Self-emulsifying drug delivery formulation with improved oral bioavailability of lipophilic compounds

Abstract

The present invention relates to a self-emulsifying drug delivery formulation with improved oral bioavailability of a lipophilic compound, comprising a lipophilic compound comprising one or a combination of more of tocotrienol, coenzyme Q10, carotenoid; vitamin E polyethylene glycol 1000 succinate (TPGS); an oil carrier and a phospholipid. The invention also relates to the use of the self-emulsifying drug delivery system in the preparation of dietary supplements with improved oral bioavailability of lipophilic compounds.

Description

Technical Field

[0001] The present invention generally relates to a drug delivery system for lipophilic compounds, and more particularly to a self-emulsifying drug delivery system with improved oral bioavailability of lipophilic compounds. Background Art

[0002] Vitamin E is a general term for lipophilic natural compounds with unique antioxidant properties, commonly found in plants and seeds. Naturally occurring vitamin E exists in eight chemical isomers, namely α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol, each with different levels of biological activity. It is well known in the art that antioxidants protect cells from oxidative damage caused by free radicals containing unpaired electrons, which are widely believed to be involved in the development of cancer and cardiovascular disease. Vitamin E has therefore become an important lipophilic nutrient with antioxidant properties that can prevent a variety of diseases and promote human health. Until recently, the α-isomer of tocopherol has been considered the most active form recognized to meet human needs. However, years of scientific research have found that tocotrienols are different from the commonly used vitamin E isomers and have more potent properties than tocopherols. Tocotrienols are usually distributed throughout the human body through the bloodstream and tend to accumulate in body tissues such as the brain, heart, myocardium, skin, liver and adipose tissue after oral administration. This suggests that the tocotrienol subfamily of vitamin E has better antioxidant properties than the tocopherol subfamily, as it displays potent neuroprotective, tumor suppressive, and cholesterol-lowering properties.

[0003] As with all lipophilic nutrients and dietary lipids, oral absorption of tocotrienols increases with increasing fat intake with bile acid secretion to promote lipolysis and micelle formation to cross the intestinal barrier. Unlike tocopherols, which are ubiquitous in dietary sources, tocotrienols are limited in natural dietary sources and have a lower affinity for certain transporters. When administered orally, tocotrienols tend to compete with tocopherols for the α-tocopherol transporter protein (α-TTP) with an affinity that is approximately 10 times lower than that of α-tocopherol. Therefore, tocotrienols generally have low or unstable oral bioavailability.

[0004] In order to avoid the problem of low or unstable oral bioavailability and to achieve the continuous high absorption of lipophilic vitamins including tocotrienols, it has been considered to use emulsions to improve. However, conventional emulsions are not ideal dosage forms because they are relatively large in volume, have a shorter shelf life due to stability issues and are not very palatable. Recently, the development of self-emulsifying drug delivery systems (SEDDS) has attracted great attention, and the system is expected to improve bioavailability, improve the repeatability of plasma profiles and reduce inter-subject and intra-subject variability. SEDDS is usually formed by mixing oil with a suitable nonionic surfactant in the absence of water, so that lipophilic drugs and compounds have enough solubility in the oil / surfactant system, thereby being encapsulated therein.

[0005] Existing SEDDS technology for effectively delivering tocotrienols has been proposed. For example, U.S. Patent No. US6596306B1 discloses a self-emulsifying drug delivery composition for oral administration of fat-soluble drugs including tocotrienols. The above-mentioned technology promotes self-emulsification by adopting a surfactant system of caprylocaproyl macrogol glyceride and polyoxyethylene 20 sorbitan monooleate and a suitable combination of suitable oils, thereby further increasing the absorption of tocotrienols, thereby being expected to enhance the oral absorption of tocotrienols. Another SEDDS technology is exemplified in U.S. Patent No. US10493055B2, which discloses a self-emulsifying drug delivery formulation for improving the delivery of tocotrienols, which comprises a combination of tocotrienols, two nonionic surfactants (i.e. sorbitan monolaurate and polyoxyethylene sorbitan 20 monooleate) and an oil carrier. Nevertheless, the bioavailability reported by the above-mentioned SEDDS technology is at least 2 to 3 times higher than traditional non-self-emulsifying preparations.

[0006] Tocotrienols that are not rapidly transported out of the liver will be catabolized by cytochrome P450 (CYP) enzymes and then beta-oxidized, conjugated to form carboxytryptophanol and conjugated counterparts. Tocotrienols can enhance the transport activity of P-glycoprotein in enterocytes at very high concentrations. However, it is not obvious to those skilled in the art to consider the effect of tocotrienols on the P-glycoprotein efflux mechanism to promote the bioavailability of tocotrienols using another inhibitor.

[0007] Some surfactants have also been reported to have the property of modulating drug cytochrome P450 enzyme metabolism. Early use of surfactants with tocotrienols, as described in the above art, did not indicate that simultaneous inhibition of P-glycoprotein (P-gp) and CYP-mediated metabolism could complement and enhance the oral bioavailability of tocotrienols in self-emulsifying formulations. In particular, α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a nonionic surfactant that improves the solubility of lipophilic drugs and, due to its P-glycoprotein inhibition, enhances drug penetration. In addition, TPGS has been shown to improve drug stability by inhibiting CYP3A4 and CYP2C9 metabolism. However, early applications of TPGS did not indicate that TPGS could enhance the oral bioavailability of another vitamin E isomer, such as tocotrienol, by competing with tocopherol for α-TTP, through a triple mechanism of spontaneous micellization, inhibition of P-gp, and CYP-mediated metabolism. The present invention facilitates the use of TPGS in a self-emulsifying drug delivery formulation to induce the above-mentioned synergistic effect, thereby enhancing the oral bioavailability of lipophilic tocotrienols. Summary of the invention

[0008] One aspect of the present invention is to provide a self-emulsifying drug delivery formulation that exhibits enhanced oral bioavailability of lipophilic compounds after oral ingestion. Advantageously, the oral bioavailability of the self-emulsifying drug delivery formulation of the present invention is increased by 2 to 3 times compared to conventional self-emulsifying drug delivery formulations.

[0009] Another aspect of the present invention is to provide a substantially stable self-emulsifying drug delivery formulation.

[0010] At least one of the aforementioned objects is met in whole or in part, wherein embodiments of the present invention describe a self-emulsifying formulation with improved oral bioavailability of a lipophilic compound, comprising: a lipophilic compound; vitamin E polyethylene glycol 1000 succinate (TPGS), an oil carrier, and a phospholipid.

[0011] In a preferred embodiment of the present invention, the lipophilic compound is selected from one or more combinations of tocotrienols, coenzyme Q10, and carotenoids.

[0012] Preferably, the tocotrienol comprises α-tocotrienol, β-tocotrienol, γ-tocotrienol or δ-tocotrienol.

[0013] Preferably, the coenzyme Q10 comprises ubiquinone and ubiquinol.

[0014] Preferably, the fat-soluble vitamin is selected from a combination of one or more of vitamin A, vitamin D, vitamin E and vitamin K.

[0015] Preferably, the fat-soluble vitamins include α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin and lycopene.

[0016] In a preferred embodiment of the present invention, it is disclosed that Vitamin E TPGS is present in an amount of 0.1% to 30% by weight of the drug delivery formulation.

[0017] In another preferred embodiment of the present invention, it is disclosed that the oil carrier is selected from a combination of one or more of glycerol fatty acid esters, propylene glycol fatty acid esters, and vegetable oils.

[0018] Preferably, the glycerol fatty acid ester is a monoglyceride, a diglyceride or a triglyceride.

[0019] Preferably, the vegetable oil is palm oil, soybean oil, sesame oil, rice bran oil, sunflower seed oil or castor oil.

[0020] More preferably, the oil carrier is present in an amount of 5% to 80% by weight of the drug delivery formulation.

[0021] A further embodiment of the present invention discloses that the phospholipid is phosphatidylcholine, including phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol.

[0022] Preferably, the phospholipid is present in an amount of 1% to 10% by weight of the drug delivery formulation.

[0023] Preferably the drug delivery formulation is in the form of a capsule or softgel.

[0024] An exemplary embodiment of the present invention discloses the use of a self-emulsifying drug delivery formulation in the preparation of a dietary supplement with improved oral bioavailability of a lipophilic compound, wherein the drug delivery formulation comprises a lipophilic compound selected from a combination of one or more of tocotrienols, coenzyme Q10, fat-soluble vitamins, carotenoids, vitamin E polyethylene glycol 1000 succinate, an oil carrier and a phospholipid; the lipophilic compound is present in an amount of 5% to 80% by weight of the drug delivery formulation, and the vitamin E polyethylene glycol 1000 succinate is present in an amount of 0.1% to 30% by weight of the drug delivery formulation.

[0025] One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned as well as those inherent therein.The embodiments described herein are not intended to limit the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] To facilitate understanding of the invention, there are shown in the accompanying drawings preferred embodiments, by observation of which, when considered in conjunction with the following description, the invention, its construction and operation, together with its numerous advantages, will be readily understood and appreciated.

[0027] Figure 1 The oral bioavailability of delta-tocotrienol expressed as blood concentration-time curves with and without a single dose of ketoconazole is described.

[0028] Figure 2 The oral bioavailability of gamma-tocotrienol expressed as blood concentration-time curves with and without a single dose of ketoconazole is described.

[0029] Figure 3 The oral bioavailability of α-tocotrienol expressed as blood concentration-time curves with and without a single dose of ketoconazole is described.

[0030] Figure 4 The oral bioavailability of delta-tocotrienol administered by control, Product X and Formulation S is depicted as blood concentration-time curves.

[0031] Figure 5 The oral bioavailability of gamma-tocotrienol administered by control, Product X and Formulation S is depicted as blood concentration-time curves.

[0032] Figure 6 The oral bioavailability of α-tocotrienol administered by control, Product X and Formulation S is depicted as blood concentration-time curves. DETAILED DESCRIPTION

[0033] The present invention will be described below according to the preferred embodiments of the present invention and with reference to the accompanying drawings. However, it should be understood that the description is limited to the preferred embodiments of the present invention only for the convenience of discussing the present invention, and it is foreseeable that those skilled in the art can design various modifications without departing from the scope of the appended claims.

[0034] The present invention provides a preparation of a self-emulsifying drug delivery system (SEDDS) for lipophilic compounds, which has enhanced oral bioavailability and high absorption of lipophilic compounds. SEDDS is essentially a mixture of oil and surfactant, and has been widely used in lipophilic formulations. SEDDS forms an oil-in-water emulsion when contacting gastrointestinal fluid and slightly agitating (e.g., peristaltic motion of the stomach and small intestine). Therefore, SEDDS effectively improves absorption and oral bioavailability. Because the solubility of lipophilic compounds in SEDDS and the efficiency of oral bioavailability depend on the selection of oil carrier and surfactant, selecting a suitable oil carrier and surfactant combination to realize the high oral bioavailability of lipophilic compounds is the basic requirement of SEDDS preparations.

[0035] In one embodiment of the present invention, the SEDDS preparation comprises a lipophilic compound, a surfactant, an oil carrier and a phospholipid. By definition, a lipophilic compound is a molecule that is attracted to other lipids, fats and oils and tends to dissolve. Those skilled in the art can select any suitable lipophilic compound. The lipophilic compound suitable for the SEDDS preparation of the present invention is selected from the group consisting of one or more of tocotrienols, coenzyme Q10, fat-soluble vitamins, and carotenoids. The lipophilic compound used in the SEDDS preparation of the present invention can be combined with the benefits provided by the surfactant, oil carrier and phospholipid in the preparation, can provide the desired nutritional or pharmaceutical benefits, and can be selected accordingly as needed. Preferably, the lipophilic compound is present in an amount of 5% to 80% by weight of the SEDDS preparation.

[0036] According to a preferred embodiment of the present invention, the tocotrienol used in the SEDDS preparation further comprises α-tocotrienol, β-tocotrienol, γ-tocotrienol or δ-tocotrienol. The tocotrienol used in the SEDDS preparation of the present invention can be natural or synthetic. For example, tocotrienol can be extracted from plants such as palm oil, bran oil, linseed oil, wheat germ, barley and certain types of nuts and cereals, but is not limited thereto.

[0037] In another embodiment of the present invention, the lipophilic compound used in the SEDDS formulation is coenzyme Q10. Coenzyme Q10 used herein is a fat-soluble quinone, which is similar in structure to vitamin K and has antioxidant properties. Suitable coenzyme Q10 for use in the SEDDS formulation of the present invention includes ubiquinone and ubiquinol.

[0038] In another embodiment of the present invention, the lipophilic compound used in the SEDDS formulation is a fat-soluble vitamin. Fat-soluble vitamins are essentially vitamins that dissolve in fat and can be absorbed by fat globules, which pass through the small intestine and are distributed throughout the body through the blood. In embodiments of the present invention, fat-soluble vitamins suitable for use in SEDDS formulations include, but are not limited to, vitamin A, vitamin D, vitamin E, and vitamin K.

[0039] In another embodiment of the present invention, the lipophilic compound used in the SEDDS formulation is a carotenoid. In general, carotenoids are plant pigments that give fruits and vegetables bright red, yellow and orange colors. Carotenoids are a class of phytonutrients that are found in the cells of a variety of plants, algae and bacteria. Carotenoids also act as antioxidants in the human body. Carotenoids suitable for use in the SEDDS formulation of the present invention include, but are not limited to, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin and lycopene.

[0040] The SEDDS preparation of the invention comprises the above-mentioned lipophilic compound and a surfactant and an oil carrier as a useful auxiliary material to provide self-emulsifying characteristics. By mixing the lipophilic compound with an acceptable oil carrier, the solubility of the lipophilic compound in the lipid system can be greatly increased, and its mixture can be easily emulsified with a surfactant. Generally, the surfactant commonly used in the SEDDS preparation includes a nonionic surfactant having a hydrophobic component (oil-soluble) and a hydrophilic component (water-soluble), characterized by a hydrophilic-lipophilic balance (HLB). The nonionic surfactant reduces the oil-water interfacial tension by being adsorbed on the oil-water interface. A variety of pharmaceutically acceptable surfactants are suitable for producing SEDDS preparations.

[0041] It is reported that the oral bioavailability of conventional SEDDS formulations is increased by 2 to 5 times compared to non-SEDDS formulations. The inventors have found that by inhibiting the P-glycoprotein efflux transporter and the metabolizing enzymes of the CYP3A4 enzyme to limit the potential limitation of the intestinal first-pass effect, the oral bioavailability of lipophilic compounds is increased by 2 to 3 times compared to conventional SEDDS formulations. In the context of the present invention, the synergistic effect of p-glycoprotein and CYP3A4 enzyme inhibition can be enhanced by using a water-soluble derivative of natural vitamin E, vitamin E polyethylene glycol 1000 succinate (TPGS). Due to its P-glycoprotein inhibitory effect, TPGS can increase the solubility of lipophilic compounds in the SEDDS formulations of the present invention and enhance their penetration. In addition, TPGS has been shown to improve compound stability by inhibiting CYP3A4 metabolism. TPGS is also an excellent emulsifier for lipophilic compounds, and the oral bioavailability of SEDDS formulations can be enhanced by forming a stable small particle size emulsion. As used herein, the term "TPGS" is used interchangeably with the term vitamin E TPGS. According to a preferred embodiment of the present invention, the amount of Vitamin E TPGS used is 0.1% to 30% by weight of the SEDDS formulation, depending on the lipophilic compound used therein.

[0042] As described above, the SEDDS preparation comprises an oil carrier combined with vitamin E TPGS to provide self-emulsifying characteristics. After stirring, the oil carrier will present small oil droplets, which are then uniformly dispersed and self-assembled into micelles in the presence of vitamin E TPGS. In a preferred embodiment of the present invention, the oil carrier suitable for use in the SEDDS preparation is selected from a combination of one or more of glycerol fatty acid esters, propylene glycol fatty acid esters, and vegetable oils. Preferably, the glycerol fatty acid ester used is a monoglyceride, a diglyceride, or a triglyceride. Suitable vegetable oils used as carrier oils in the SEDDS preparations of the present invention include, but are not limited to, palm olein, soybean oil, sesame oil, rice bran oil, corn oil, sunflower seed oil, or castor oil. In order to provide sufficient self-emulsifying characteristics to the SEDDS preparation, the amount of the oil carrier used is 5% to 80% of the weight of the SEDDS preparation. It should be noted that the amount of the oil carrier can be adjusted according to the amount of vitamin E TPGS used in the SEDDS preparation.

[0043] Another excipient used in the SEDDS preparation of the present invention is a phospholipid, more preferably a plant-based phospholipid. Studies have found that the combination of phospholipids and oil carriers has a significant stabilizing effect on the micellar structure of the SEDDS preparation for delivering lipophilic compounds. In this way, the oral bioavailability of lipophilic compounds can be enhanced. In a preferred embodiment of the present invention, the phospholipid used is lecithin, including phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol. Preferably, the amount of phospholipid used is 1% to 10% by weight of the SEDDS preparation.

[0044] In one embodiment of the present invention, the SEDDS formulation is prepared by adding one or more lipophilic compounds to Vitamin E TPGS, which is heated to about 45°C to 50°C. A suitable oil carrier and phospholipid are then added to the mixture and mixed continuously for about 30 minutes to obtain a uniform mixture. To obtain the SEDDS formulation of the present invention, the amounts of lipophilic compounds, Vitamin E TPGS, oil carriers, and phospholipids are given above. The uniform mixture is then cooled to room temperature and then filled into any suitable oral dosage form. In a preferred embodiment of the present invention, the SEDDS formulation is encapsulated in a hard or soft capsule.

[0045] Exemplary embodiments of the present invention disclose the use of SEDDS formulations in the manufacture of dietary supplements with improved oral bioavailability of lipophilic compounds. It should be understood that the SEDDS formulations of the present invention can be combined with and can contain flavoring agents, coloring agents, excipients, stabilizers and other agents known to any person skilled in the art of dietary supplement formulations.

[0046] Example

[0047] Preferred embodiments of the invention are illustrated by the following non-limiting examples.

[0048] Embodiment 1:

[0049] A 2-cycle, 2-sequence crossover experiment was conducted using rats to study the effect of ketoconazole, a strong inhibitor of p-glycoprotein and CYP3A4 enzyme, on the oral bioavailability of tocotrienol (T3), a substrate of p-glycoprotein and CYP3A4 enzyme. The rats were randomly divided into 2 groups and administered in the order shown in Table 1:

[0050] Table 1

[0051]

[0052]

[0053] A non-self-emulsifying tocotrienol oil suspension was prepared by mixing tocotrienol-rich fraction (TRF) and palm oil in a ratio of 1:1. The total tocotrienols administered to each rat were equivalent to 10 mg / kg body weight. A single dose of ketoconazole (water suspension) was administered at 32 mg / kg body weight.

[0054] The rats were fasted for at least 12 hours before the study. During Phase 1, rats in Group 1 were given only the tocotrienol oily suspension, while Group 2 was given a single dose of ketoconazole half an hour before the tocotrienols. Phase 2 was conducted after a 1-week washout period. Blood samples were collected from the tail vein according to pre-set sampling intervals, and the blood levels of individual tocotrienol isomers at each time point were analyzed using an HPLC assay.

[0055] The effect of CYP3A4 enzyme and P-glycoprotein inhibition on the oral bioavailability of tocotrienols has been demonstrated. Co-administration of ketoconazole (a strong inhibitor of P-glycoprotein and CYP3A4 enzymes) increased the oral bioavailability of tocotrienols in rats by approximately 2.4-fold. Table 2 summarizes the improvement in oral bioavailability of individual tocotrienol isomers compared to controls. Figure 1 –3 describes the oral bioavailability of each tocotrienol with and without a single dose of ketoconazole and is presented as a plasma concentration-time curve.

[0056] Table 2

[0057]

[0058] Typically, if a compound is co-administered with a strong inhibitor (such as ketoconazole) that inhibits the efflux transport of P-glycoprotein and metabolism by CYP enzymes, thereby significantly improving oral bioavailability, it can be identified as a substrate for P-glycoprotein and CYP3A4 enzymes. In this experiment, a single dose of ketoconazole was given before the administration of the tocotrienol preparation, resulting in an approximately 2.4-fold increase in total tocotrienols detected in the blood. Therefore, it can be concluded that tocotrienols are substrates for P-glycoprotein and CYP3A4 enzymes.

[0059] Embodiment 2:

[0060] A 3-period, 3-sequence crossover study was conducted using rats to compare the oral bioavailability of tocotrienols in a control (non-self-emulsifying oily suspension), Product X (commercial self-emulsifying formulation) and Formulation S (self-emulsifying drug delivery formulation of the present invention). The animals were randomly divided into 3 groups and the drugs were administered in the order shown in Table 3 below.

[0061] Table 3

[0062]

[0063] The control (non-self-emulsifying oily suspension) was prepared by mixing tocotrienol-rich fraction (TRF) and palm olein in a 1:1 ratio.

[0064] Product X (a self-emulsifying commercial product) contains tocotrienols formulated using a patented self-emulsifying system for enhanced oral bioavailability.

[0065] Preparation S comprises tocotrienol, oil carrier, TPGS and phospholipid phase, the weight of oil carrier is 5-80% of the weight of preparation S, and the weight of TPGS is 0.1-30% of the weight of preparation S. The ratio of tocotrienol to oil carrier can be 1:1 to 1:10, and the ratio of TPGS to phospholipid can be 1:1 to 1:20.

[0066] Before the study, rats were fasted for at least 12 hours. During the first phase, rats in group 1 were given T3 oily suspension (non-self-emulsifying control), group 2 was given formulation S, and group 3 was given commodity X. The total amount of tocotrienols given to each rat of each formulation was equivalent to 10 mg / kg body weight. Phases 2 and 3 were carried out after a one-week cleanout period. Blood samples were collected from the tail vein according to the following predetermined sampling intervals, and the blood levels of each tocotrienol isomer at each time point were analyzed using the HPLC assay.

[0067] Product X increased the oral bioavailability of total tocotrienols by approximately 4.6-fold, while Formulation S increased the oral bioavailability by 11.5-fold compared to the non-SEC. Formulation S demonstrated a synergistic effect of the combined use of excipients, resulting in a significantly enhanced oral bioavailability that far exceeded the bioavailability improvement observed with simple inhibition of metabolizing enzymes using ketoconazole and was also superior to the improvement in bioavailability from the simple SEC formulation in Product X. Table 4 summarizes the improvements in oral bioavailability of individual and total tocotrienol isomers compared to the control, Product X, and Formulation S. Figure 4-6 The oral bioavailability of each tocotrienol isomer administered by control, Product X and Formulation S is depicted as blood concentration-time curves.

[0068] Table 4

[0069]

[0070] Self-emulsifying formulations are a common strategy for improving the oral bioavailability of oil-soluble compounds. The typical enhancement effect of self-emulsifying formulations described in the literature is 2 to 5 times that of non-self-emulsifying formulations. Example 1 above shows that tocotrienols, which are substrates of P-glycoprotein and CYP3A4 enzymes, can achieve enhanced oral bioavailability by inhibiting P-glycoprotein and CYP enzymes using ketoconazole, with bioavailability increased by 2 to 3 times compared to the case without ketoconazole.

[0071] In the present invention, formulation S is a combination of TPGS, phospholipids and oil-soluble tocotrienols, which promotes spontaneous micellization, limits intestinal first-pass effects by inhibiting P-glycoprotein and CYP3A enzyme metabolism, and stabilizes the emulsion, allowing greater intestinal absorption of tocotrienols. The improvement in bioavailability of the present invention far exceeds the expected performance of the individual strategies (through an additive effect), i.e., co-administration of inhibitor / ketoconazole alone or the use of conventional self-emulsifying formulations alone. By the present invention, the oral bioavailability of tocotrienols was improved by 11.5 times compared to non-self-emulsifying oily formulations of tocotrienols, which has not been previously recorded.

[0072] Embodiment 3:

[0073] The test device for evaluating the efficiency of the self-emulsifying agent of the present invention consists of a light source, a paddle stirrer, a 250 ml beaker, a current relay and a phototransistor, which are arranged accordingly. The light source comes from a 40 watt bulb, which emits a light intensity of about 1000 lux, passing through a glass beaker containing 250 ml of distilled water. The phototransistor is connected to the current relay and a stopwatch. The paddle stirrer is set to rotate at a speed of 100 rpm.

[0074] To evaluate the self-emulsifying properties of the present invention, a 1 ml syringe containing 0.5 ml of the liquid formulation was placed 1 cm below the water surface in a beaker before injection. When the sample was introduced into 250 ml of distilled water (37° C.), a stopwatch was started simultaneously. A paddle stirrer gently stirred the contents of the beaker. If an emulsion forms and blocks light transmission through the beaker, the phototransistor will not detect any light and the stopwatch will be triggered to stop by a current relay. The recorded times are used to compare the self-emulsifying efficiency between different samples, see Table 5:

[0075] Table 5

[0076] preparation A(Product X) B C D Time (seconds) 3.8±0.2 3.9±0.3 3.8±0.4 3.9±0.2

[0077] Note: n time is in seconds (mean ± SD, n = 3)

[0078] The physical stability of the emulsion products formed after standing at room temperature (25°C) for 20 minutes was evaluated. 1 ml of each formulation was dispersed in 50 ml of distilled water and rotated on a rotator for 5 minutes. The test tubes were allowed to stand and visually inspected. Based on visual inspection, the physical stability of the emulsion products was divided into no separation, slight emulsification, emulsification, and complete phase separation, as summarized in Table 6 below. All experiments were performed in triplicate.

[0079] Table 6

[0080]

[0081]

[0082] The self-emulsification efficiency of Formulation A (Product X) remained comparable to Formulations B, C, and D (Formulation B was the final formulation tested in the animal study of Example 2). The comparable results indicate that the formulations self-emulsified almost immediately when dispersed in water, as determined by the time required to block light transmission in the first part of this experiment.

[0083] However, when the self-emulsifying formulations were left to stand for a period of time, there were significant differences in the stability of the self-emulsified state of the formulations. Formulation A (Product X) began to slightly emulsify (indicating the onset of separation) at 10 minutes, while Formulations B, C, and D remained stable and did not separate even for up to 20 minutes.

[0084] The present invention discloses the contents contained in the attached claims and the foregoing description. Although the present invention has been described in detail in its preferred form, it should be understood that the disclosure of the preferred form of the present invention is only by way of example, and many changes may be made to the structural details and the combination and arrangement of parts without departing from the scope of protection of the present invention.

Claims

1. A self-emulsifying drug delivery formulation with improved oral bioavailability of a lipophilic compound, comprising: Lipophilic compounds; Vitamin E polyethylene glycol 1000 succinate; Oil carrier; and phospholipids.

2. The drug delivery preparation according to claim 1, characterized in that The lipophilic compound comprises one or more combinations of tocotrienol, coenzyme Q10, and carotenoids.

3. The drug delivery formulation according to claim 2, wherein the tocotrienol is selected from a combination of one or more of α-tocotrienol, γ-tocotrienol and δ-tocotrienol.

4. The drug delivery preparation according to claim 2, wherein the coenzyme Q10 is selected from one or a combination of ubiquinone and ubiquinol.

5. The drug delivery formulation according to claim 2, characterized in that The fat-soluble vitamins are selected from one or more combinations of vitamin A, vitamin D, vitamin E, and vitamin K.

6. The drug delivery formulation according to claim 2, wherein the carotenoid is selected from a combination of one or more of α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene.

7. The drug delivery formulation according to any one of claims 1 to 6, characterized in that The lipophilic compound is present in an amount of 5% to 80% by weight of the drug delivery formulation.

8. The drug delivery formulation according to claim 1, characterized in that The vitamin E polyethylene glycol 1000 succinate is present in an amount of 0.1% to 30% by weight of the drug delivery formulation.

9. The drug delivery formulation according to claim 1, characterized in that The oil carrier is selected from one or more combinations of glycerol fatty acid esters, propylene glycol fatty acid esters, and vegetable oils.

10. The drug delivery formulation according to claim 9, characterized in that The glycerol fatty acid ester is monoglyceride, diglyceride or triglyceride.

11. The drug delivery formulation according to claim 9, characterized in that The vegetable oil is palm oil, soybean oil, sesame oil, rice bran oil, corn oil, sunflower seed oil or castor oil.

12. The drug delivery formulation according to any one of claims 9 to 11, characterized in that The oil carrier is present in an amount of 5% to 80% by weight of the drug delivery formulation.

13. The drug delivery formulation according to claim 1, characterized in that The phospholipids are phosphatidylcholine, including phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol.

14. The drug delivery formulation according to claim 13, characterized in that The phospholipid is present in an amount of 1% to 10% by weight of the drug delivery formulation.

15. The drug delivery formulation according to any one of claims 1 to 14, characterized in that The drug delivery formulation is in the form of a capsule or soft gelatin capsule.

16. Use of a self-emulsifying drug delivery formulation in the preparation of a dietary supplement with improved oral bioavailability of a lipophilic compound, the drug delivery formulation comprising a lipophilic compound, the lipophilic compound being selected from a combination of one or more of tocotrienols, coenzyme Q10, fat-soluble vitamins, carotenoids, vitamin E polyethylene glycol 1000 succinate, an oil carrier and a phospholipid; the lipophilic compound is present in an amount of 5% to 80% by weight of the drug delivery formulation, and the vitamin E polyethylene glycol 1000 succinate is present in an amount of 0.1% to 30% by weight of the drug delivery formulation.

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