocopherol hemisuccinate (acid) . TPGS is a water soluble compound (to 20% w/v) and forms micellar solutions with a critical micelle concentration (CMC) of 0.4-0.6 mM/L (about 0.075%). The hydrophilic-lipophilic balance (HLB) of TPGS is about 15-19. The amphipathic nature of TPGS, high HLB and water solubility and low CMC make the molecule an excellent emulsifying agent for lipophilic compounds. The emulsification and subsequent increase in surface area of the lipophilic substance results in increased gastrointestinal drug absorption and bioavailability.

Toxicological studies have shown that TPGS is safe for ingestion by humans as a dietary or nutritional supplement. In conclusion, TPGS can be safely used as a surfactant and a bioenhancer for lipophilic compounds of limited absorption in gastrointestinal region. Moreover, antioxidative properties of TPGS improve stability of TPGS containing formulations .

According to the present invention it now is disclosed that solid TPGS coprecipitate formulations self-emulsify when dispersed in a aqueous medium like gastric fluid forming very small drug mixed-micelles. Lipophilic substances loaded in TPGS solid coprecipitate formulations will be absorbed more easily by the gastrointestinal tract enhancing its oral bioavailability.

The solid TPGS coprecipitates of the present invention are composed of three essential ingredients: a lipophilic substance with low water solubility, tocopheryl polyethyleneglycol succinate, and at least one dispersion adjuvant.

According to a preferred embodiment of the present invention, the solid TPGS coprecipitates of the present invention, comprise a dispersion adjuvant selected from the group consisting of polyvinylpyrrolidone (PVP) ; a medium chain triglyceride or MCT oil; a long chain triglyceride or LCT oil; tocopherol acetate; polyethyleneglycol; or other adjuvant substances that can improve the dissolution of the lipophilic substance into the mixture or to help the lipophilic substance disperse homogeneously in the TPGS.

PF (BASF/ Germany); MCT oil, e.g., Miglyol 812 (Hulls, Germany); LCT oil (Croda) ; PEG, e.g., Carbowax 1450 (Union Carbide, USA) .

The solid TPGS coprecipitates of the present invention may further comprise any suitable nontoxic carrier or diluent powder as is known in the art to serve as freeflow imparting agent. Common examples of such additives are silicon dioxide, starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate. The tablets or pills can be coated or otherwise compounded with pharmaceutically acceptable materials known in the art to provide a dosage form affording prolonged action or sustained release. The solid TPGS coprecipitates may also be prepared in gelatin capsules. According to a preferred embodiment solid TPGS coprecipitates are further mixed with fumed silica such as CAB-O-SIL® (Cabot Corp., IL., US) which is fumed silicon dioxide, a powder material with extremely small particle size and enormous surface area.

The sub-microscopic size and enormous surface area of fumed silica enables it to function as a spacing agent between the relatively large particles of most powdered materials. Fumed silica acts as a dry lubricant, promoting free flow of the powder and preventing caking and lumping. The fumed silica layer decreases bulk tensile strength and shear strength, while neutralizing the electrostatic charge on the particles. The moisture adsorbing ability of fumed silica also helps it to perform its anti-caking function. Even powders which have already become caked can According to a more preferred embodiment of the present invention, the solid TPGS coprecipitates of the present invention, may advantageously further comprise a free-flowing imparting agent like fumed silica (Cab-O-Sil, Cabot Corp . , USA) .

Lipophilic substances incorporated in the solid TPGS coprecipitates of the present invention have shown unexpectedly improved in vitro drug release in simulated gastric fluid and enhanced oral bioavailability.

The lipophilic substance content in the solid TPGS coprecipitates of the present invention may range from 0.01-50% of total weight, more preferably in the range of 5-30% of total weight and still more preferably 10-20% of total weight.

The content of TPGS in the final coprecipitate formulations of the present invention is in the range of 5-65% of total weight of solids, more preferably in the range of 10-60% of total weight of solids, and still more preferably in the range of 10-50% of total weight of solids.

The content of dispersion adjuvant in the final coprecipitate formulations of the present invention is in the range of 5-75% of total weight of solids, more preferably in the range of 10-40% of total weight of solids, and still more preferably in the range of 10-30% of total weight of solids.

Examples of dispersion adjuvants for the preparation of of solid TPGS coprecipitates of the present invention are: PVP, e.g. Povidone (ISP Technologies, USA), or Kollidon usually be rendered free flowing by blending in 2% fumed silica by weight, or less.

The free-flow, anti-caking and anti-clogging characteristics which are imparted to powders, granules and pellets by the addition of small amounts of fumed silica are the result of several actions. The submicroscopic size of the silica aggregates permits them to move easily between the larger particles of the other dry ingredients, and in most cases fumed silica probably forms a coating on the powder particles. The tremendous surface area of fumed silica is the reason very small amounts can provide effective action.

After blending with the other powders, fumed silica adsorbs some or all the moisture which may be present in or on the product particles. The fumed silica aggregates prevent other particles from contacting each other to form the nuclei that would otherwise lead to the formation of larger lumps and cakes. This spacing and lubricating action helps to keep materials moving through such apertures as process equipment valves, spray heads, storage bin openings, bag and drum spouts and aerosol nozzle orifices.

Most powdered materials can be kept free flowing by a concentration of fumed silica in the final product range of 0.5-25%. The optimum concentration can be determined by working up or down in small steps. The more preferred weight percent of fumed silica in the final product will be in the range of 1-20%.

Products which cannot be processed Beyond a sticky or tacky powder can be made free flowing by adding the proper level of fumed silica as a final finishing step. Fumed silica can also be used to promote free flow in spray-dried or freeze-dried products.

In some cases it can be introduced into the original emulsion, suspension or solution, or blended in later. Fumed silica has also been used to coat powdered and pelletized products to prevent them from caking later. The content of silicon dioxide in the final solid TPGS coprecipitates is commonly in the range 5-20% of total weight of solids , and more preferably in the range of 10-20% of total weight of solids.

The preparation of solid TPGS powdered coprecipitates of lipophilic substances of the present invention may be prepared by different methods as described in the following non-limiting examples.

EXAMPLES Example 1: Preparation of tocopheryl polyethyleneglycol succinate/polyvinylpyrrolidone powdered coprecipitates of Dexanabinol by freeze-drying.

This example illustrates the preparation of tocopheryl polyethyleneglycol succinate/polyvinylpyrrolidone (TPGS/PVP) powdered coprecipitates of Dexanabinol by freeze-drying. The final weight/weight % composition of the different formulations prepared were as described in Table 1.

Table 1. Weight/weight % composition of TPGS/PVP/Dexanabinol coprecipitates TPGS (Eastman-Kodak Co., USA) was comelted with PVP (Kollidon PF 12, BASF, Germany, added from a 10% solution in water) at 40-60 C in a water bath. Dexanabinol was added to the melted materials and the mixtures were gently agitated for several minutes. Cab-O-Sil (Cabot CORP., USA, added from a 5% solution in water) was added and the mixtures were agitated again for several minutes. After cooling to room temperature TPGS/PVP/dexanabinol coprecipitates were formed. The coprecipitates were freeze-dried overnight using a Christ beta lyophilize (Germany) . Powdered free-flowing coprecipitates quickly dispersible in water were obtained.

TPGS/PVP/dexanabinol coprecipitates containing additionally tocopherol acetate and Miglyol 812 as described in Table 2 were also prepared by freeze-drying using the same method and resulting also in the formation of powdered free-flowing coprecipitates quickly dispersible in water.

Table 2. Weight/weight % composition of TPGS/PVP/Dexanabinol coprecipitates containing Miglyol and tocopherol acetate.

The obtained powdered coprecipitates were filled in hard gelatin capsules (No. 1) for in vitro release experiments in simulated gastric fluids and for oral bioavailability studies in rats (minicapsules, Torpac, USA) .

Example 2: Preparation of TPGS/PVP powdered coprecipitates of Dexanabinol by spray-drying.

This example illustrates the preparation of TPGS/PVP powdered coprecipitate of Dexanabinol by spray-drying. The final weight/weight % composition of the formulation prepared was as described in Table 3: Table 3. Weight/weight % composition of TPGS/PVP/Dexanabinol coprecipitate formulation prepared by spray-drying Formulation Code AY-91-175-3 and Ingredients TPGS 30 Dexanabinol 30 PVP 26 Cab-O-Sil 14 TPGS (249 mg) were melted in a water bath at 50 C.

Dexanabinol (249 mg)were then added to the melted TPGS and the mixture was shaken for several minutes at 50 C. PVP (2.2 ml of a 10% solution in water) was added to the comelted mixture of TPGS/Dexanabinol TPGS and the mixture was shaken again for several minutes. Finally, Cab-O-Sil (2.3 ml of a 5% solution in water) was added and the formulation was shaken again for 1 hr at 50 C.

The resultant formulation was spray-dried using a Yamato Pulvis GA32 Mini spray-dryer. The drying conditions were: flow rate 7 ml/min, inlet temperature 130 C, outlet temperature 80 C, and drying air flow 0.45 m3/min. A homogeneous and quickly water-dispersible dry powder of the TPGS/PVP/Dexanabinol coprecipitate was obtained.

Example 3: In vitro release of Dexanabinol from Solid TPGS coprecipitates in simulated gastric fluid.

In vitro drug release of Dexanabinol from solid TPGS coprecipitates was determined by placing a hard gelatin capsule No. 1 containing the formulation in 50 ml of simulated gastric fluid (150 mM NaCl, pH 1.2, 37° C, containing 1% Tween 80 as sink) . Gentle stirring was provided by a magnetic bar. Samples were drawn from the release medium at prefixed time intervals and filtered through a 2.7 μια PTFE filter (Whatman).

Dexanabinol was determined by HPLC using a Kontron instrument equipped with pump, UV detector, and autosampler. A summary of the typical chromatographic conditions of the method is provided below: Column: Merck 50980 supersphere 100RP-18, 75x4 mm, 4um. Mobile Phase: 30% phosphate buffer (θ θΙΜ KH2P04 , pH 3.0) : 70% acetonitrile (v/v) . Flow rate: 1 ml/min. Detector wavelength: 280 nm. Injection volume: 20μ1. Column temperature: ambient. Retention time: about 5.8 min. Run time: about 9 min.

Figure 1 shows the in vitro release data for TPGS/PVP/ Dexanabinol coprecipitate formulations in simulated gastric fluid. Depending on the specific composition of the formulation, very good Dexanabinol release from 60-95% were obtained mainly during the initial 10-20 min.

Example 4: Enhanced oral bioavailability of Dexanabinol in solid TPGS coprecipitate formulations.

The solid TPGS powdered coprecipitates were filled in hard gelatin minicapsules (Torpac, NJ, USA) and tested for oral bioavailability studies in rats. Male Sprague-Dawley rats (220-260 g, n=4) were administered orally with Dexanabinol formulated either as TPGS coprecipitates filled in hard gelatin minicapsules (Torpac, NJ, USA) or in MCT oil solution at 10, 25, and 50 mg/kg doses. Blood samples were collected at 0,0.5, 1.0, 2.0,3.0, 5.0,8.0, and 24 hours time intervals. The samples were centrifuged at 10,000 rpm for 5 min and the plasma* was separated and stored frozen at -20 C until plasma Dexanabinol levels were analyzed. Determination of Dexanabinol in plasma was performed by HPLC. The chromatographic conditions were as described in Example 3. Plasma samples stored at -20C were defrosted and diluted 1:4 as follows: 150 μΐ plasma sample was transferred into a 1.8 ml Eppendorf tube and 150μ1 of acetonitrile were added. The sample was vortexed and centrifuged in a microfuge for 10 minutes at 10,000 rpm. The upper clear liquid transferred into HPLC glass conical vial. A calibration curve was used for calculating Dexanabinol plasma levels. Corrections of sample peak areas were done by subtraction of average value of peak area obtained for samples at zero time (blank plasma) .

Figure 2 shows the oral pharmacokinetics of Dexanabinol administered at a 50 mg/kg dose as a TPGS coprecipitate compared to a solution of the drug in MCT oil ( iglyol 812) . A two fold increase in Dexanabinol plasma levels was obtained with the coprecipitate formulation compared to the oil solution demonstrating and enhanced oral absorption of Dexanabinol from the solid TPGS coprecipitate formulation indicating the good water dispersibility of the formulation which probably facilitates the uptake of the drug from the gastrointestinal tract.

Figure 3 shows the oral pharmacokinetics of Dexanabinol from TPGS coprecipitate formulation at three different doses. A maximal drug concentration (Cmax)was obtained after 5 hours (tmaxJfor all three doses tested, 10, 25, and 50 mg/kg.

Example 5: Preparation of solid TPGS coprecipitates of Ubiquinone (coenzyme Q10) .

This example illustrates the preparation of tocopheryl polyethyleneglycol succinate coprecipitates of Coenzyme Q10. The final weight/weight % composition of the; different formulations prepared were as described in Table 4: Table 4. Weight/weight % composition of TPGS/CoQIO coprecipitates .

Ubiquinone (Coenzyme Q10) was obtained from Global Marketing Associates, Inc. (San Francisco, CA) . The polyethyleneglycol used was Carbowax PEG 1450 from Union Carbide (CT, USA) . The MCT oil (medium chain triglycerides) used was Miglyol 812 (Hulls, Germany). LCT oil (long chain triglycerides) was from Croda. TPGS/CoQIO coprecipitates were prepared by heating together all the components at 50-60 C with consequent cooling to room temperature. Compositions containing polyvinylpyrrolidone (PVP K-12) were prepared using 50% PVP solutions in absolute ethanol and drying of the obtained mixture at 40- 45 C for 4-6 hours. The obtained TPGS/CoQIO coprecipitates showed quick water dispersibility with rapid release of the CoQIO.

Example 6: Preparation of TPGS/PVP powdered coprecipitates of Ubiquinone (coenzyme Q10) by freeze- drying.

This example illustrates the preparation of tocopheryl polyethyleneglycol succinate powdered coprecipitates of Coenzyme Q10 by freeze-drying. The final weight/weight % composition of the different formulations prepared were as described in Table 5: Table 5. Weight/weight % composition of TPGS/PVP/CoQIO powdered coprecipitates .

TPGS (Eastman-Kodak Co., USA) was melted at 40-60 C in a water bath. Coenzyme Q10 was added to the melted TPGS and the mixtures were gently agitated for several minutes. PVP (Kollidon PF 12, BASF, Germany) was then added from a 30% solution in water and the mixtures were shaken at 40 C for 1-2 hr. Cab-O-Sil (Cabot CORP., USA, added from a 5% solution in water) was added and the mixtures were agitated again for several minutes. After cooling to room temperature TPGS/PVP/CoQIO coprecipitates were formed. The coprecipitates were freeze-dried overnight using a Christ beta lyophilizer (Germany) . Powdered free-flowing coprecipitates quickly dispersible in water were obtained. They were packed in hard gelatin capsules for in vitro release studies.

Example 7: In vitro Release of Coenzyme Q10 from powdered TPGS/PVP coprecipitates in simulated gastric fluid.

In vitro drug release of CoQlO from a powdered TPGS/PVP coprecipitate formulation and from a commercial product containing equivalent amounts of CoQlO were determined by placing a hard gelatin capsule in 50 ml of simulated gastric fluid (150 mM NaCl, pH 1.2, 37° C) containing 1% Tween 80 as sink. Gentle stirring was provided by a magnetic bar. Samples were drawn from the release medium at prefixed time intervals, filtered through a 2.7 um Whatman GF filter and analyzed for CoQlO concentration. Figure 4 shows the in vitro release patterns of CoQlO from a powdered TPGS/PVP coprecipitate formulation compared to a commercial product ENERGYCO® CoQlO (Herbamed-Assutech Ltd., Rehovot, Israel) in simulated gastric fluid.

CoQlO was determined in the commercial product, powdered TPGS/PVP coprecipitate formulation, and in release medium of in vitro study by extraction with Dole reagent (isopropanol:heptane:water, 45:36:17) and measuring absorbance at 270 nm using a calibration curve. CoQlO samples (0.5 ml) were added to 3.5 ml of Dole reagent and mixed thoroughly and the two phases were allowed to separate for 10 min at room temperature. CoQlO was extracted selectively in Dole heptane upper phase which was transferred to a quartz cuvette for absorbance measurement.

The % release of CoQlO from the marketed product was very low compared to a very quick and significant release from the powdered TPGS/PVP coprecipitate formulation. Each E ERGYCO® COQ10 hard gelatin capsule contains 50 mg of CoQlO mixed with rice powder. After capsule disruption in the simulated gastric fluid, big aggregates or clusters of CoQlO and swelled rice powder were observed which may explain the low CoQlO dissolution into the release medium. Since particle size is a determinant factor in the rate and extent of drug absorption from the gastrointestinal tract, this result indicates low oral bioavailability of CoQlO from the commercial product compared to powdered TPGS/PVP coprecipitate formulation of the present invention which is quickly dispersible in the simulated gastric fluid.

Example 8: Preparation of TPGS/PVP powdered coprecipitate of Melatonin.

TPGS (500 mg) was melted at 40-60 C in a water bath. Melatonin (100 mg, from Jansenn Chimica, Belgium) was added to the melted material and the mixture was agitated for several minutes. A small amount of absolute ethanol (up to 5%,v/v) was added in order to get an homogeneous mixture. PVP (Kollidon PF 12, 2.6 ml of a 10% solution in water) was then added and the mixture was agitated again for several minutes. Cab-O-Sil (2.8 ml of a 5% solution in water) was added and the mixture was agitated again for several minutes. The resultant TPGS/PVP/melatonin mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) . A powdered free-flowing TPGS/PVP/melatonin coprecipitate quickly dispersible in water was obtained.

Example 9: Preparation of TPGS/PVP powdered coprecipitate of Amphothericin B.

TPGS (500 mg) was melted at 40-60 C in a water bath. Amphothericin B (100 mg, from Dumex, Denmark) was added to the melted material and the mixture was agitated for several minutes. A small amount of absolute ethanol (up to 5%,v/v) was added in order to get an homogeneous mixture. PVP (Kollidon PF 12, 2.6 ml of a 10% solution in water) was then added and the mixture was agitated again for several minutes. Cab-O-Sil (2.8 ml of a 5% solution in water) was added and the mixture was agitated again for several minutes. The resultant TPGS/PVP/melatonin mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) . A powdered free-flowing TPGS/PVP/Amphothericin B coprecipitate quickly dispersible in water was obtained.

Example 10: Preparation of TPGS/PVP powdered coprecipitate of Tamoxifen methyliodide.

TPGS (500 mg) was melted at 40-60 C in a water bath. Tamoxifen methiodide (100 mg, from Pharmos Corp., FL, USA) was added to the melted material and the mixture was agitated for several minutes. A small amount of absolute ethanol (up to 5%,v/v) was added in order to get an homogeneous mixture. PVP (Kollidon PF 12, 2.6 ml of a 10% solution in water) was then added and the mixture was agitated again for several minutes. Cab-O-Sil (2.8 ml of a 5% solution in water) was added and the mixture was agitated again for several minutes. The resultant TPGS/PVP/Tamoxifen methiodide mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) . A powdered free-flowing TPGS/PVP/melatonin coprecipitate quickly dispersible in water was obtained.

Example 11: Preparation of TPGS/PVP powdered coprecipitate of Etoposide.

TPGS (500 mg) was melted at 40-60 C in a water bath. Etoposide (100 mg, from Sigma, St. Louis, USA) was added to the melted material and the mixture was agitated for several minutes. A small amount of absplute ethanol (up to 5%,v/v) was added in order to get an homogeneous mixture. PVP (Kollidon PF 12, 2.6 ml of a 10% solution in water) was then added and the mixture was agitated again for several minutes. Cab-O-Sil (2.8 ml of a 5% solution in water) was added and the mixture was agitated again for several minutes. The resultant TPGS/PVP/melatonin mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) . A powdered free-flowing TPGS/PVP/Etoposide coprecipitate quickly dispersible in water was obtained.

It will be appreciated by the artisan that many additional modifications or variations of these compositions are feasible. The scope of the invention is not to be construed as limited to the foregoing examples, but rather by the scope of the following claims. 119176/2 11 THE

Claims (13)

CLAIMS What is claimed is:

1. A solid composition comprising: a lipophilic substance having a water solubility of less than 200 ,ug/inL at 25°C in an amount sufficient to provide a therapeutic effect when administered to a mammal; about 5-65%, based on the total solid weight of the composition, of tocopherol polyethyleneglycol succinate (TPGS) ; and about 5-75%, based on the total solid weight of the composition, of a dispersion adjuvant, wherein the lipophilic substance and the dispersion adjuvant are different compounds .

2. The composition of claim 1 wherein the dispersion adjuvant is selected from the group consisting of a polyvinylpyrrolidone, a medium chain triglyceride, a long chain triglyceride, a polyethyleneglycol, and a tocopherol acetate.

3. The composition of claim 1 which further comprises a solid carrier or diluent.

4. The composition of claim 1 wherein the lipophilic substance comprises about 0.01-50% of the total solid weight of the composition.

5. The composition of claim 1 wherein the dispersion adjuvant is polyvinylpyrrolidone.

6. The composition of claim 5 which further comprises a second dispersion adjuvant selected from the group consisting of an MCT oil, an LCT oil, polyethylene glycol, and tocopherol acetate.

7. The composition of claim 3, wherein the solid carrier or diluent comprises fumed silicon dioxide in the amount of about 1-20% of the total solid weight of the composition.

8. 3. The composition of claim l, wherein the composition is present in a unit dosage form.

9. The composition of claim 3, wherein the unit dosage form is selected from the group consisting of a gelatin capsule and a tablet.

10. The composition of claim 1 wherein the lipophilic substance is a drug.

11. The composition of claim 1 wherein the lipophilic substance is selected from the group consisting of a vitamin, a hormone, a peptide and protein.

12. The composition of claim 1 wherein the lipophilic substance is selected from the group consisting of a steroid, steroid antagonist, non-steroidal anti-inflammatory agent, antifungal agent, antibacterial agent, antiviral agent, anticancer agent, anti-hypertensive agent, anti-oxidant agent, anti-epileptic agent, anti-depressant agent. 13. The composition of claim 1 wherein the lipophilic substance is selected from the group consisting 5f dexanabinol, etoposide, coenzyme Q10, melatonin, cyclosporin A, amphotericin, tamoxifen and tamoxifen methiodide. 14. The composition of claim 1, wherein the lipophilic substance has a solubility in water of less than 50 μq/m^L at 25°C. 119176/2 15. A method for preparing the solid coprecipitate of claim 1, comprising: comelting the TPGS and the lipophilic substance at about 40°-60°C; adding the dispersion adjuvant to the melted mixture .with agitation; and drying the resultant mixture to obtain a dry coprecipitate. 16. The method of claim 15 in which the drying is achieved by spray drying or freeze drying of the mixture. 17. The method of claim 15 wherein the dispersion adjuvant comprises a solution of a polyvinyl pyrrolidone.

13. The method of claim 15 which further comprises adding fumed silica to the mixture of TPGS, lipophilic substance and dispersion adjuvant with agitation.