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

Abstract

The present invention relates to a self-emulsifying drug delivery formulation having improved oral bioavailability of the lipophilic compound, comprising a lipophilic compound, Vitamin E polyethylene glycol 1000 succinate (TPGS), an oil carrier and a phospholipid. The present invention also relates to the use of the self-emulsifying drug delivery system in the manufacture of a dietary supplement having improved oral bioavailability of the lipophilic compound.

Description

[Technical Field]

[0001] The present invention relates generally 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 technology]

[0002] Vitamin E is a general term for lipophilic, naturally occurring compounds with pronounced antioxidant properties, typically found in plants and seeds. Naturally occurring vitamin E exists in eight chemical isomers, namely, alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol, each with varying levels of biological activity. Antioxidants contain unpaired electrons and are well known in the art to protect cells from oxidative damage caused by free radicals, which are a widespread cause of cancer and cardiovascular disease. Therefore, vitamin E has emerged as an essential lipophilic nutrient with antioxidant properties for the prevention of numerous diseases and promoting health in the human body. Until recently, the alpha isomer of tocopherol was considered the most active form recognized to meet human needs. However, years of scientific research have revealed that tocotrienol is distinct from commonly used vitamin E isomers, suggesting more potent properties than tocopherol. Tocotrienols are generally distributed throughout the human body via the bloodstream and tend to accumulate in body tissues, such as the brain, heart, cardiac muscle, skin, liver and adipose tissue, after oral administration, indicating that the tocotrienol subfamily of vitamin E has better antioxidant properties than the tocopherol subfamily, as it exhibits potent neuroprotective, tumor-suppressing and cholesterol-lowering properties.

[0003] Like all lipophilic nutrients and dietary fats, oral absorption of tocotrienol increases with increased fat uptake due to the secretion of bile acids, facilitating lipolysis and micelle formation for transport across the intestinal barrier.Unlike tocopherol, which is ubiquitous in food sources, tocotrienol is limited to natural food sources and has a lower affinity for some transport proteins.When administered orally, tocotrienol tends to compete with tocopherol for alpha-tocopherol transport protein (α-TTP) with an affinity approximately 10 times lower than that of alpha-tocopherol.Therefore, tocotrienol typically has low or unstable oral bioavailability.

[0004] In order to avoid the problem of low or unstable oral bioavailability and to achieve consistently high absorption of lipophilic vitamins, including tocotrienols, emulsions have been considered as an improvement.However, conventional emulsions are relatively bulky, have a shorter shelf life due to stability issues, and are not very palatable, making them undesirable dosage forms.In recent years, much attention has been paid to the development of self-emulsifying drug delivery systems (SEDDSs), which ensure improved bioavailability, improved reproducibility of plasma profiles, and reduced inter- and intra-subject variability.SEDDSs are generally formulated in the absence of water by mixing oil with a suitable nonionic surfactant, so that lipophilic drugs and compounds with sufficient solubility in the oil / surfactant system can be encapsulated therein.

[0005] Existing SEDDS technologies have been proposed for the effective delivery of tocotrienol. For example, U.S. Patent No. 6,596,306 B1 discloses a self-emulsifying drug delivery composition for oral administration of fat-soluble drugs, including tocotrienol. This technology uses a suitable combination of a surfactant system of caprylocaproyl macrogolglyceride and polyoxyethylene glycol 20 sorbitan monooleate with an appropriate oil to promote self-emulsification, thereby further increasing the absorption of tocotrienol and ensuring improved oral absorption of tocotrienol. Another SEDDS technology is exemplified in U.S. Patent No. 1,0493,055 B2, which discloses a self-emulsifying drug delivery formulation for improved delivery of tocotrienol, comprising tocotrienol, a combination of two nonionic surfactants, i.e., sorbitan monolaurate and polyoxyethylene sorbitan 20 monooleate, and an oil carrier. Despite this, the SEDDS technology is believed to report at least a 2- to 3-fold improvement in bioavailability over conventional non-self-emulsifying formulations.

[0006] Tocotrienols that are not rapidly transported out of the liver undergo catabolism by cytochrome P450 (CYP) enzymes, followed by beta-oxidation and conjugation to generate carboxychromanol and conjugated equivalents. At very high concentrations, tocotrienols can enhance the translocation activity of P-glycoprotein in enterocytes. However, such teachings do not make it clear to those skilled in the art how to enhance the bioavailability of tocotrienols with other inhibitors, taking into account the effect of tocotrienol on the P-glycoprotein efflux mechanism.

[0007] Some surfactants have also been reported to have regulatory properties on the cytochrome P450 enzyme metabolism of drugs. The previous use of surfactants with tocotrienol, as described above, has not demonstrated any potential for simultaneous inhibition of P-glycoprotein and CYP-mediated metabolism, which could complement and enhance the performance of self-emulsifying formulations for the oral bioavailability of tocotrienol. In particular, alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a nonionic surfactant that can improve lipophilic drug solubility and enhance drug permeation due to its P-glycoprotein inhibitory effect. Furthermore, TPGS has been demonstrated to improve drug stability by inhibiting CYP3A4 and CYP2C9 metabolism. However, the previous use of TPGS has not demonstrated that TPGS can enhance the oral bioavailability of other vitamin E isomers, such as tocotrienol, which compete with tocopherol for α-TTP through a triple mechanism of action: spontaneous micellization, inhibition of P-gp, and CYP-mediated metabolism. The present invention facilitates the utilization of TPGS in self-emulsifying drug delivery formulations to induce the above synergistic effect that may enhance the oral bioavailability of lipophilic tocotrienols. Summary of the Invention [Means for solving the problem]

[0008] One aspect of the present invention is to provide self-emulsifying drug delivery formulations that exhibit improved oral bioavailability of lipophilic compounds upon oral ingestion. Advantageously, the self-emulsifying drug delivery formulations of the present invention exhibit a 2- to 3-fold improved oral bioavailability compared to conventional self-emulsifying drug delivery formulations.

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

[0010] At least one of the foregoing objects is achieved in whole or in part, and embodiments of the present invention describe a self-emulsifying formulation having 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, it is disclosed that the lipophilic compound is selected from the group consisting of tocotrienol, coenzyme Q10, fat-soluble vitamins, carotenoids, or a combination of two or more thereof.

[0012] Preferably, the tocotrienol further comprises alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol or delta-tocotrienol.

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

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

[0015] Preferably, the carotenoids further include alpha-carotene, beta-carotene, beta-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 ranging from 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 the group consisting of fatty acid esters of glycerol, fatty acid esters of propylene glycol, vegetable oils, or a combination of two or more thereof.

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

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

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

[0021] A further embodiment of the present invention discloses that the phospholipid is a lecithin comprising phosphatidylcholine, phosphatidylethanolamine and phosphatidylinosinol.

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

[0023] The drug delivery formulation is preferably 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 manufacture of a dietary supplement having improved oral bioavailability of a lipophilic compound, the formulation comprising: a lipophilic compound selected from the group consisting of tocotrienol, coenzyme Q10, a fat-soluble vitamin, a carotenoid, or a combination of two or more thereof, present in an amount ranging from 5% to 80% by weight of the drug delivery formulation; vitamin E polyethylene glycol 1000 succinate (TPGS) present in an amount ranging from 0.1% to 30% by weight of the drug delivery formulation; an oil carrier; and a phospholipid.

[0025] Those 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 invention.

[0026] For purposes of facilitating an understanding of the present invention, there are illustrated in the accompanying drawings preferred embodiments from which the invention, its construction and operation, and many of its advantages, can be readily understood and appreciated when considered in conjunction with the following detailed description. [Brief explanation of the drawings]

[0027] [Figure 1] 1 shows the oral bioavailability of a single dose of delta-tocotrienol with and without ketoconazole as depicted in blood concentration-time curves. [Figure 2] 1 shows the oral bioavailability of a single dose of gamma-tocotrienol with and without ketoconazole as depicted in blood concentration-time curves. [Figure 3] 1 shows the oral bioavailability of a single dose of alpha-tocotrienol with and without ketoconazole as depicted in blood concentration-time curves. [Figure 4] 1 shows the oral bioavailability of delta-tocotrienol administered via control, product X and formulation S as represented by blood concentration-time curves. [Figure 5] 1 shows the oral bioavailability of gamma-tocotrienol administered via control, product X and formulation S as represented by blood concentration-time curves. [Figure 6] 1 shows the oral bioavailability of alpha-tocotrienol administered via control, Product X and Formulation S as represented by blood concentration-time curves. DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention will now be described in accordance with the preferred embodiments of the present invention by referring to the accompanying detailed description and drawings. However, it should be understood that the limitation of the detailed description to the preferred embodiments of the present invention is merely to facilitate the discussion of the present invention, and it is envisioned that those skilled in the art may devise various modifications without departing from the scope of the appended claims.

[0029] The present invention provides a formulation for a self-emulsifying drug delivery system (SEDDS) for lipophilic compounds, which has improved oral bioavailability and consistently high absorption of lipophilic compounds. SEDDS are essentially mixtures of oil and surfactants and are widely used in lipophilic compound-based formulations. SEDDS form oil-in-water emulsions upon exposure to gastrointestinal fluids with gentle agitation, e.g., peristaltic movement in the stomach and small intestine. Therefore, SEDDS efficiently improve absorption and oral bioavailability. Because the solubility and oral bioavailability efficiency of lipophilic compounds from SEDDS are determined by the selection of the oil carrier and surfactant, selecting a suitable combination of oil carrier and surfactant is an essential requirement for formulating SEDDS to achieve consistently high oral bioavailability of lipophilic compounds.

[0030] In one embodiment of the present invention, the SEDDS formulation comprises a lipophilic compound, a surfactant, an oil carrier, and a phospholipid. By definition, a lipophilic compound is a molecule that has an affinity for and tends to dissolve in other lipids, fats, and oils. Any suitable lipophilic compound can be selected by one of skill in the art. Lipophilic compounds suitable for use in the SEDDS formulations of the present invention are selected from the group consisting of tocotrienols, coenzyme Q10, fat-soluble vitamins, carotenoids, or combinations of two or more thereof. The lipophilic compounds used in the SEDDS formulations of the present invention may provide additional desired nutritional or pharmaceutical benefits in combination with the benefits provided by the surfactant, oil carrier, and phospholipids in the formulation and can be selected as desired. Preferably, the lipophilic compound is present in an amount ranging from 5% to 80% by weight of the SEDDS formulation.

[0031] According to a preferred embodiment of the present invention, the tocotrienol used in the SEDDS formulation further comprises alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, or delta-tocotrienol. The tocotrienol used in the SEDDS formulation of the present invention can be of natural or synthetic origin. For example, tocotrienol can be extracted from plants, including, but not limited to, palm oil, rice bran oil, linseed oil, germ, barley, and certain nuts and grains.

[0032] In another embodiment of the present invention, the lipophilic compound used in the SEDDS formulation is coenzyme Q10. As used herein, coenzyme Q10 is a fat-soluble quinone with a structure similar to that of vitamin K and has antioxidant properties. Suitable coenzyme Q10 forms for use in the SEDDS formulations of the present invention include ubiquinone and ubiquinol.

[0033] 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, are absorbed by fat globules that travel through the small intestine, and are distributed throughout the body in the bloodstream. In an embodiment of the present invention, fat-soluble vitamins used in the SEDDS formulation include, but are not limited to, vitamin A, vitamin D, vitamin E, and vitamin K.

[0034] In another embodiment of the present invention, the lipophilic compound used in the SEDDS formulation is a carotenoid. Generally, carotenoids are plant pigments responsible for the bright red, yellow, and orange hues of fruits and vegetables. Carotenoids are a class of phytonutrients found in a wide variety of plant, algae, and bacterial cells. Carotenoids also act as antioxidants in the human body. Suitable carotenoids 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.

[0035] The SEDDS formulations of the present invention contain the lipophilic compound in combination with a surfactant and an oil carrier as additives useful for providing self-emulsification. The solubility of the lipophilic compound in a lipid system can be greatly increased by mixing the lipophilic compound with an acceptable oil carrier, and the mixture can be easily emulsified with a surfactant. Conventionally, surfactants commonly used in SEDDS formulations include nonionic surfactants, which have a hydrophobic component (oil-soluble) and a hydrophilic component (water-soluble) and are characterized by their hydrophilic-lipophilic balance (HLB). Nonionic surfactants serve to reduce the interfacial tension between oil and water by adsorption at the interface between the oil and water. A variety of pharmaceutically acceptable surfactants are suitable for use in producing SEDDS formulations.

[0036] Conventional SEDDS formulations have been reported to improve oral bioavailability by 2-5 times compared to non-SEDDS formulations. The inventors have found that potential limitation of the intestinal first-pass effect through inhibition of both the P-glycoprotein efflux transporter protein and the CYP3A4 enzyme metabolizing enzyme further improves oral bioavailability of lipophilic compounds by 2-3 times compared to that achieved with 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, i.e., vitamin E polyethylene glycol 1000 succinate (TPGS). TPGS can improve the solubility of lipophilic compounds in the SEDDS formulations of the present invention and enhance their permeation due to its P-glycoprotein inhibitory effect. Furthermore, TPGS has been demonstrated to improve compound stability by inhibiting CYP3A4 metabolism. TPGS is an excellent emulsifier for lipophilic compounds and also an enhancer of oral bioavailability in SEDDS formulations by forming stable emulsions with small particle sizes. As used herein, the term "TPGS" is used interchangeably with the term Vitamin E TPGS. According to preferred embodiments of the present invention, Vitamin E TPGS is present in an amount ranging from 0.1% to 30% by weight of the SEDDS formulation, depending on the lipophilic compounds used in the SEDDS formulation.

[0037] As described above, the SEDDS formulation includes an oil carrier in combination with vitamin E TPGS to provide self-emulsifying properties. Upon agitation, the oil carrier breaks into small oil droplets, which then disperse evenly in the presence of vitamin E TPGS and self-assemble into micelles. In a preferred embodiment of the present invention, the oil carrier used in the SEDDS formulation is selected from the group consisting of a fatty acid ester of glycerol, a fatty acid ester of propylene glycol, a vegetable oil, or a combination of two or more thereof. Preferably, the fatty acid ester of glycerol used is a monoglyceride, a diglyceride, or a triglyceride. Suitable vegetable oils for use as carrier oils in the SEDDS formulation of the present invention include, but are not limited to, palm olein, soybean oil, sesame oil, rice bran oil, corn oil, sunflower oil, or castor oil. To provide sufficient self-emulsifying properties of the SEDDS formulation, the oil carrier used is present in an amount ranging from 5% to 80% by weight of the SEDDS formulation. It should be noted that the amount of oil carrier may be adjusted depending on the amount of Vitamin E TPGS used in the SEDDS formulation.

[0038] Another additive used in the SEDDS formulation of the present invention is a phospholipid, more preferably a plant-derived phospholipid. It has been found that the combination of a phospholipid with an oil carrier significantly stabilizes the micellar structure of the SEDDS formulation for delivering lipophilic compounds. Thus, the oral bioavailability of lipophilic compounds can be improved. In a preferred embodiment of the present invention, the phospholipid used is lecithin, which contains phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinosinol. Preferably, the phospholipid used is present in an amount ranging from 1% to 10% by weight of the SEDDS formulation.

[0039] In one embodiment of the present invention, the SEDDS formulation is prepared by adding one or more lipophilic compounds to vitamin E TPGS and heating it to about 45°C to 50°C. A suitable oil carrier and phospholipid are then added to the mixture, and the mixture is continuously mixed for about 30 minutes to obtain a homogeneous mixture. The amounts of lipophilic compounds, vitamin E TPGS, oil carrier, and phospholipid to obtain the SEDDS formulation of the present invention are as described above. The homogeneous 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 capsule or soft gel capsule.

[0040] Accordingly, exemplary embodiments of the present invention disclose the use of SEDDS formulations in the manufacture of dietary supplements having improved oral bioavailability of lipophilic compounds. It should be understood that the SEDDS formulations of the present invention may be combined with and contain flavoring agents, coloring agents, excipients, stabilizers, and other agents known to those skilled in the art of dietary supplement formulation. [Example]

[0041] The following non-limiting examples were carried out to illustrate preferred embodiments of the present invention.

[0042] Example 1: A two-period, two-sequence crossover study was conducted in rats to investigate the effect of coadministration of ketoconazole, a potent inhibitor of P-glycoprotein and CYP3A4 enzymes, on the oral bioavailability of tocotrienol (T3), a substrate of P-glycoprotein and CYP3A4 enzymes. Animals were randomly divided into two groups and administered the preparations according to the sequence shown in Table 1 below.

[0043] [Table 1]

[0044] A non-self-emulsifying tocotrienol oil suspension was prepared by mixing tocotrienol-rich fraction (TRF) and palm olein in a 1:1 ratio. The total tocotrienol administered per rat was equivalent to 10 mg / kg body weight. A single dose of ketoconazole (suspension in water) was administered at a dose of 32 mg / kg body weight.

[0045] The rats were fasted overnight for at least 12 hours before the study. During the first phase, rats in Group 1 were given only tocotrienol oil suspension, while rats in Group 2 were given a single dose of ketoconazole 30 minutes before the administration of tocotrienol. Phase 2 was conducted after a one-week washout period. Blood samples were collected from the tail vein according to the following predetermined sampling intervals. Blood levels of individual tocotrienol isomers at each time point were analyzed using an HPLC assay.

[0046] The effects of CYP3A4 enzyme and P-glycoprotein inhibition on the oral bioavailability of tocotrienol were determined. Co-administration of ketoconazole (a potent inhibitor of P-glycoprotein and CYP3A4 enzyme) increased the oral bioavailability of tocotrienol in rats by approximately 2.4-fold. Table 2 summarizes the improvement in oral bioavailability of individual tocotrienol isomers compared to the control. Figures 1-3 show the oral bioavailability of individual tocotrienol isomers with and without a single dose of ketoconazole, as represented by blood concentration-time curves.

[0047] [Table 2]

[0048] Typically, if a compound achieves significantly improved oral bioavailability with co-administration of a potent inhibitor of P-glycoprotein efflux transport and CYP enzyme metabolism, such as ketoconazole, the compound can be determined to be a substrate of P-glycoprotein and CYP3A4 enzyme. In this experiment, administration of a single dose of ketoconazole before administration of a tocotrienol preparation resulted in an approximately 2.4-fold increase in total tocotrienol detected in the blood. Therefore, it can be concluded that tocotrienol is a substrate of P-glycoprotein and CYP3A4 enzyme.

[0049] Example 2: A three-period, three-order crossover study was conducted using rats to compare the oral bioavailability of tocotrienols in control (non-self-emulsifying oil suspension), Product X (a commercially available self-emulsifying formulation), and Formulation S (a self-emulsifying drug delivery formulation of the present invention). Animals were randomly divided into three groups and administered the formulations according to the sequence shown in Table 3 below.

[0050] [Table 3]

[0051] A control (non-self-emulsifying oil suspension) was prepared by mixing tocotrienol-rich fraction (TRF) and palm olein in a 1:1 ratio.

[0052] Product X (a self-emulsifying commercial product) contains tocotrienols formulated with a patented self-emulsifying system for enhanced oral bioavailability.

[0053] Formulation S comprises tocotrienol: about 5-80% by weight of oil carrier, and about 0.1-30% by weight of TPGS: phospholipid phase. The ratio of tocotrienol to oil carrier may be in the range of 1:1 to 1:10. The ratio of TPGS to phospholipid may be in the range of 1:1 to 1:20.

[0054] The rats were fasted overnight for at least 12 hours prior to testing. During Phase 1, Group 1 rats received T3 oil suspension (non-self-emulsifying control), Group 2 received Formulation S, and Group 3 received commercial product X. The total tocotrienol administered per rat for each formulation was equivalent to 10 mg / kg body weight. Phases 2 and 3 were conducted after a one-week washout period. Blood samples were collected from the tail vein according to the following predetermined sampling intervals. Blood levels of individual tocotrienol isomers at each time point were analyzed using an HPLC assay.

[0055] Compared with the non-self-emulsifying control, commercial Product X increased the oral bioavailability of total tocotrienols approximately 4.6-fold, while Formulation S increased its oral bioavailability by 11.5-fold. Formulation S demonstrated a synergistic effect of the additive combination, resulting in greatly improved oral bioavailability that far exceeded the bioavailability improvement observed with simple inhibition of metabolic enzymes using ketoconazole and even exceeded the bioavailability improvement seen with a simple self-emulsifying formulation, Product X. Table 4 summarizes the oral bioavailability improvements of individual and total tocotrienol isomers compared using the control, Product X, and Formulation S. Figures 4-6 show the oral bioavailability of individual tocotrienol isomers administered via the control, Product X, and Formulation S, as represented by blood concentration-time curves.

[0056] [Table 4]

[0057] Self-emulsifying formulations are a common strategy for improving the oral bioavailability of oil-soluble compounds. Typical improvements with self-emulsifying preparations described in the literature are 2-5 fold compared to non-self-emulsifying preparations. Example 1 above suggested that tocotrienol, a substrate for P-glycoprotein and CYP3A4 enzymes, can achieve improved oral bioavailability with inhibition of P-glycoprotein and CYP enzymes using ketoconazole. The documented improvement in bioavailability is 2-3 fold greater than without ketoconazole.

[0058] In the present invention, Formulation S contains a combination of TPGS:phospholipid with oil-soluble tocotrienol, which promotes spontaneous micellization, limits the intestinal first-pass effect through inhibition of P-glycoprotein and CYP3A enzyme metabolism, and stabilizes the emulsion, resulting in greater intestinal absorption of tocotrienol upon oral administration. The bioavailability improvement of the present invention far exceeds the expected (due to additive effects) function of individual measures, i.e., co-administration of inhibitor / ketoconazole alone or conventional self-emulsifying preparations alone. According to the present invention, the oral bioavailability of tocotrienol is improved by 11.5-fold compared to a non-self-emulsifying oil-based preparation of tocotrienol, which has not been reported previously.

[0059] Example 3: The test apparatus used to evaluate the self-emulsifying efficiency of the present invention consisted of a properly aligned light source, paddle stirrer, 250 ml beaker, current relay, and phototransistor. The light source was from a 40 watt bulb and provided a light intensity of approximately 1000 lux that passed through a glass beaker filled with 250 ml of distilled water. The phototransistor was connected to a current relay and a stopwatch. The paddle stirrer was set to rotate at 100 rpm.

[0060] To evaluate the self-emulsifying properties of the present invention, a 1 ml syringe containing 0.5 ml of liquid formulation was placed 1 cm below the water surface of a beaker before injection. When the sample was introduced into 250 ml of distilled water (37°C), a stopwatch was simultaneously started. A paddle stirrer provided gentle agitation to the contents of the beaker. When an emulsion formed and blocked the transmission of light through the beaker, the phototransistor could not detect any light, and the stopwatch was triggered to stop via a current relay. The recorded times were used to compare the self-emulsifying efficiency between the samples, as shown in Table 5 below.

[0061] [Table 5]

[0062] The physical stability of the emulsion products formed after standing for 20 minutes at room temperature (25°C) was evaluated. A certain amount (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. The physical stability of the emulsion products based on visual observation was classified as no phase separation, slight creaming, creaming, and complete separation and is summarized in Table 6 below. All experiments were performed in triplicate.

[0063] [Table 6]

[0064] Self-emulsification efficiency remained comparable for Formulation A (Product X) and Formulations B, C, and D (Formulation B was the final formulation tested in the animal study in Example 2). Comparable results indicate that when the formulations were dispersed in water, they self-emulsified almost immediately, as determined by the time it took for them to block light transmission in the first part of the experiment.

[0065] However, when the self-emulsifying formulations were allowed to stand undisturbed over time, there were significant differences in the stability of the self-emulsifying state of the formulations. Formulation A (Product X) began to exhibit slight creaming (indicating the onset of separation) at 10 minutes, whereas Formulations B, C, and D remained stable without separation for up to 20 minutes.

[0066] The present disclosure includes that contained in the appended claims and that described in the above detailed description. Although the present invention has been described in some detail and in its preferred embodiments, it will be understood that the present disclosure of the preferred forms is made by way of example only, and that numerous changes in details of construction and in the combination and arrangement of parts may be made without departing from the scope of the invention.

Claims

1. lipophilic compounds; Vitamin E polyethylene glycol 1000 succinate (TPGS); an oil carrier; and phospholipids Including, said lipophilic compounds being selected from tocotrienols; Self-emulsifying drug delivery formulations with improved oral bioavailability of lipophilic compounds.

2. 10. The drug delivery formulation of claim 1, wherein the tocotrienol further comprises alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, or delta-tocotrienol.

3. 10. The drug delivery formulation of claim 1, wherein the lipophilic compound is present in an amount ranging from 5% to 80% by weight of the drug delivery formulation.

4. 10. The drug delivery formulation of claim 1, wherein the TPGS is present in an amount ranging from 0.1% to 30% by weight of the drug delivery formulation.

5. 2. The drug delivery formulation of claim 1, wherein the oil carrier is selected from the group consisting of fatty acid esters of glycerol, fatty acid esters of propylene glycol, vegetable oils, or combinations of two or more thereof.

6. 6. The drug delivery formulation of claim 5, wherein the fatty acid ester of glycerol is a monoglyceride, a diglyceride, or a triglyceride.

7. 6. The drug delivery formulation of claim 5, wherein the vegetable oil is palm olein, soybean oil, sesame oil, rice bran oil, corn oil, sunflower oil, or castor oil.

8. 6. The drug delivery formulation of claim 5, wherein the oil carrier is present in an amount ranging from 5% to 80% by weight of the drug delivery formulation.

9. 10. The drug delivery formulation of claim 1, wherein the phospholipid is a lecithin containing phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinosinol.

10. 10. The drug delivery formulation of claim 9, wherein the phospholipid is present in an amount ranging from 1% to 10% by weight of the drug delivery formulation.

11. The drug delivery formulation of any one of claims 1 to 10, in the form of a capsule or softgel.

12. 1. Use of a self-emulsifying drug delivery formulation in the manufacture of a dietary supplement having improved oral bioavailability of a lipophilic compound, the formulation comprising a lipophilic compound selected from tocotrienol, present in an amount ranging from 5% to 80% by weight of the drug delivery formulation, vitamin E polyethylene glycol 1000 succinate (TPGS), present in an amount ranging from 0.1% to 30% by weight of the drug delivery formulation, an oil carrier, and a phospholipid.

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