High purity geranylgeraniol and tocotrienol, methods of preparations and uses thereof

Abstract

The present disclosure relates to methods of preparations of high purity geranylgeraniol or any of the isomers thereof, and methods of preparations of high purity tocotrienol or any of the isomers thereof. The preparation methods are based on fractional distillation and / or liquid-solid extraction and can achieve the production of ultra-high purity geranylgeraniol, or any of the isomers thereof, or ultra-high purity tocotrienol, or any of the isomers thereof. The disclosure also relates to compositions of high purity geranylgeraniol or any of the isomers thereof, and compositions of high purity tocotrienol or any of the isomers thereof. The disclosure further relates to uses of these high and ultra-high purity geranylgeraniol, tocotrienol, and any of the isomers and compositions comprising high and ultra-high purity geranylgeraniol, tocotrienol, and any of the isomers.

Description

Attorney Docket No: 148232.001602 HIGH PURITY GERANYLGERANIOL AND TOCOTRIENOL, METHODS OF PREPARATIONS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No.63 / 584,537, filed on September 22, 2023, which is incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure relates to methods of preparing high purity geranylgeraniol or any of the isomers thereof, methods of preparing high purity tocotrienol or any of the isomers thereof, compositions of high purity geranylgeraniol or any of the isomers thereof, compositions of high purity tocotrienol or any of the isomers thereof, and methods of using the compositions thereof. The preparation methods are based on fractional distillation and / or liquid-solid extraction. BACKGROUND

[0003] Geranylgeraniol (GG) is a tetra-isoprenoid, i.e., four 5-carbon isoprene (IP) units, that is ubiquitous and endogenous in all mammals. GG is also known as a di-terpenoid, i.e., two 10- carbon terpene units, that is ubiquitous and endogenous in all plants. GG in plants is known to be converted to all colorless, yellow, orange, and red shades of carotenoids, lipid vitamins (e.g., E & K vitamers), and all green shades of photo-synthesizing chlorophylls, and serves as branch- points to many phytonutrient polyphenols. In animals, GG can be broadly classified into three categories of usage, namely, for endogenous synthesis, for endogenous systems, and for endogenous function.

[0004] For use in endogenous synthesis, GG is part of the mevalonate acid (MVA) pathway. Therefore, GG is involved in MVA-downstream substrate synthesis. Trans-GG is used for the synthesis of the ETC ubiquinone-10 (CoQ10) and the vitamin K2 menaquinone-4 (MK4); the “10” and “4” designate 10-IP and 4-IP units, respectively. Cis-GG is used for the synthesis of dolichols (sugar transporter in the brain) and hemoglobin (red blood cell component for respiration).Attorney Docket No: 148232.001602

[0005] For use in endogenous systems, GG is involved in many protein syntheses systemically. For example, GG is used for skeletal muscle protein (SMP) synthesis, as muscle constitutes about 40% of human mass. GG is used for calcium transport and balance. About 95% of calcium is in bones, and about 5% of calcium is in soft tissues; such lopsided balance is dependent on calcium transport by GG. GG is important to survival (e.g. pancreas and liver organ function) and the nutritional welfare of animals, including mammals and humans.

[0006] For use in endogenous function, GG is involved in various body functions. For example, GG regulates body temperature, reduces pain, maintains memory, supports immunity, kills germs, increases steroid hormones (testosterone and progesterone), and regulates sugar. As scientists are discovering GG’s endogenous functions, it should be underscored that there is still much to learn.

[0007] Tocotrienol (T3) is a class of Vitamin E; the other class of Vitamin E is tocopherol (T). There are four T3 (alpha-, beta-, delta-, and gamma-) and four T (alpha-, beta-, delta-, and gamma-) isomers, making a total of eight. Vitamin E is not an endogenous nutrient but is needed in human body to maintain the body functions.

[0008] Vitamin Es act as antioxidants to lipids. Vitamin Es are best-known to protect phospholipids (PL) that neatly align cell-membranes that enwrap all intracellular and intercellular walls, among others. The order of decreasing potency of PL protection is delta-T3, gamma-T3, alpha-T3, followed by delta-T, gamma-T, and alpha-T, where beta-T3 and beta-T are nearly non-existent in natural abundance. The published literature consistently points to superior functions of delta-T3 followed by gamma-T3.

[0009] Although T3 and T share some functions, T3 also has different functions than T. Asaf Qureshi (University of Wisconsin-Madison, circa 1980) first showed differences in T3 and T properties where T3, but not T, lowered cholesterol lipids. Since then, T3 has been discovered to have properties (not shared by T) of mitigating chronic conditions and cardiovascular diseases (CVD) such as dyslipidemia, metabolic syndrome, prediabetes, diabetes, obesity, weight loss, fatty liver disease, hypertension, inflammation, as well as osteopenia / osteoporosis, cancer, and radiation damage.

[0010] Tocotrienol is subject to alpha-tocopherol (alpha-T) interference. Asaf Qureshi (University of Wisconsin-Madison in 1997) first showed alpha-T interfered with T3 to lower AFLICPQCOLI IGMGB TFCOC Y.0& ?IMF?*= 'QL QFC QLQ?I >GQ?JGK 5( TLRIB ALRKQCO?AQ QL = / DRKAQGLKPAttorney Docket No: 148232.001602 and <15% alpha-T may not interfere. Since then, such alpha-T interference has extended to studies of many areas, especially chronic conditions, CVD, and cancer. The composition to reduce alpha-T interference to T3 functions was studied in T3-T mixtures (Tan & Llobrera, U.S. Pat. No.8,586,109; 2013). The desirable nature-designed ratio of T:T3 in plants is 0:100 in annatto, 25:75 in palm, or 50:50 in rice bran.

[0011] Studies have shown the clear efficacy of delta-T3 (e.g., as a chemotherapeutic drug and / or chemotherapeutic potentiation), gamma-T3 (e.g., in radiation oncology to protect normal cells), and alpha-T3 (e.g., in brain trauma and stroke). The two isomers that stand out to mitigate chronic conditions are delta-T3 and gamma-T3, followed by alpha-T3. It is useful to obtain essentially pure delta-T3, gamma-T3, and alpha-T3 in order to treat different indications.

[0012] High purity GG is needed for pharmaceutical applications (e.g., myopathy, Bisphosphonate Related Osteonecrosis of the Jaw (BRONJ), and for synthesis of pharmaceutical-grade GG derivatives (e.g., anti-cancer drugs). High purity T3 (especially delta- T3, gamma-T3, and alpha-T3 isomers) is needed for pharmaceutical applications (e.g., cancer, non-alcoholic fatty liver disease (NAFLD), genetic disorders, epilepsy, neurologic disorders) and for the synthesis of pharmaceutical-grade T3 (using delta-T3, gamma-T3, alpha-T3 isomers) to further make other isomeric derivatives.

[0013] To obtain high purity GG or high purity T3, it is important to gauge the purification methods in the context of the manufacturing processes, as the impurities and impurity amounts depend on the manufacturing methods.

[0014] One common way to manufacture GG is by chemical synthesis (Coates, R.M. et. al., 1978; China Pat. No.1218918C, 2005). The earliest GG synthesis was known in 1939 (Ruzicka & Firmenich). T3 chemical synthesis was demonstrated by Asaf Qureshi and colleagues (Pearce, B.C. et. al., 1993; Wright, J.J. et. al., U.S. Pat. No.5,217,992, 1993).

[0015] Drawbacks to chemical synthesis are the extensive synthesis and purification procedures to attain the final product and to increase the product purity (Coates, 1978). Invariably, purification by chromatography requires solvent recovery in large amounts, the procedure of which is complicated and not suitable for industrial application. Purification by distillation is considered extremely difficult because of the high boiling points of GG and T3 and the possibility of trans-to-cis isomerization of GG at high temperatures. An adduct to GG was made to crystallize preferentially trans-GG (Mori, T. et. al., U.S. Pat. No. 5,663,461, 1997).Attorney Docket No: 148232.001602 However, the Mori method was not advantageous due to its complexity (i.e., requiring various reaction steps, solvent usage, temperature control, distillation, emulsion, and repeated crystallization to improve purity).

[0016] Another method to synthesize GG and T3 is by fermentation biosynthesis. Genetically engineered microbial biosynthesis of GG by fermentation is reported recently (Wang, J. et. al., 2021 & 2023). These methods produced biomass that contained up to 5g / L and 8g / L, or <1% w / w. Fermentation biosynthesis of T3 was also recently reported (Jiao, X. et. al., 2023; China Pat. No.113736677B, 2023; China Pat. No.116411013A, 2023).

[0017] Drawbacks to fermentation biosynthesis are a large amount of unwanted biomass being produced, and the yield is at best low. Invariably, all GG and T3 products contain genetically modified materials rather than nature-derived nutrients. Furthermore, solvent usage and subsequent recovery are required for biomass extraction, which would lead to product loss.

[0018] The manufactured GG or T3 from fermentation biosynthesis has 1% purity (w / w) in the product at best. Sigma deems GG of 85% purity (w / w) as “pure” GG. Also, it is difficult to separate different GG isomers and to obtain a specific GG isomer of high purity. The same difficulty persists for T3 isomers as well. Challenges exist to i) separate trans-GG and cis-GG to obtain high purity trans-GG or cis-GG, ii) separate delta-T3 and gamma-T3 to obtain high purity delta-T3 or gamma-T3, and iii) remove alpha-T or other T isomers in the T3 and T mixture to obtain high purity T3 or any of T3 isomers of high purity.

[0019] Therefore, there are unmet needs to obtain high purity GG, or T3, any of the GG isomer, or any of the T3 isomers due to the complexity of the manufacturing and purification procedures, the large amount of product loss, the inability to separate the desired component or isomers, and the lack of practicality for commercial applications. The present disclosure addresses these needs. SUMMARY

[0020] Provided herein is a method of preparing high purity geranylgeraniol, said method comprising: a) providing a composition comprising low purity geranylgeraniol; b) distilling the composition in a fractional distillation system under subatmospheric pressure; andAttorney Docket No: 148232.001602 c) obtaining a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising the low purity geranylgeraniol in step (a).

[0021] Further provided herein is a method of preparing high purity geranylgeraniol, said method comprising: a) providing a composition comprising low purity geranylgeraniol; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with geranylgeraniol; d) mixing the absorbent bonded with geranylgeraniol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising geranylgeraniol; and f) concentrating the filtrate to obtain a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising low purity geranylgeraniol in step a).

[0022] Also provided herein is a method of preparing a composition comprising high purity geranylgeraniol, said method comprising: a) loading a composition comprising low purity geranylgeraniol and other components onto a column packed with an absorbent; b) separating geranylgeraniol from other components by column chromatography; and c) obtaining a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising low purity geranylgeraniol in step a).

[0023] Further provided herein is a composition comprising high purity geranylgeraniol prepared by any one of the methods as described herein.

[0024] Further provided herein is a composition comprising geranylgeraniol of at least 40% purity.

[0025] Provided herein is a method of preparing high purity tocotrienol, said method comprising: a) providing a composition comprising low purity tocotrienol;Attorney Docket No: 148232.001602 b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity tocotrienol with increased purity of tocotrienol as compared to the composition comprising the low purity tocotrienol in step a).

[0026] Further provided herein is a method of preparing a composition comprising high purity tocotrienol, said method comprising: a) providing a composition comprising low purity tocotrienol; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with tocotrienol; d) contacting the absorbent bonded with tocotrienol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising tocotrienol; and f) concentrating the filtrate to obtain the composition comprising high purity tocotrienol with increased purity as compared to the composition comprising the low purity tocotrienol in step a).

[0027] Also provided herein is a method of preparing a composition comprising high purity tocotrienol, said method comprising: a) loading a composition comprising low purity tocotrienol and other components onto a column packed with an absorbent; b) separating tocotrienol from other components by column chromatography; and c) obtaining a composition comprising high purity tocotrienol with increased purity of tocotrienol as compared to the composition comprising the low purity tocotrienol in step a).

[0028] Further provided herein is a composition comprising high purity tocotrienol prepared by any one of the methods as described herein.

[0029] Further provided herein is a composition comprising tocotrienol of at least about 40% purity.Attorney Docket No: 148232.001602

[0030] Also provided herein is a composition comprising high purity geranylgeraniol prepared by the methods as described herein and high purity tocotrienol prepared by any one of the methods as described herein.

[0031] Also provided herein is a composition comprising geranylgeraniol of at least about 40% purity. In one embodiment, the geranylgeraniol consists essentially of trans-geranylgeraniol.

[0032] Also provided herein is a composition comprising tocotrienol of at least about 40% purity. In one embodiment, the tocotrienol consists essentially of delta-tocotrienol.

[0033] Provided herein is a method, the method comprising: i. causing an antioxidant, anti-inflammatory, hypolipidemic, or neuroprotective effect; ii. reducing atherogenic apolipoprotein B, lipoprotein(a) (Lpa), triglyceride (TG), and / or low-density lipoprotein (LDL) plasma levels; iii. suppressing cholesterol level; iv. inducing apoptosis of breast cancer cells or prostate cancer cells; v. protecting normal cells in radiation oncology; vi. preventing or treating pre-diabetes, Type 2 diabetes, or metabolic syndrome; vii. preventing or treating ovarian cancer, pancreatic cancer, or colon cancer; viii. preventing or treating a Non-Alcoholic Fatty Liver Disease (NAFLD); ix. preventing or treating genetic, epilepsy, or neurologic disorders; x. preventing or treating brain trauma or strokes; or xi. preventing or treating inflammation-associated diseases, cardiovascular disease, or cancer, in a subject in need of, comprising administering to the subject in need of the composition comprising high purity tocotrienol as described herein or a composition comprising high purity tocotrienol prepared according to any one of the methods as described herein.

[0034] Also provided herein is a method, the method comprising: i. promoting the maintenance and growth of skeletal muscle proteins; ii. preventing or treating Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ);Attorney Docket No: 148232.001602 iii. preventing or treating Statin-Associated Muscle Symptoms (SAMS), sarcopenia, preventing loss of muscle, or maintaining muscle mass; iv. promoting or increasing muscle force production and / or energy production; v. promoting or increasing the biosynthesis of CoQ10, MK-4, and / or testosterone; vi. promoting or increasing bone mineralization or density; vii. preventing or treating calcified atherosclerosis, kidney stone, biliary stone, gallstone, osteopenia, or osteoporosis; viii. increasing vitamin K-dependent proteins (VKDP), osteocalcin, Matrix Gla Protein (MGP); ix. reversing depressive symptoms and improving cognitive memory; x. promoting or increasing the conversion of white adipose tissue (WAT) to brown tissue (BAT); xi. maintaining and regulating body temperature and blood sugar; or xii. boosting immunity and reducing pain, in a subject in need of, comprising administering to the subject in need of the composition comprising high purity geranylgeraniol as described herein or a composition comprising high purity geranylgeraniol prepared according to any one of the methods as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 shows the gas chromatogram of the separation of delta-tocotrienol and gamma-tocotrienol. The peak at the retention time of 11.186 min presents internal standard '9<=4( 'PNR?ICKC Y 21&(+

[0036] Figure 2 shows the fractional distillation setup. DETAILED DESCRIPTION

[0037] Unless defined otherwise, all technical and scientific terms have the same meaning as is commonly understood by one of ordinary skill in the art to which the embodiments disclosed belongs.

[0038] As used herein, the terms “a” or “an” means that “at least one” or “one or more” unless the context clearly indicates otherwise.Attorney Docket No: 148232.001602

[0039] As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

[0040] As used herein, the term “at least” is used to indicate a minimum amount, degree, or level. As used herein, the term “up to” is used to indicate a maximum amount, degree, or level.

[0041] As used herein, a ratio of “at least” a:b means any ratio with the numerical value of a / b or higher. The numerical value of a / b is the quotient obtained by dividing a by b. For example, at least 80:20 means the ratio is 80:20 or higher than 80 / 20, covering (not limited to) 80:20, 90:10, 95:5, 98:2, 99:1, 99.9:0.1, 99.99:0.01, 100:0, etc. At least 98:2 means the ratio is 98:2 or higher than 98:2, covering (not limited to) 98:2, 99:1, 99.9:0.1, 99.99:0.01, 100:0, etc. A ratio of “at least” a:b means a ratio ranging from a:b to 100:0.

[0042] As used herein, a ratio of “up to” a:b means any ratio with the numerical value of a / b or lower. For example, at least 5:95 means the ratio is 5:95 or lower than 5:95, covering (not limited to) 0:100, 0.01:99.99, 0.1:99.9, 1:99, 2:98, and 5:95, etc. A ratio of “up to” a:b means a ratio ranging from a:b to 100:0.

[0043] As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0044] As used herein, the term “consist essentially of” means at least 90% (w / w) of the component in the composition.

[0045] As used herein, the term “free of” means a weight percentage of less than 1%.

[0046] As used herein, the term “substantially less” or “substantially more” means the end amount changes by at least about 50% (w%) relative to the start amount.

[0047] As used herein, the term “percent”, “percentage”, or “%” means the weight percentage (“w%”) of the total weight of the composition (i.e., by weight of the total composition), unless specified as percentage by volume.

[0048] “Geranylgeraniol (GG)” is a tetra-isoprenoid, i.e., four 5-carbon isoprene (IP) units, and is also known as a di-terpenoid, i.e., two 10-carbon terpene units. There exist trans and cisAttorney Docket No: 148232.001602 isomers of GG. In some embodiments, the terms “GG”, “isoprenoid”, and “terpenoid” are used interchangeably.

[0049] “Tocotrienols” generally are classified as farsnesylated chromanols (FC) and mixed terpenoids. Tocotrienol (T3) is a class of Vitamin E. There are four T3 (alpha-, beta-, delta-, and gamma-) isomers. “Tocopherols” are another class of Vitamin E. There are four tocopherol (alpha-, beta-, delta-, and gamma-) isomers. In some embodiments, the terms “tocotrienol”, “tocopherol”, and “Vitamin E” are used interchangeably.

[0050] As used herein, "purity" means the percentage of the amount of one component over the overall amount of the composition. In one embodiment, the purity of geranylgeraniol or tocotrienol means the weight percentage of geranylgeraniol or tocotrienol in the overall composition. In one embodiment, the purity of one component (such as geranylgeraniol, tocotrienol, or any of its isomers) is measured by gas chromatography based on the ratio of the peak area of the component over the total area of all peaks for the composition.

[0051] As used herein, "high purity" means a purity of at least 40% by weight in the total weight of the composition.

[0052] As used herein, "ultra-high purity" means a purity of at least 90%, preferably at least 95%, more preferably at least 99%, most preferably 99.9% by weight in the total weight of the composition.

[0053] As used herein, "low purity" means a purity of less than 40% by weight in the total weight of the composition.

[0054] In some embodiments, “low purity” refers to the purity in the start material (the composition before the purification process is applied). The term “high purity” is relative to “low purity”. In some embodiments, “high purity” refers to an end purity that is at least 4% greater than a start purity of the same component in the start material.

[0055] As used herein, the terms “individual,” “subject,” and “patient,” used interchangeably, mean any animal or pet including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.

[0056] As used herein, the term “in need thereof” in reference to a subject has been identified as having a need for the particular composition, compound, method, or treatment. In some embodiments, the subject can be in need thereof.Attorney Docket No: 148232.001602

[0057] As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment wherein the object is to slow down (i.e., lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. Without limitation, beneficial or desired clinical results include alleviation of symptoms; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; delay in onset or slowing of condition, disorder or disease progression; or enhancement or improvement of condition, disorder or disease. Treatment includes prolonging survival as compared to expected survival if not receiving treatment. Treatment also includes eliciting a clinically significant response without excessive levels of side effects.

[0058] As used herein, “yield” or “recovery” means the percentage of the amount of one component in the product over the amount of the component in the starting material. The term “yield” and the term “recovery” are used interchangeably. In one embodiment, the yield is calculated based on the percentage of the amount of one component in the product over the amount of the component in the starting material. In one embodiment, the geranylgeraniol yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in the last step of the purification process over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a). In one embodiment, the tocotrienol yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step of the purification process over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0059] “Distilling” or “distillation” is the process of separating the components within a liquid mixture based on boiling point, by performing boiling and subsequent condensation. In some embodiments, the terms “vaporizing”, “vaporization”, “evaporating”, “evaporation”, “distilling”, “distillation”, “separation”, and “separating” are used interchangeably. In some embodiments, the terms “vaporize”, “evaporate”, “distillate”, and “separate” are used interchangeably.

[0060] “Fractional distillation” is the process of distillation using a fractionating column and may be used to separate components (hence fractionating components) that are closer in boilingAttorney Docket No: 148232.001602 point vs. a simple distillation. In some embodiments, “fractionate” and “distillate” are used interchangeably. In some embodiments, “fractionate” and “separate” are used interchangeably. In some embodiments, “fractionate”, “separate”, and “distillate” are used interchangeably. In some embodiments, “fractionation” and “distillation” are used interchangeably. In some embodiments, “fractionation” and “separation” are used interchangeably. In some embodiments, “fractionation”, “separation”, and “distillation” are used interchangeably.

[0061] “Column chromatography” is a technique to separate compounds based on their polarity through absorption of the compounds to the absorbent in the column. In some embodiments, column chromatography carries out liquid-solid extraction.

[0062] “Liquid-solid extraction” or “LSE” is a form of separation or to separate components between a liquid-solid interphase. The LSE can be performed in a column as in column chromatography or in a container (e.g., a beaker) containing a liquid (i.e., solvent) and a solid (i.e., absorbent). In both cases, components are separated between a liquid-solid interphase. In some embodiments, separation in a container refers to, but is not limited to, LSE. GG and T3 from Natural Sources

[0063] GG and T3 can be obtained from natural sources. Tocols, which includes tocopherols and tocotrienols, can be extracted from natural sources, including several vegetable oils, such as rice bran, soybean, sesame, and palm oils. Tocotrienols have been discovered in the seeds of Bixa orellana Linn, otherwise known as the achiote tree. See, Jondiko, I.S., et al., “Terpenoids and an Apocarotenoid from Seeds of Bixa Orellana,” Phytochemistry, 28(11):3159-3162 (1989). Each source of tocotrienols and tocopherols generally contains more than a single tocol homolog. For example, palm oil and rice bran oil generally include both tocotrienols and tocopherols. 6ROQFCO) Z*QLALMFCOLI F?P @CCK OCMLOQCB QL ?QQCKR?QC ACOQ?GK CDDCAQP LD QLALQOGCKLIP) PRAF ?P QFC AFLICPQCOLI*PRMMOCPPGSC ?AQGSGQV LD [*QLALQOGCKLI+ <CC) DLO CU?JMIC) ;ROCPFG) CQ ?I+) PRMO?+ 9K addition, because of their structural similarity, tocotrienols and tocopherols can be difficult to separate.

[0064] A natural source of material known as a byproduct solution of Bixa orellana seed components, which is obtained as an oily material after the bulk of annatto colorant, is removed from annatto seeds. This byproduct contains a tocotrienol component and a geranylgeraniol component and it is known that this byproduct can be used as a source for the recovery of aAttorney Docket No: 148232.001602 tocotrienol component and a geranylgeraniol component (U.S. Pat. No.6,350,453). The reference of U.S. Pat. No.6,350,453 is incorporated by reference herewith.

[0065] The purification processes in the present disclosure are used to purify compositions comprising GG, T3, or any of the isomers thereof, from chemical synthesis, fermentation biosynthesis, extraction of natural sources, or other production methods. Methods of Preparations of High Purity Geranylgeraniol Compositions Methods of Preparations of High Purity Geranylgeraniol Compositions Using Fractional Distillation

[0066] Provided herein is a method of preparing high purity geranylgeraniol, said method comprising: a) providing a composition comprising low purity geranylgeraniol; b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising the low purity geranylgeraniol in step (a).

[0067] In some embodiments, the composition in step a) comprises both trans-geranylgeraniol and cis-geranylgeraniol.

[0068] In some embodiments, the obtained composition in step c) consists essentially of trans- geranylgeraniol.

[0069] In some embodiments, the obtained composition in step c) consists essentially of cis- geranylgeraniol.

[0070] Provided herein is a method of preparing high purity trans-geranylgeraniol, said method comprising: a) providing a composition comprising low purity trans-geranylgeraniol, optionally wherein the composition comprises both trans-geranylgeraniol and cis-geranylgeraniol; b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity trans-geranylgeraniol with increased purity of trans-geranylgeraniol as compared to the composition comprising theAttorney Docket No: 148232.001602 low purity trans-geranylgeraniol in step (a), optionally wherein the obtained composition consists essentially of trans-geranylgeraniol.

[0071] The steps of a) -c) can be repeated to continuously increase the purity of geranylgeraniol or the purity of trans-geranylgeraniol to above about 99%, and the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol to above 99.9:0.1.

[0072] Provided herein is a method of preparing high purity cis-geranylgeraniol, said method comprising: a) providing a composition comprising low purity cis-geranylgeraniol, optionally wherein the composition comprises both trans-geranylgeraniol and cis- geranylgeraniol; b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity cis-geranylgeraniol with increased purity of cis-geranylgeraniol as compared to the composition comprising the low purity cis-geranylgeraniol in step (a), optionally wherein the obtained composition consists essentially of cis-geranylgeraniol.

[0073] In some embodiments, step c) comprises: obtaining one or more fractions comprising high purity geranylgeraniol; or obtaining the composition comprising high purity geranylgeraniol in the residue after one or more fractions are vaporized.

[0074] In another embodiment, step c) comprises obtaining one or more fractions comprising high purity geranylgeraniol.

[0075] In some embodiments, the fraction is collected at about 80°C to about 220°C.

[0076] In another embodiment, the fraction is collected at about 130°C to about 180°C.

[0077] In another embodiment, the fraction is collected at about 155°C to about 160°C.

[0078] In some embodiments, the fraction is collected at about 25°C, at about 50°C, at about 70°C, at about 80°C, at about 100°C, at about 120°C, at about 130°C, at about 140°C, at about 150°C, at about 155°C, at about 160°C, at about 165°C, at about 170°C, at about 180°C, at about 190°C, at about 200°C, at about 220°C, at about 300°C, at about 450°C, or at about 600°C.

[0079] In some embodiments, the fraction is collected at less than about 25°C, about 25°C to about 50°C, at about 25°C to about 70°C, at about 25°C to about 80°C, at about 25°C to aboutAttorney Docket No: 148232.001602 100°C, at about 25°C to about 120°C, at about 25°C to about 130°C, at about 25°C to about 140°C, at about 25°C to about 150°C, at about 25°C to about 155°C, at about 25°C to about 160°C, at about 25°C to about 165°C, at about 25°C to about 170°C, at about 25°C to about 180°C, at about 25°C to about 190°C, at about 25°C to about 200°C, at about 25°C to about 220°C, at about 25°C to about 300°C, at about 25°C to about 450°C, at about 25°C to about 600°C, at about 50°C to about 70°C, at about 50°C to about 80°C, at about 50°C to about 100°C, at about 50°C to about 120°C, at about 50°C to about 130°C, at about 50°C to about 140°C, at about 50°C to about 150°C, at about 50°C to about 155°C, at about 50°C to about 160°C, at about 50°C to about 165°C, at about 50°C to about 170°C, at about 50°C to about 180°C, at about 50°C to about 190°C, at about 50°C to about 200°C, at about 50°C to about 220°C, at about 50°C to about 300°C, at about 50°C to about 450°C, at about 50°C to about 600°C, at about 70°C to about 80°C, at about 70°C to about 100°C, at about 70°C to about 120°C, at about 70°C to about 130°C, at about 70°C to about 140°C, at about 70°C to about 150°C, at about 70°C to about 155°C, at about 70°C to about 160°C, at about 70°C to about 165°C, at about 70°C to about 170°C, at about 70°C to about 180°C, at about 70°C to about 190°C, at about 70°C to about 200°C, at about 70°C to about 220°C, at about 70°C to about 300°C, at about 70°C to about 450°C, at about 70°C to about 600°C, at about 80°C to about 100°C, at about 80°C to about 120°C, at about 80°C to about 130°C, at about 80°C to about 140°C, at about 80°C to about 150°C, at about 80°C to about 155°C, at about 80°C to about 160°C, at about 80°C to about 165°C, at about 80°C to about 170°C, at about 80°C to about 180°C, at about 80°C to about 190°C, at about 80°C to about 200°C, at about 80°C to about 220°C, at about 80°C to about 300°C, at about 80°C to about 450°C, at about 80°C to about 600°C, at about 100°C to about 120°C, at about 100°C to about 130°C, at about 100°C to about 140°C, at about 100°C to about 150°C, at about 100°C to about 155°C, at about 100°C to about 160°C, at about 100°C to about 165°C, at about 100°C to about 170°C, at about 100°C to about 180°C, at about 100°C to about 190°C, at about 100°C to about 200°C, at about 100°C to about 220°C, at about 100°C to about 300°C, at about 100°C to about 450°C, at about 100°C to about 600°C, at about 120°C to about 130°C, at about 120°C to about 140°C, at about 120°C to about 150°C, at about 120°C to about 155°C, at about 120°C to about 160°C, at about 120°C to about 165°C, at about 120°C to about 170°C, at about 120°C to about 180°C, at about 120°C to about 190°C, at about 120°C to about 200°C, at about 120°C to about 220°C, at about 120°C to about 300°C, at aboutAttorney Docket No: 148232.001602 out 130°C to about 140°C, at aboutout 130°C to about 160°C, at aboutout 130°C to about 180°C, at aboutout 130°C to about 220°C, at aboutout 130°C to about 600°C, at aboutout 140°C to about 160°C, at aboutout 140°C to about 180°C, at aboutout 140°C to about 220°C, at aboutout 140°C to about 600°C, at aboutout 150°C to about 165°C, at aboutout 150°C to about 190°C, at aboutout 150°C to about 300°C, at aboutout 155°C to about 160°C, at aboutout 155°C to about 180°C, at aboutout 155°C to about 220°C, at aboutout 155°C to about 600°C, at aboutout 160°C to about 180°C, at aboutout 160°C to about 220°C, at aboutout 160°C to about 600°C, at aboutout 165°C to about 190°C, at aboutout 165°C to about 300°C, at aboutout 170°C to about 180°C, at aboutout 170°C to about 220°C, at aboutout 170°C to about 600°C, at aboutout 180°C to about 220°C, at aboutout 180°C to about 600°C, at aboutout 190°C to about 300°C, at aboutout 200°C to about 220°C, at aboutout 200°C to about 600°C, at aboutout 220°C to about 600°C, at about about 450°C to about 600°C.Attorney Docket No: 148232.001602

[0080] In some embodiments, the fraction is collected at lower than about 0.9 torr.

[0081] In one embodiment, the fraction is collected at lower than about 0.3 Torr.

[0082] In some embodiments, the fraction is collected at lower than about 0.1 Torr or about 0.1 to about 0.3 Torr.

[0083] In some embodiments, the fraction is collected at lower than about 0.01 Torr, 0.025 Torr, about 0.05 Torr, about 0.075 Torr, about 0.1 Torr, about 0.15 Torr, about 0.2 Torr, about 0.25 Torr, about 0.3 Torr, about 0.35 Torr, about 0.4 Torr, about 0.5 Torr, about 0.6 Torr, about 0.7 Torr, about 0.8 Torr, about 0.9 Torr, or about 1 Torr.

[0084] In some embodiments, the fraction is collected at about 0 to 0.01 Torr, about 0.01 to about 0.02 Torr, about 0.02 Torr to about 0.025 Torr, about 0.025 Torr to about 0.05 Torr, about 0.025 Torr to about 0.075 Torr, about 0.025 Torr to about 0.1 Torr, about 0.025 Torr to about 0.15 Torr, about 0.025 Torr to about 0.2 Torr, about 0.025 Torr to about 0.25 Torr, about 0.025 Torr to about 0.3 Torr, about 0.025 Torr to about 0.35 Torr, about 0.025 Torr to about 0.4 Torr, about 0.025 Torr to about 0.5 Torr, about 0.025 Torr to about 0.6 Torr, about 0.025 Torr to about 0.7 Torr, about 0.025 Torr to about 0.8 Torr, about 0.025 Torr to about 0.9 Torr, about 0.025 Torr to about 1 Torr, about 0.05 Torr to about 0.075 Torr, about 0.05 Torr to about 0.1 Torr, about 0.05 Torr to about 0.15 Torr, about 0.05 Torr to about 0.2 Torr, about 0.05 Torr to about 0.25 Torr, about 0.05 Torr to about 0.3 Torr, about 0.05 Torr to about 0.35 Torr, about 0.05 Torr to about 0.4 Torr, about 0.05 Torr to about 0.5 Torr, about 0.05 Torr to about 0.6 Torr, about 0.05 Torr to about 0.7 Torr, about 0.05 Torr to about 0.8 Torr, about 0.05 Torr to about 0.9 Torr, about 0.05 Torr to about 1 Torr, about 0.075 Torr to about 0.1 Torr, about 0.075 Torr to about 0.15 Torr, about 0.075 Torr to about 0.2 Torr, about 0.075 Torr to about 0.25 Torr, about 0.075 Torr to about 0.3 Torr, about 0.075 Torr to about 0.35 Torr, about 0.075 Torr to about 0.4 Torr, about 0.075 Torr to about 0.5 Torr, about 0.075 Torr to about 0.6 Torr, about 0.075 Torr to about 0.7 Torr, about 0.075 Torr to about 0.8 Torr, about 0.075 Torr to about 0.9 Torr, about 0.075 Torr to about 1 Torr, about 0.1 Torr to about 0.15 Torr, about 0.1 Torr to about 0.2 Torr, about 0.1 Torr to about 0.25 Torr, about 0.1 Torr to about 0.3 Torr, about 0.1 Torr to about 0.35 Torr, about 0.1 Torr to about 0.4 Torr, about 0.1 Torr to about 0.5 Torr, about 0.1 Torr to about 0.6 Torr, about 0.1 Torr to about 0.7 Torr, about 0.1 Torr to about 0.8 Torr, about 0.1 Torr to about 0.9 Torr, about 0.1 Torr to about 1 Torr, about 0.15 Torr to about 0.2 Torr, about 0.15 Torr to about 0.25 Torr, about 0.15 Torr to about 0.3 Torr, about 0.15 Torr to about 0.35 Torr, aboutAttorney Docket No: 148232.001602 0.15 Torr to about 0.4 Torr, about 0.15 Torr to about 0.5 Torr, about 0.15 Torr to about 0.6 Torr, about 0.15 Torr to about 0.7 Torr, about 0.15 Torr to about 0.8 Torr, about 0.15 Torr to about 0.9 Torr, about 0.15 Torr to about 1 Torr, about 0.2 Torr to about 0.25 Torr, about 0.2 Torr to about 0.3 Torr, about 0.2 Torr to about 0.35 Torr, about 0.2 Torr to about 0.4 Torr, about 0.2 Torr to about 0.5 Torr, about 0.2 Torr to about 0.6 Torr, about 0.2 Torr to about 0.7 Torr, about 0.2 Torr to about 0.8 Torr, about 0.2 Torr to about 0.9 Torr, about 0.2 Torr to about 1 Torr, about 0.25 Torr to about 0.3 Torr, about 0.25 Torr to about 0.35 Torr, about 0.25 Torr to about 0.4 Torr, about 0.25 Torr to about 0.5 Torr, about 0.25 Torr to about 0.6 Torr, about 0.25 Torr to about 0.7 Torr, about 0.25 Torr to about 0.8 Torr, about 0.25 Torr to about 0.9 Torr, about 0.25 Torr to about 1 Torr, about 0.3 Torr to about 0.35 Torr, about 0.3 Torr to about 0.4 Torr, about 0.3 Torr to about 0.5 Torr, about 0.3 Torr to about 0.6 Torr, about 0.3 Torr to about 0.7 Torr, about 0.3 Torr to about 0.8 Torr, about 0.3 Torr to about 0.9 Torr, about 0.3 Torr to about 1 Torr, about 0.35 Torr to about 0.4 Torr, about 0.35 Torr to about 0.5 Torr, about 0.35 Torr to about 0.6 Torr, about 0.35 Torr to about 0.7 Torr, about 0.35 Torr to about 0.8 Torr, about 0.35 Torr to about 0.9 Torr, about 0.35 Torr to about 1 Torr, about 0.4 Torr to about 0.5 Torr, about 0.4 Torr to about 0.6 Torr, about 0.4 Torr to about 0.7 Torr, about 0.4 Torr to about 0.8 Torr, about 0.4 Torr to about 0.9 Torr, about 0.5 Torr to about 0.6 Torr, about 0.5 Torr to about 0.7 Torr, about 0.5 Torr to about 0.8 Torr, about 0.5 Torr to about 0.9 Torr, about 0.5 Torr to about 1 Torr, about 0.6 Torr to about 0.7 Torr, about 0.6 Torr to about 0.8 Torr, about 0.6 Torr to about 0.9 Torr, about 0.6 Torr to about 1 Torr, about 0.7 Torr to about 0.8 Torr, about 0.7 Torr to about 0.9 Torr, about 0.7 Torr to about 1 Torr, about 0.8 Torr to about 0.9 Torr, about 0.8 Torr to about 1 Torr, or about 0.9 Torr to about 1 Torr.

[0085] In some embodiments, the fraction is collected at vacuum.

[0086] In another embodiment, the fraction is collected at about 80°C to about 220°C and about 0.1 Torr.

[0087] In another embodiment, the fraction is collected at about 130°C to about 180°C and about 0.1 Torr.

[0088] In another embodiment, the fraction is collected at about 155°C to about 160°C and about 0.1 Torr.

[0089] In another embodiment, the fraction is collected at about 80°C to about 220°C and about 0.15 Torr.Attorney Docket No: 148232.001602

[0090] In another embodiment, the fraction is collected at about 130°C to about 180°C and about 0.15 Torr.

[0091] In another embodiment, the fraction is collected at about 155°C to about 160°C and about 0.15 Torr.

[0092] In another embodiment, the fraction is collected at about 80°C to about 220°C and about 0.2 Torr.

[0093] In another embodiment, the fraction is collected at about 130°C to about 180°C and about 0.2 Torr.

[0094] In another embodiment, the fraction is collected at about 155°C to about 160°C and about 0.2 Torr.

[0095] In another embodiment, the fraction is collected at about 80°C to about 220°C and about 0.25 Torr.

[0096] In another embodiment, the fraction is collected at about 130°C to about 180°C and about 0.25 Torr.

[0097] In another embodiment, the fraction is collected at about 155°C to about 160°C and about 0.25 Torr.

[0098] In another embodiment, the fraction is collected at about 80°C to about 220°C and about 0.3 Torr.

[0099] In another embodiment, the fraction is collected at about 130°C to about 180°C and about 0.3 Torr.

[0100] In another embodiment, the fraction is collected at about 155°C to about 160°C and about 0.3 Torr.

[0101] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 70%.

[0102] In another embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 50%.

[0103] In another embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 40%.

[0104] In one embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 20%.Attorney Docket No: 148232.001602

[0105] In one embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is about 12%, about 27%, about 53%, or about 73%.

[0106] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 85%, less than about 80%, less than about 73%, less than about 70%, less than about 65%, less than about 60%, less than about 53%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 27%, less than about 20%, less than about 12%, less than about 10%, or less than about 5%.

[0107] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 70%, about 65%, about 60%, about 53%, about 50%, about 45%, about 40%, about 35%, about 30%, about 27%, about 20%, about 12%, about 10%, or about 5%.

[0108] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is about 85%, about 80%, about 73%, about 70%, about 65%, about 60%, about 53%, about 50%, about 45%, about 40%, about 35%, about 30%, about 27%, about 20%, about 12%, about 10%, or about 5%.

[0109] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is about 85% to about 80%, about 85% to about 73%, about 85% to about 70%, about 85% to about 65%, about 85% to about 60%, about 85% to about 53%, about 85% to about 50%, about 85% to about 45%, about 85% to about 40%, about 85% to about 35%, about 85% to about 30%, about 85% to about 27%, about 85% to about 20%, about 85% to about 12%, about 85% to about 10%, about 85% to about 5%, about 80% to about 73%, about 80% to about 70%, about 80% to about 65%, about 80% to about 60%, about 80% to about 53%, about 80% to about 50%, about 80% to about 45%, about 80% to about 40%, about 80% to about 35%, about 80% to about 30%, about 80% to about 27%, about 80% to about 20%, about 80% to about 12%, about 80% to about 10%, about 80% to about 5%, about 73% to about 70%, about 73% to about 65%, about 73% to about 60%, about 73% to about 53%, about 73% to about 50%, about 73% to about 45%, about 73% to about 40%, about 73% to about 35%, about 73% to about 30%, about 73% to about 27%, about 73% to about 20%, about 73% to about 12%, about 73% to about 10%, about 73% to about 5%, about 70% to about 65%, about 70% to about 60%, about 70% to about 53%, about 70% to about 50%, about 70% to about 45%, about 70% to about 40%, about 70% toAttorney Docket No: 148232.001602 about 35%, about 70% to about 30%, about 70% to about 27%, about 70% to about 20%, about 70% to about 12%, about 70% to about 10%, about 70% to about 5%, about 65% to about 60%, about 65% to about 53%, about 65% to about 50%, about 65% to about 45%, about 65% to about 40%, about 65% to about 35%, about 65% to about 30%, about 65% to about 27%, about 65% to about 20%, about 65% to about 12%, about 65% to about 10%, about 65% to about 5%, about 60% to about 53%, about 60% to about 50%, about 60% to about 45%, about 60% to about 40%, about 60% to about 35%, about 60% to about 30%, about 60% to about 27%, about 60% to about 20%, about 60% to about 12%, about 60% to about 10%, about 60% to about 5%, about 53% to about 50%, about 53% to about 45%, about 53% to about 40%, about 53% to about 35%, about 53% to about 30%, about 53% to about 27%, about 53% to about 20%, about 53% to about 12%, about 53% to about 10%, about 53% to about 5%, about 50% to about 45%, about 50% to about 40%, about 50% to about 35%, about 50% to about 30%, about 50% to about 27%, about 50% to about 20%, about 50% to about 12%, about 50% to about 10%, about 50% to about 5%, about 45% to about 40%, about 45% to about 35%, about 45% to about 30%, about 45% to about 27%, about 45% to about 20%, about 45% to about 12%, about 45% to about 10%, about 45% to about 5%, about 40% to about 35%, about 40% to about 30%, about 40% to about 27%, about 40% to about 20%, about 40% to about 12%, about 40% to about 10%, about 40% to about 5%, about 35% to about 30%, about 35% to about 27%, about 35% to about 20%, about 35% to about 12%, about 35% to about 10%, about 35% to about 5%, about 30% to about 27%, about 30% to about 20%, about 30% to about 12%, about 30% to about 10%, about 30% to about 5%, about 27% to about 20%, about 27% to about 12%, about 27% to about 10%, about 27% to about 5%, about 20% to about 12%, about 20% to about 10%, about 20% to about 5%, about 12% to about 10%, about 12% to about 5%, or about 10% to about 5%.

[0110] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 4% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0111] In another embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is about 4% to about 20%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).Attorney Docket No: 148232.001602

[0112] In another embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is about 4% to about 80% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0113] In another embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is about 30% to about 70% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0114] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least 4% greater, about 5% greater, about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, or about 95% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0115] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 40%.

[0116] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 70%.

[0117] In an additional embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 80%.

[0118] In an additional embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 90%.

[0119] In an additional embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 95%.

[0120] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99%.

[0121] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 75%, about 30%Attorney Docket No: 148232.001602 to about 80%, about 30% to about 85%, about 30% to about 90%, about 30% to about 92%, about 30% to about 95%, about 30% to about 97%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 40% to about 85%, about 40% to about 90%, about 40% to about 92%, about 40% to about 95%, about 40% to about 97%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 50% to about 92%, about 50% to about 95%, about 50% to about 97%, about 50% to about 99%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 60% to about 85%, about 60% to about 90%, about 60% to about 92%, about 60% to about 95%, about 60% to about 97%, about 60% to about 99%, about 70% to about 75%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 70% to about 92%, about 70% to about 95%, about 70% to about 97%, about 70% to about 99%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 75% to about 92%, about 75% to about 95%, about 75% to about 97%, about 75% to about 99%, about 80% to about 85%, about 80% to about 90%, about 80% to about 92%, about 80% to about 95%, about 80% to about 97%, about 80% to about 99%, about 85% to about 90%, about 85% to about 92%, about 85% to about 95%, about 85% to about 97%, about 85% to about 99%, about 90% to about 92%, about 90% to about 95%, about 90% to about 97%, about 90% to about 99%, about 92% to about 95%, about 92% to about 97%, about 92% to about 99%, about 95% to about 97%, about 95% to about 99%, or about 97% to about 99%.

[0122] In some embodiments, the composition in step (a) comprises both trans-geranylgeraniol and cis-geranylgeraniol.

[0123] In some embodiments, the high purity geranylgeraniol obtained in step c) consists essentially of trans-geranylgeraniol.

[0124] In some embodiments, the high purity geranylgeraniol obtained in step c) consists essentially of cis-geranylgeraniol.

[0125] In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in the last step is at least about 98:2. In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in the last step is at least about 99:1. In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in the last step is at least about 99.9:0.1.Attorney Docket No: 148232.001602

[0126] In some embodiments, wherein the purity of trans-geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%, or at least about 99%.

[0127] In some embodiments, the yield of geranylgeraniol is at least about 30% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0128] In some embodiments, the yield of geranylgeraniol is at least about 10% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0129] In some embodiments, the yield of geranylgeraniol is at least about 20% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0130] In some embodiments, the yield of geranylgeraniol is at least about 25% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0131] In some embodiments, the yield of geranylgeraniol is at least about 35% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0132] In some embodiments, the yield of geranylgeraniol is at least about 40% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0133] In some embodiments, the yield of geranylgeraniol is at least about 50% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).Attorney Docket No: 148232.001602

[0134] In some embodiments, the yield of geranylgeraniol is at least about 60% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0135] In some embodiments, the yield of geranylgeraniol is at least about 70% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0136] In some embodiments, the yield of geranylgeraniol is at least about 80% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0137] In some embodiments, the yield of geranylgeraniol is at least about 90% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

[0138] In some embodiments, the purity of geranylgeraniol is measured by gas chromatography based on the ratio of the peak area of geranylgeraniol over the total area of all peaks. Methods of Preparations of High Purity Geranylgeraniol Compositions Using Liquid-Solid Extraction (in a Container or in Column Chromatography)

[0139] Provided herein is a method of preparing high purity geranylgeraniol, said method comprising: a) providing a composition comprising low purity geranylgeraniol; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with geranylgeraniol; d) mixing the absorbent bonded with geranylgeraniol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising geranylgeraniol; andAttorney Docket No: 148232.001602 f) concentrating the filtrate to obtain a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising low purity geranylgeraniol in step a).

[0140] In some embodiments, the high purity geranylgeraniol obtained in step f) consists essentially of trans-geranylgeraniol.

[0141] In some embodiments, the high purity geranylgeraniol obtained in step f) consists essentially of cis-geranylgeraniol.

[0142] In some embodiments, the composition in step (a) comprises both trans-geranylgeraniol and cis-geranylgeraniol.

[0143] Provided herein is a method of preparing high purity trans-geranylgeraniol, said method comprising: a) providing a composition comprising low purity trans-geranylgeraniol, optionally wherein the composition comprises both trans- and cis-geranylgeraniol; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with trans-geranylgeraniol; d) mixing the absorbent bonded with trans-geranylgeraniol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising trans-geranylgeraniol; and f) concentrating the filtrate to obtain a composition comprising high purity trans- geranylgeraniol with increased purity of trans-geranylgeraniol as compared to the composition comprising low purity trans-geranylgeraniol in step a), optionally wherein the obtained composition consists essentially of trans-geranylgeraniol.

[0144] The steps can be repeated to continuously increase the purity of geranylgeraniol or the purity of trans-geranylgeraniol to above about 99%, and the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol to above 99.9:0.1.

[0145] Provided herein is a method of preparing high purity cis-geranylgeraniol, said method comprising: a) providing a composition comprising low purity cis-geranylgeraniol, optionally wherein the composition comprises both trans- and cis-geranylgeraniol;Attorney Docket No: 148232.001602 b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with cis-geranylgeraniol; d) mixing the absorbent bonded with cis-geranylgeraniol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising cis-geranylgeraniol; and f) concentrating the filtrate to obtain a composition comprising high purity cis- geranylgeraniol with increased purity of cis-geranylgeraniol as compared to the composition comprising low purity cis-geranylgeraniol in step a), optionally wherein the obtained composition consists essentially of cis-geranylgeraniol.

[0146] In some embodiments, step b) further comprises stirring the first mixture for at least about 5 minutes.

[0147] In an additional embodiment, step b) further comprises stirring the first mixture for at least about 1 hour.

[0148] In some embodiments, step b) further comprises stirring the first mixture for at least about 1 minute, at least about 2 minutes, at least about 4 minutes, at least about 5 minutes, at least about 8 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 3 hours.

[0149] In some embodiments, step c) further comprises rinsing the first mixture with the non- polar solvent at filtration.

[0150] In some embodiments, step d) further comprises stirring the second mixture for at least about 5 minutes.

[0151] In an additional embodiment, step d) further comprises stirring the second mixture for at least about 1 hour.

[0152] In some embodiments, step d) further comprises stirring the second mixture for at least about 1 minute, at least about 2 minutes, at least about 4 minutes, at least about 5 minutes, at least about 8 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at leastAttorney Docket No: 148232.001602 about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 3 hours.

[0153] In some embodiments, step e) further comprises rinsing the second mixture with the polar solvent at filtration.

[0154] In some embodiments, step f) further comprises using a rotary evaporator to remove the solvent.

[0155] In some embodiments, the method further comprises repeating steps a)-f) to increase the purity of geranylgeraniol.

[0156] In some embodiments, each of the steps is performed in a container. In some embodiments, one or more of the steps are performed in a container. In some embodiment, none of the steps comprises using a column, a chromatography, or a column chromatography.

[0157] Provided herein is a method of preparing a composition comprising high purity geranylgeraniol, said method comprising: a) loading a composition comprising low purity geranylgeraniol and other components onto a column packed with an absorbent; b) separating geranylgeraniol from other components by column chromatography; and c) obtaining a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising low purity geranylgeraniol in step a).

[0158] In some embodiments, the composition in step a) comprises both trans-geranylgeraniol and cis-geranylgeraniol.

[0159] In some embodiments, the geranylgeraniol in the obtained composition in step c) consists essentially of trans-geranylgeraniol.

[0160] In some embodiments, the geranylgeraniol in the obtained composition in step c) consists essentially of cis-geranylgeraniol.

[0161] The steps can be repeated to continuously increase the purity of geranylgeraniol or the purity of trans-geranylgeraniol to above about 99%, and the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol to above 99.9:0.1.

[0162] In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in the last step is at least about 98:2. In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in theAttorney Docket No: 148232.001602 last step is at least about 99:1. In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in the last step is at least about 99.9:0.1.

[0163] In some embodiments, wherein the purity of trans-geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in the last step c) is at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%, or at least about 99%.

[0164] Provided herein is a method of preparing a composition comprising high purity trans- geranylgeraniol, said method comprising: a) loading a composition comprising low purity trans-geranylgeraniol and other components onto a column packed with an absorbent, optionally wherein the composition comprises both trans-geranylgeraniol and cis-geranylgeraniol; b) separating trans-geranylgeraniol from other components by column chromatography; and c) obtaining a composition comprising high purity trans-geranylgeraniol with increased purity of trans-geranylgeraniol as compared to the composition comprising low purity trans- geranylgeraniol in step a), optionally wherein the geranylgeraniol in the obtained composition consists essentially of trans-geranylgeraniol.

[0165] Provided herein is a method of preparing a composition comprising high purity cis- geranylgeraniol, said method comprising: a) loading a composition comprising low purity cis-geranylgeraniol and other components onto a column packed with an absorbent, optionally wherein the composition comprises both trans-geranylgeraniol and cis-geranylgeraniol; b) separating cis-geranylgeraniol from other components by column chromatography; and c) obtaining a composition comprising high purity cis-geranylgeraniol with increased purity of cis-geranylgeraniol as compared to the composition comprising low purity cis- geranylgeraniol in step a), optionally wherein the geranylgeraniol in the obtained composition consists essentially of cis-geranylgeraniol.

[0166] In some embodiments, step b) further comprises: i. eluting the column with a non-polar solvent and then a polar solvent; ii. eluting the column with a non-polar solvent and then a mixture of non-polar and polar solvents; orAttorney Docket No: 148232.001602 iii. eluting the column with a gradient mobile phase that is a mixture of non-polar and polar solvents with an increased ratio of the polar solvent to the non-polar solvent over time.

[0167] In one embodiment, the column of column chromatography is regenerative.

[0168] In some embodiments, step b) further comprises using a rotary evaporator to remove the solvent.

[0169] In some embodiments, the method further comprises repeating steps a)-c) to increase the purity of geranylgeraniol.

[0170] The fractional distillation and liquid-solid extraction methods can be combined in any of the combinations thereof. In one embodiment, the product from one method is subsequently provided as the start material of a different method. In one embodiment, the product from one method is subsequently provided as the start material of the same method.

[0171] In some embodiments, the non-polar solvent is a C3 to C12 alkane, a C3 to C12 alkene, a C3 to C12 alkyne, a C6 to C12 arene, or any of the combinations thereof.

[0172] In an additional embodiment, the non-polar solvent is a C3 to C12 alkane.

[0173] In one embodiment, the C3 to C12 alkane is pentane, hexane, heptane, or any of the combinations thereof.

[0174] In one embodiment, the C3 to C12 alkane is hexane.

[0175] In an additional embodiment, the non-polar solvent is a C3 to C12 alkene.

[0176] In one embodiment, the C3to C12alkene is limonene.

[0177] In an additional embodiment, the non-polar solvent is a C3to C12arene.

[0178] In one embodiment, the C3to C12arene is benzene, toluene, xylene, or any of the combinations thereof.

[0179] In some embodiments, the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane and ethyl acetate, optionally at a ratio of about 3:1 to about 6:1 in (ii).

[0180] In some embodiments, the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane and ethyl acetate, optionally at a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, or about 15:1 in (ii).

[0181] In some embodiments, the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane and ethyl acetate, optionally at a ratio of about 1:1 to about 2:1, about 1:1 to about 3:1, about 1:1 to about 4:1, about 1:1 to about 5:1, about 1:1 to about 6:1, about 1:1 toAttorney Docket No: 148232.001602 about 7:1, about 1:1 to about 8:1, about 1:1 to about 9:1, about 1:1 to about 10:1, about 1:1 to about 12:1, about 1:1 to about 15:1, about 2:1 to about 3:1, about 2:1 to about 4:1, about 2:1 to about 5:1, about 2:1 to about 6:1, about 2:1 to about 7:1, about 2:1 to about 8:1, about 2:1 to about 9:1, about 2:1 to about 10:1, about 2:1 to about 12:1, about 2:1 to about 15:1, about 3:1 to about 4:1, about 3:1 to about 5:1, about 3:1 to about 6:1, about 3:1 to about 7:1, about 3:1 to about 8:1, about 3:1 to about 9:1, about 3:1 to about 10:1, about 3:1 to about 12:1, about 3:1 to about 15:1, about 4:1 to about 5:1, about 4:1 to about 6:1, about 4:1 to about 7:1, about 4:1 to about 8:1, about 4:1 to about 9:1, about 4:1 to about 10:1, about 4:1 to about 12:1, about 4:1 to about 15:1, about 5:1 to about 6:1, about 5:1 to about 7:1, about 5:1 to about 8:1, about 5:1 to about 9:1, about 5:1 to about 10:1, about 5:1 to about 12:1, about 5:1 to about 15:1, about 6:1 to about 7:1, about 6:1 to about 8:1, about 6:1 to about 9:1, about 6:1 to about 10:1, about 6:1 to about 12:1, about 6:1 to about 15:1, about 7:1 to about 8:1, about 7:1 to about 9:1, about 7:1 to about 10:1, about 7:1 to about 12:1, about 7:1 to about 15:1, about 8:1 to about 9:1, about 8:1 to about 10:1, about 8:1 to about 12:1, about 8:1 to about 15:1, about 8:1 to about 9:1, about 8:1 to about 10:1, about 8:1 to about 12:1, about 8:1 to about 15:1, about 9:1 to about 10:1, about 9:1 to about 12:1, about 9:1 to about 15:1, about 10:1 to about 12:1, about 10:1 to about 15:1, or about 12:1 to about 15:1 in (ii).

[0182] In an additional embodiment, the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane, water, and ethanol.

[0183] In some embodiments, the absorbent comprises alumina, aluminum oxide, silica, silicon dioxide (SiO2), or a combination thereof.

[0184] In one embodiment, the absorbent comprises aluminum oxide.

[0185] In an additional embodiment, the aluminum oxide is acidic, basic, or neutral.

[0186] In one embodiment, the aluminum oxide is basic.

[0187] In one embodiment, the absorbent comprises SiO2.

[0188] In one embodiment, the absorbent is silica gel or silica.

[0189] In some embodiments, the polar solvent comprises a C1to C10alkyl alcohol, water, acetic acid, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, hexamethyl phosphoric triamide (HMPT), or any of the combinations thereof.Attorney Docket No: 148232.001602

[0190] In one embodiment, the C1to C10alkyl alcohol is ethanol. In one embodiment, the C1to C10alkyl alcohol is methanol. In one embodiment, the C1to C10alkyl alcohol is propanol.

[0191] In one embodiment, the polar solvent comprises ethyl acetate.

[0192] In one embodiment, the polar solvent comprises a mixture of C1-C10ethanol and water.

[0193] In one embodiment, the polar solvent comprises a mixture of ethanol and water, and ethanol is at least 35% by volume over the total volume of ethanol and water.

[0194] In an additional embodiment, the polar solvent comprises a mixture of ethanol and water, and ethanol is about 35% to about 95% by volume over the total volume of ethanol and water.

[0195] In some embodiments, the polar solvent comprises a mixture of ethanol and water, and ethanol is at least about 10%, at least about 20%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% by volume over the total volume of ethanol and water.

[0196] In some embodiments, the polar solvent comprises a mixture of ethanol and water, and ethanol is about 10% to about 20%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 55%, about 10% to about 60%, about 10% to about 65%, about 10% to about 70%, about 10% to about 75%, about 10% to about 80%, about 10% to about 85%, about 10% to about 90%, about 10% to about 95%, about 10% to about 99%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 55%, about 20% to about 60%, about 20% to about 65%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 20% to about 85%, about 20% to about 90%, about 20% to about 95%, about 20% to about 99%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about 30% to about 65%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 30% to about 85%, about 30% to about 90%, about 30% to about 95%, about 30% to about 99%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55%, about 35% to about 60%, about 35% to about 65%, about 35% to about 70%, about 35% to about 75%, about 35% to about 80%, about 35% to about 85%, about 35% to aboutAttorney Docket No: 148232.001602 90%, about 35% to about 95%, about 35% to about 99%, about 40% to about 45%, about 40% to about 50%, about 40% to about 55%, about 40% to about 60%, about 40% to about 65%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 40% to about 85%, about 40% to about 90%, about 40% to about 95%, about 40% to about 99%, about 45% to about 50%, about 45% to about 55%, about 45% to about 60%, about 45% to about 65%, about 45% to about 70%, about 45% to about 75%, about 45% to about 80%, about 45% to about 85%, about 45% to about 90%, about 45% to about 95%, about 45% to about 99%, about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 50% to about 95%, about 50% to about 99%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 55% to about 75%, about 55% to about 80%, about 55% to about 85%, about 55% to about 90%, about 55% to about 95%, about 55% to about 99%, about 60% to about 65%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 60% to about 85%, about 60% to about 90%, about 60% to about 95%, about 60% to about 99%, about 65% to about 70%, about 65% to about 75%, about 65% to about 80%, about 65% to about 85%, about 65% to about 90%, about 65% to about 95%, about 65% to about 99%, about 70% to about 75%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 70% to about 95%, about 70% to about 99%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 75% to about 95%, about 75% to about 99%, about 80% to about 85%, about 80% to about 90%, about 80% to about 95%, about 80% to about 99%, about 85% to about 90%, about 85% to about 95%, about 85% to about 99%, about 90% to about 95%, about 90% to about 99%, or about 95% to about 99% by volume over the total volume of ethanol and water.

[0197] In some embodiments, the weight ratio of geranylgeraniol to the absorbent is about 1:1 to about 1:100.

[0198] In another embodiment, the weight ratio of geranylgeraniol to the absorbent is about 1:1 to about 1:10.

[0199] In another embodiment, the weight ratio of geranylgeraniol to the absorbent is about 1:1, 1:3, 1:4, or 1:6.

[0200] In one embodiment, the weight ratio of geranylgeraniol to the absorbent is about 1:6.

[0201] In some embodiments, the weight ratio of geranylgeraniol to the absorbent is about 1:0.5, about 1:0.75, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7,Attorney Docket No: 148232.001602 about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:50, about 1:70, about 1:90, about 1:100, about 1:120, about 1:150, or about 1:200.

[0202] In some embodiments, the weight ratio of geranylgeraniol to the absorbent is about 1:0.5 to about 1:0.75, about 1:0.5 to about 1:1, about 1:0.5 to about 1:2, about 1:0.5 to about 1:3, about 1:0.5 to about 1:4, about 1:0.5 to about 1:5, about 1:0.5 to about 1:6, about 1:0.5 to about 1:7, about 1:0.5 to about 1:8, about 1:0.5 to about 1:9, about 1:0.5 to about 1:10, about 1:0.5 to about 1:15, about 1:0.5 to about 1:20, about 1:0.5 to about 1:30, about 1:0.5 to about 1:50, about 1:0.5 to about 1:70, about 1:0.5 to about 1:90, about 1:0.5 to about 1:100, about 1:0.5 to about 1:120, about 1:0.5 to about 1:150, about 1:0.5 to about 1:200, about 1:0.75 to about 1:1, about 1:0.75 to about 1:2, about 1:0.75 to about 1:3, about 1:0.75 to about 1:4, about 1:0.75 to about 1:5, about 1:0.75 to about 1:6, about 1:0.75 to about 1:7, about 1:0.75 to about 1:8, about 1:0.75 to about 1:9, about 1:0.75 to about 1:10, about 1:0.75 to about 1:15, about 1:0.75 to about 1:20, about 1:0.75 to about 1:30, about 1:0.75 to about 1:50, about 1:0.75 to about 1:70, about 1:0.75 to about 1:90, about 1:0.75 to about 1:100, about 1:0.75 to about 1:120, about 1:0.75 to about 1:150, about 1:0.75 to about 1:200, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1 to about 1:4, about 1:1 to about 1:5, about 1:1 to about 1:6, about 1:1 to about 1:7, about 1:1 to about 1:8, about 1:1 to about 1:9, about 1:1 to about 1:10, about 1:1 to about 1:15, about 1:1 to about 1:20, about 1:1 to about 1:30, about 1:1 to about 1:50, about 1:1 to about 1:70, about 1:1 to about 1:90, about 1:1 to about 1:100, about 1:1 to about 1:120, about 1:1 to about 1:150, about 1:1 to about 1:200, about 1:2 to about 1:3, about 1:2 to about 1:4, about 1:2 to about 1:5, about 1:2 to about 1:6, about 1:2 to about 1:7, about 1:2 to about 1:8, about 1:2 to about 1:9, about 1:2 to about 1:10, about 1:2 to about 1:15, about 1:2 to about 1:20, about 1:2 to about 1:30, about 1:2 to about 1:50, about 1:2 to about 1:70, about 1:2 to about 1:90, about 1:2 to about 1:100, about 1:2 to about 1:120, about 1:2 to about 1:150, about 1:2 to about 1:200, about 1:3 to about 1:4, about 1:3 to about 1:5, about 1:3 to about 1:6, about 1:3 to about 1:7, about 1:3 to about 1:8, about 1:3 to about 1:9, about 1:3 to about 1:10, about 1:3 to about 1:15, about 1:3 to about 1:20, about 1:3 to about 1:30, about 1:3 to about 1:50, about 1:3 to about 1:70, about 1:3 to about 1:90, about 1:3 to about 1:100, about 1:3 to about 1:120, about 1:3 to about 1:150, about 1:3 to about 1:200, about 1:4 to about 1:5, about 1:4 to about 1:6, about 1:4 to about 1:7, about 1:4 to about 1:8, about 1:4 to about 1:9, about 1:4 to about 1:10, about 1:4 to about 1:15, about 1:4 to about 1:20, about 1:4 to about 1:30, about 1:4 to about 1:50, about 1:4 to about 1:70, about 1:4 to aboutAttorney Docket No: 148232.001602 1:90, about 1:4 to about 1:100, about 1:4 to about 1:120, about 1:4 to about 1:150, about 1:4 to about 1:200, about 1:5 to about 1:6, about 1:5 to about 1:7, about 1:5 to about 1:8, about 1:5 to about 1:9, about 1:5 to about 1:10, about 1:5 to about 1:15, about 1:5 to about 1:20, about 1:5 to about 1:30, about 1:5 to about 1:50, about 1:5 to about 1:70, about 1:5 to about 1:90, about 1:5 to about 1:100, about 1:5 to about 1:120, about 1:5 to about 1:150, about 1:5 to about 1:200, about 1:6 to about 1:7, about 1:6 to about 1:8, about 1:6 to about 1:9, about 1:6 to about 1:10, about 1:6 to about 1:15, about 1:6 to about 1:20, about 1:6 to about 1:30, about 1:6 to about 1:50, about 1:6 to about 1:70, about 1:6 to about 1:90, about 1:6 to about 1:100, about 1:6 to about 1:120, about 1:6 to about 1:150, about 1:6 to about 1:200, about 1:7 to about 1:8, about 1:7 to about 1:9, about 1:7 to about 1:10, about 1:7 to about 1:15, about 1:7 to about 1:20, about 1:7 to about 1:30, about 1:7 to about 1:50, about 1:7 to about 1:70, about 1:7 to about 1:90, about 1:7 to about 1:100, about 1:7 to about 1:120, about 1:7 to about 1:150, about 1:7 to about 1:200, about 1:8 to about 1:9, about 1:8 to about 1:10, about 1:8 to about 1:15, about 1:8 to about 1:20, about 1:8 to about 1:30, about 1:8 to about 1:50, about 1:8 to about 1:70, about 1:8 to about 1:90, about 1:8 to about 1:100, about 1:8 to about 1:120, about 1:8 to about 1:150, about 1:8 to about 1:200, about 1:9 to about 1:10, about 1:9 to about 1:15, about 1:9 to about 1:20, about 1:9 to about 1:30, about 1:9 to about 1:50, about 1:9 to about 1:70, about 1:9 to about 1:90, about 1:9 to about 1:100, about 1:9 to about 1:120, about 1:9 to about 1:150, about 1:9 to about 1:200, about 1:10 to about 1:15, about 1:10 to about 1:20, about 1:10 to about 1:30, about 1:10 to about 1:50, about 1:10 to about 1:70, about 1:10 to about 1:90, about 1:10 to about 1:100, about 1:10 to about 1:120, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:15 to about 1:20, about 1:15 to about 1:30, about 1:15 to about 1:50, about 1:15 to about 1:70, about 1:15 to about 1:90, about 1:15 to about 1:100, about 1:15 to about 1:120, about 1:15 to about 1:150, about 1:15 to about 1:200, about 1:20 to about 1:30, about 1:20 to about 1:50, about 1:20 to about 1:70, about 1:20 to about 1:90, about 1:20 to about 1:100, about 1:20 to about 1:120, about 1:20 to about 1:150, about 1:20 to about 1:200, about 1:30 to about 1:50, about 1:30 to about 1:70, about 1:30 to about 1:90, about 1:30 to about 1:100, about 1:30 to about 1:120, about 1:30 to about 1:150, about 1:30 to about 1:200, about 1:50 to about 1:70, about 1:50 to about 1:90, about 1:50 to about 1:100, about 1:50 to about 1:120, about 1:50 to about 1:150, about 1:50 to about 1:200, about 1:70 to about 1:90, about 1:70 to about 1:100, about 1:70 to about 1:120, about 1:70 to about 1:150, about 1:70 to about 1:200, about 1:90 to about 1:100, about 1:90 to about 1:120, about 1:90 to about 1:150,Attorney Docket No: 148232.001602 about 1:90 to about 1:200, about 1:100 to about 1:120, about 1:100 to about 1:150, about 1:100 to about 1:200, about 1:120 to about 1:150, about 1:120 to about 1:200, or about 1:150 to about 1:200.

[0203] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 70%.

[0204] In an additional embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 50%.

[0205] In an additional embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 40%.

[0206] In an additional embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 20%.

[0207] In one embodiment, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is about 38%, about 40%, or about 48%, or about 75%.

[0208] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 15%, is less than about 20%, is less than about 25%, is less than about 30%, is less than about 38%, is less than about 40%, is less than about 48%, is less than about 50%, is less than about 60%, is less than about 70%, is less than about 75%, or is less than about 80%.

[0209] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is about 1% to about 5%, about 5% to about 15%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 38%, about 15% to about 40%, about 15% to about 48%, about 15% to about 50%, about 15% to about 60%, about 15% to about 70%, about 15% to about 75%, about 15% to about 80%, about 20% to about 25%, about 20% to about 30%, about 20% to about 38%, about 20% to about 40%, about 20% to about 48%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 25% to about 30%, about 25% to about 38%, about 25% to about 40%, about 25% to about 48%, about 25% to about 50%, about 25% to about 60%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, about 30% to about 38%, about 30% to about 40%, about 30% to about 48%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 38% to about 40%, about 38% to about 48%, about 38% to about 50%, about 38% to aboutAttorney Docket No: 148232.001602 60%, about 38% to about 70%, about 38% to about 75%, about 38% to about 80%, about 40% to about 48%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 48% to about 50%, about 48% to about 60%, about 48% to about 70%, about 48% to about 75%, about 48% to about 80%, about 50% to about 60%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 70% to about 75%, about 70% to about 80%, or about 75% to about 80%.

[0210] In some embodiments, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is about 15%, about 20%, about 25%, about 30%, about 38%, about 40%, about 48%, about 50%, about 60%, about 70%, about 75%, or about 80%.

[0211] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 4% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0212] In one embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 7% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0213] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is about 4% to about 20%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0214] In an additional embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is about 10% to about 50% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0215] In an additional embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is about 20% to about 40% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0216] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is about 1% greater, about 2% greater, about 3% greater, about 4% greater, about 5% greater, about 7% greater, about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70%Attorney Docket No: 148232.001602 greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, or about 95% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0217] In one embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 40%.

[0218] In one embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 70%.

[0219] In one embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 80%.

[0220] In one embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 90%.

[0221] In one embodiment, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 95%.

[0222] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99%.

[0223] In some embodiments, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 30% to at least about 40%, at least about 30% to at least about 50%, at least about 30% to at least about 60%, at least about 30% to at least about 70%, at least about 30% to at least about 75%, at least about 30% to at least about 80%, at least about 30% to at least about 85%, at least about 30% to at least about 90%, at least about 30% to at least about 92%, at least about 30% to at least about 95%, at least about 30% to at least about 97%, at least about 30% to at least about 99%, at least about 40% to at least about 50%, at least about 40% to at least about 60%, at least about 40% to at least about 70%, at least about 40% to at least about 75%, at least about 40% to at least about 80%, at least about 40% to at least about 85%, at least about 40% to at least about 90%, at least about 40% to at least about 92%, at least about 40% to at least about 95%, at least about 40% to at least about 97%, at least about 40% to at least about 99%, at least about 50% to about 60%, at least about 50% to about 70%, at least about 50% to about 75%, at least about 50% to about 80%, at least about 50% to about 85%, atAttorney Docket No: 148232.001602 least about 50% to about 90%, at least about 50% to about 92%, at least about 50% to about 95%, at least about 50% to about 97%, at least about 50% to about 99%, at least about 60% to about 70%, at least about 60% to about 75%, at least about 60% to about 80%, at least about 60% to about 85%, at least about 60% to about 90%, at least about 60% to about 92%, at least about 60% to about 95%, at least about 60% to about 97%, at least about 60% to about 99%, at least about 70% to about 75%, at least about 70% to about 80%, at least about 70% to about 85%, at least about 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 80%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 80% to about 85%, at least about 80% to about 90%, at least about 80% to about 92%, at least about 80% to about 95%, at least about 80% to about 97%, at least about 80% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% to about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99%.

[0224] In some embodiments, the geranylgeraniol in the composition comprising high purity geranylgeraniol consists essentially of trans-geranylgeraniol.

[0225] In some embodiments, the geranylgeraniol in the composition comprising high purity geranylgeraniol consists essentially of cis-geranylgeraniol.

[0226] In some embodiments, the yield of geranylgeraniol is at least about 30% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0227] In some embodiments, the yield of geranylgeraniol is at least about 10% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.Attorney Docket No: 148232.001602

[0228] In some embodiments, the yield of geranylgeraniol is at least about 20% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0229] In some embodiments, the yield of geranylgeraniol is at least about 25% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0230] In some embodiments, the yield of geranylgeraniol is at least about 35% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0231] In some embodiments, the yield of geranylgeraniol is at least about 40% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0232] In some embodiments, the yield of geranylgeraniol is at least about 50% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0233] In some embodiments, the yield of geranylgeraniol is at least about 60% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0234] In some embodiments, the yield of geranylgeraniol is at least about 70% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0235] In some embodiments, the yield of geranylgeraniol is at least about 80% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in theAttorney Docket No: 148232.001602 composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0236] In some embodiments, the yield of geranylgeraniol is at least about 90% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

[0237] In some embodiments, the purity of geranylgeraniol is measured by gas chromatography based on the ratio of the peak area of geranylgeraniol over the total area of all peaks.

[0238] In some embodiments, the composition comprising low purity geranylgeraniol in step a) is obtained from the byproduct solution of Bixa orellana seed components.

[0239] In an additional embodiment, the byproduct solution of Bixa orellana seed components comprises natural annatto extracts.

[0240] In another embodiment, the composition comprising low purity geranylgeraniol in step a) is obtained from annatto extracts.

[0241] In another embodiment, the composition comprising low purity geranylgeraniol in step a) is obtained from extracts of linseed oil, Cedrela toona wood, or palm oil. Compositions of High Purity Geranylgeraniol

[0242] Provided herein is a composition comprising high purity geranylgeraniol prepared by any one of the methods as described herein.

[0243] In some embodiments, the composition further comprises limonene and / or tocotrienol.

[0244] In some embodiments, the composition is free of ethanol.

[0245] Provided herein is a composition comprising geranylgeraniol of at least 40% purity.

[0246] In some embodiments, the composition comprises geranylgeraniol of at least 70% purity.

[0247] In some embodiments, the composition comprises geranylgeraniol of at least 80% purity.

[0248] In some embodiments, the composition comprises geranylgeraniol of at least 90% purity.

[0249] In some embodiments, the composition comprises geranylgeraniol of at least 95% purity.Attorney Docket No: 148232.001602

[0250] In some embodiments, the composition comprises geranylgeraniol of at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% purity.

[0251] In some embodiments, the composition comprises geranylgeraniol of at least about 30% to at least about 40%, at least about 30% to at least about 50%, at least about 30% to at least about 60%, at least about 30% to at least about 70%, at least about 30% to at least about 75%, at least about 30% to at least about 80%, at least about 30% to at least about 85%, at least about 30% to at least about 90%, at least about 30% to at least about 92%, at least about 30% to at least about 95%, at least about 30% to at least about 97%, at least about 30% to at least about 99%, at least about 40% to at least about 50%, at least about 40% to at least about 60%, at least about 40% to at least about 70%, at least about 40% to at least about 75%, at least about 40% to at least about 80%, at least about 40% to at least about 85%, at least about 40% to at least about 90%, at least about 40% to at least about 92%, at least about 40% to at least about 95%, at least about 40% to at least about 97%, at least about 40% to at least about 99%, at least about 50% to about 60%, at least about 50% to about 70%, at least about 50% to about 75%, at least about 50% to about 80%, at least about 50% to about 85%, at least about 50% to about 90%, at least about 50% to about 92%, at least about 50% to about 95%, at least about 50% to about 97%, at least about 50% to about 99%, at least about 60% to about 70%, at least about 60% to about 75%, at least about 60% to about 80%, at least about 60% to about 85%, at least about 60% to about 90%, at least about 60% to about 92%, at least about 60% to about 95%, at least about 60% to about 97%, at least about 60% to about 99%, at least about 70% to about 75%, at least about 70% to about 80%, at least about 70% to about 85%, at least about 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 80%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 80% to about 85%, at least about 80% to about 90%, at least about 80% to about 92%, at least about 80% to about 95%, at least about 80% to about 97%, at least about 80% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% toAttorney Docket No: 148232.001602 about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99% purity. In some embodiments, the geranylgeraniol is trans- geranylgeraniol. In some embodiments, the geranylgeraniol is cis-geranylgeraniol. In some embodiments, the geranylgeraniol comprises both trans-geranylgeraniol and cis-geranylgeraniol.

[0252] In some embodiments, the geranylgeraniol consists essentially of trans-geranylgeraniol.

[0253] In some embodiments, the geranylgeraniol consists essentially of cis-geranylgeraniol.

[0254] In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the composition is at least about 98:2. In some embodiments, the weight ratio of trans- geranylgeraniol to cis-geranylgeraniol in the composition is at least about 99:1. In some embodiments, the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the composition is at least about 99.9:0.1.

[0255] In some embodiments, wherein the purity of trans-geranylgeraniol in the composition is at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%, or at least about 99%.

[0256] In some embodiments, the composition comprises geranylgeraniol of at least 70% purity, wherein the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the composition is at least about 98:2.

[0257] In some embodiments, the composition comprises geranylgeraniol of at least 90% purity, wherein the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the composition is at least about 98:2.

[0258] In some embodiments, the composition comprises geranylgeraniol of at least about 40% purity, at least about 70% purity, at least about 80% purity, at least about 90% purity, at least about 95% purity, at least about 98% purity, or at least about 99% purity, wherein the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the composition is at least about 98:2.

[0259] In some embodiments, the composition comprises geranylgeraniol of at least about 40% purity, at least about 70% purity, at least about 80% purity, at least about 90% purity, at least about 95% purity, at least about 98% purity, or at least about 99% purity, wherein theAttorney Docket No: 148232.001602 weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the composition is at least about 98:2, wherein the composition is free of ethanol.

[0260] In some embodiments, the composition comprises geranylgeraniol of at least about 40% purity, at least about 70% purity, at least about 80% purity, at least about 90% purity, at least about 95% purity, at least about 98% purity, or at least about 99% purity, wherein the geranylgeraniol consists essentially of trans-geranylgeraniol.

[0261] In some embodiments, the purity of geranylgeraniol is measured by gas chromatography based on the ratio of the peak area of geranylgeraniol over the total area of all peaks.

[0262] In some embodiments, the composition comprising low purity geranylgeraniol is obtained from chemical synthesis, fermentation biosynthesis, or extraction of natural sources.

[0263] In some embodiments, the composition comprising low purity geranylgeraniol is obtained from the byproduct solution of Bixa orellana seed components.

[0264] In some embodiments, the byproduct solution of Bixa orellana seed components comprises natural annatto extracts.

[0265] In some embodiments, the composition is obtained from annatto extracts.

[0266] In some embodiments, the composition further comprises less than about 1% of tocotrienols in the total weight of the composition.

[0267] In some embodiments, the composition further comprises less than about 5% of tocotrienols in the total weight of the composition.

[0268] In some embodiments, the composition is obtained from extracts of linseed oil, Cedrela toona wood, or palm oil.

[0269] In some embodiments, the start material is the composition comprising low purity geranylgeraniol obtained from annatto extracts, extracts of linseed oil, Cedrela toona wood, or palm oil, or the further purified composition based on the purification method known in the art or in the present disclosure. In some embodiments, the start material is 0.01-1kg. In some embodiments, the start material is 1-100 kg. In some embodiments, the start material is 100-1000 kg. In some embodiments, the start material is 1000-10000 kg.

[0270] In some embodiments, any of the above described compositions of geranylgeraniol further comprises less than about 1% of tocotrienol. The tocotrienol functions as an antioxidant to stabilize the composition.Attorney Docket No: 148232.001602 Methods of Preparations of High Purity Tocotrienol Compositions Methods of Preparations of High Purity Tocotrienol Compositions Using Fractional Distillation

[0271] Provided herein is a method of preparing high purity tocotrienol, said method comprising: a) providing a composition comprising low purity tocotrienol; b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity tocotrienol with increased purity of tocotrienol as compared to the composition comprising the low purity tocotrienol in step a).

[0272] The steps can be repeated to continuously increase the purity of tocotrienol or the purity of delta-tocotrienol to above about 99%, and the weight ratio of delta-tocotrienol to gamma- tocotrienol to above about 99:1 or even above about 99.9:0.1.

[0273] In some embodiments, the composition in step a) comprises alpha-tocotrienol, beta- tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol, beta-tocopherol, delta- tocopherol, gamma-tocopherol, or any of the combinations thereof.

[0274] In some embodiments, the obtained high purity tocotrienol consists essentially of delta- tocotrienol.

[0275] In some embodiments, the obtained high purity tocotrienol consists essentially of gamma-tocotrienol.

[0276] In some embodiments, the obtained composition in step c) as described above is free of alpha-tocopherol, or the obtained composition in step c) has substantially less alpha-tocopherol as compared to the amount of alpha-tocopherol in the composition in step a).

[0277] Provided herein is a method of preparing high purity delta-tocotrienol, said method comprising: a) providing a composition comprising low purity delta-tocotrienol, optionally wherein the composition comprises alpha-tocotrienol, beta-tocotrienol, delta- tocotrienol, gamma-tocotrienol, alpha-tocopherol, beta-tocopherol, delta- tocopherol, gamma-tocopherol, or any of the combinations thereof; b) distilling the composition in a fractional distillation system under subatmospheric pressure; andAttorney Docket No: 148232.001602 c) obtaining a composition comprising high purity delta-tocotrienol with increased purity of delta-tocotrienol as compared to the composition comprising the low purity delta-tocotrienol in step a), optionally wherein the obtained composition consists essentially of delta-tocotrienol.

[0278] Provided herein is a method of preparing high purity gamma-tocotrienol, said method comprising: a) providing a composition comprising low purity gamma-tocotrienol, optionally wherein the composition comprises alpha-tocotrienol, beta-tocotrienol, delta- tocotrienol, gamma-tocotrienol, alpha-tocopherol, beta-tocopherol, delta- tocopherol, gamma-tocopherol, or any of the combinations thereof; b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity gamma-tocotrienol with increased purity of gamma-tocotrienol as compared to the composition comprising the low purity gamma-tocotrienol in step a), optionally wherein the obtained composition consists essentially of gamma-tocotrienol.

[0279] In some embodiments, the composition comprising low purity tocotrienol in step a) comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha- tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof.

[0280] In an additional embodiment, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol, gamma-tocotrienol, or a combination thereof.

[0281] In another embodiment, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol and gamma-tocotrienol.

[0282] In one embodiment, the method prepares high purity delta-tocotrienol, high purity gamma-tocotrienol, or a combination thereof.

[0283] In some embodiments, the method as described herein, wherein: the method prepares high purity delta-tocotrienol; the composition comprising low purity tocotrienol in step a) is a composition comprising low purity delta-tocotrienol; andAttorney Docket No: 148232.001602 the composition comprising high purity tocotrienol in step c) is a composition comprising high purity delta-tocotrienol with increased purity of delta-tocotrienol as compared to the composition comprising the low purity delta-tocotrienol in step a).

[0284] In some embodiments, the high purity tocotrienol consists essentially of delta- tocotrienol.

[0285] In some embodiments, step c) comprises obtaining one or more fractions comprising high purity tocotrienol, or obtaining the composition comprising high purity tocotrienol in the residue after one or more fractions are vaporized.

[0286] In an additional embodiment, step c) comprises obtaining one or more fractions comprising high purity tocotrienol.

[0287] In some embodiments, the fraction is collected at about 200°C to about 280°C.

[0288] In an additional embodiment, the fraction is collected at about 200°C to about 250°C.

[0289] In one embodiment, the fraction is collected at about 250°C.

[0290] In some embodiments, the fraction is collected at about 100°C, at about 150°C, at about 175°C, at about 200°C, at about 225°C, at about 250°C, at about 260°C, at about 280°C, at about 350°C, at about 450°C, or at about 600°C.

[0291] In some embodiments, the fraction is collected at about 100°C to about 150°C, at about 100°C to about 175°C, at about 100°C to about 200°C, at about 100°C to about 225°C, at about 100°C to about 250°C, at about 100°C to about 260°C, at about 100°C to about 280°C, at about 100°C to about 350°C, at about 100°C to about 450°C, at about 100°C to about 600°C, at about 150°C to about 175°C, at about 150°C to about 200°C, at about 150°C to about 225°C, at about 150°C to about 250°C, at about 150°C to about 260°C, at about 150°C to about 280°C, at about 150°C to about 350°C, at about 150°C to about 450°C, at about 150°C to about 600°C, at about 175°C to about 200°C, at about 175°C to about 225°C, at about 175°C to about 250°C, at about 175°C to about 260°C, at about 175°C to about 280°C, at about 175°C to about 350°C, at about 175°C to about 450°C, at about 175°C to about 600°C, at about 200°C to about 225°C, at about 200°C to about 250°C, at about 200°C to about 260°C, at about 200°C to about 280°C, at about 200°C to about 350°C, at about 200°C to about 450°C, at about 200°C to about 600°C, at about 225°C to about 250°C, at about 225°C to about 260°C, at about 225°C to about 280°C, at about 225°C to about 350°C, at about 225°C to about 450°C, at about 225°C to about 600°C, at about 250°C to about 260°C, at about 250°C to about 280°C, at about 250°C to about 350°C, at aboutAttorney Docket No: 148232.001602 250°C to about 450°C, at about 250°C to about 600°C, at about 260°C to about 280°C, at about 260°C to about 350°C, at about 260°C to about 450°C, at about 260°C to about 600°C, at about 280°C to about 350°C, at about 280°C to about 450°C, at about 280°C to about 600°C, at about 350°C to about 450°C, at about 350°C to about 600°C, or at about 450°C to about 600°C.

[0292] In some embodiments, the fraction is collected at lower than about 0.9 torr.

[0293] In an additional embodiment, the fraction is collected at lower than about 0.3 Torr.

[0294] In one embodiment, the fraction is collected at lower than 0.1 Torr or about 0.1 to about 0.3 Torr.

[0295] In some embodiments, the fraction is collected at lower than about 0.01 Torr, about 0.025 Torr, about 0.05 Torr, about 0.075 Torr, about 0.1 Torr, about 0.15 Torr, about 0.2 Torr, about 0.25 Torr, about 0.3 Torr, about 0.35 Torr, about 0.4 Torr, about 0.5 Torr, about 0.6 Torr, about 0.7 Torr, about 0.8 Torr, or about 0.9 Torr.

[0296] In some embodiments, the fraction is collected at about 0 to about 0.01 Torr, about 0.01 to about 0.02 Torr, about 0.02 Torr to about 0.025 Torr, about 0.025 Torr to about 0.05 Torr, about 0.025 Torr to about 0.075 Torr, about 0.025 Torr to about 0.1 Torr, about 0.025 Torr to about 0.15 Torr, about 0.025 Torr to about 0.2 Torr, about 0.025 Torr to about 0.25 Torr, about 0.025 Torr to about 0.3 Torr, about 0.025 Torr to about 0.35 Torr, about 0.025 Torr to about 0.4 Torr, about 0.025 Torr to about 0.5 Torr, about 0.025 Torr to about 0.6 Torr, about 0.025 Torr to about 0.7 Torr, about 0.025 Torr to about 0.8 Torr, about 0.025 Torr to about 0.9 Torr, about 0.025 Torr to about 1 Torr, about 0.05 Torr to about 0.075 Torr, about 0.05 Torr to about 0.1 Torr, about 0.05 Torr to about 0.15 Torr, about 0.05 Torr to about 0.2 Torr, about 0.05 Torr to about 0.25 Torr, about 0.05 Torr to about 0.3 Torr, about 0.05 Torr to about 0.35 Torr, about 0.05 Torr to about 0.4 Torr, about 0.05 Torr to about 0.5 Torr, about 0.05 Torr to about 0.6 Torr, about 0.05 Torr to about 0.7 Torr, about 0.05 Torr to about 0.8 Torr, about 0.05 Torr to about 0.9 Torr, about 0.05 Torr to about 1 Torr, about 0.075 Torr to about 0.1 Torr, about 0.075 Torr to about 0.15 Torr, about 0.075 Torr to about 0.2 Torr, about 0.075 Torr to about 0.25 Torr, about 0.075 Torr to about 0.3 Torr, about 0.075 Torr to about 0.35 Torr, about 0.075 Torr to about 0.4 Torr, about 0.075 Torr to about 0.5 Torr, about 0.075 Torr to about 0.6 Torr, about 0.075 Torr to about 0.7 Torr, about 0.075 Torr to about 0.8 Torr, about 0.075 Torr to about 0.9 Torr, about 0.075 Torr to about 1 Torr, about 0.1 Torr to about 0.15 Torr, about 0.1 Torr to about 0.2 Torr, about 0.1 Torr to about 0.25 Torr, about 0.1 Torr to about 0.3 Torr, about 0.1 Torr to about 0.35Attorney Docket No: 148232.001602 Torr, about 0.1 Torr to about 0.4 Torr, about 0.1 Torr to about 0.5 Torr, about 0.1 Torr to about 0.6 Torr, about 0.1 Torr to about 0.7 Torr, about 0.1 Torr to about 0.8 Torr, about 0.1 Torr to about 0.9 Torr, about 0.1 Torr to about 1 Torr, about 0.15 Torr to about 0.2 Torr, about 0.15 Torr to about 0.25 Torr, about 0.15 Torr to about 0.3 Torr, about 0.15 Torr to about 0.35 Torr, about 0.15 Torr to about 0.4 Torr, about 0.15 Torr to about 0.5 Torr, about 0.15 Torr to about 0.6 Torr, about 0.15 Torr to about 0.7 Torr, about 0.15 Torr to about 0.8 Torr, about 0.15 Torr to about 0.9 Torr, about 0.15 Torr to about 1 Torr, about 0.2 Torr to about 0.25 Torr, about 0.2 Torr to about 0.3 Torr, about 0.2 Torr to about 0.35 Torr, about 0.2 Torr to about 0.4 Torr, about 0.2 Torr to about 0.5 Torr, about 0.2 Torr to about 0.6 Torr, about 0.2 Torr to about 0.7 Torr, about 0.2 Torr to about 0.8 Torr, about 0.2 Torr to about 0.9 Torr, about 0.2 Torr to about 1 Torr, about 0.25 Torr to about 0.3 Torr, about 0.25 Torr to about 0.35 Torr, about 0.25 Torr to about 0.4 Torr, about 0.25 Torr to about 0.5 Torr, about 0.25 Torr to about 0.6 Torr, about 0.25 Torr to about 0.7 Torr, about 0.25 Torr to about 0.8 Torr, about 0.25 Torr to about 0.9 Torr, about 0.25 Torr to about 1 Torr, about 0.3 Torr to about 0.35 Torr, about 0.3 Torr to about 0.4 Torr, about 0.3 Torr to about 0.5 Torr, about 0.3 Torr to about 0.6 Torr, about 0.3 Torr to about 0.7 Torr, about 0.3 Torr to about 0.8 Torr, about 0.3 Torr to about 0.9 Torr, about 0.3 Torr to about 1 Torr, about 0.35 Torr to about 0.4 Torr, about 0.35 Torr to about 0.5 Torr, about 0.35 Torr to about 0.6 Torr, about 0.35 Torr to about 0.7 Torr, about 0.35 Torr to about 0.8 Torr, about 0.35 Torr to about 0.9 Torr, about 0.35 Torr to about 1 Torr, about 0.4 Torr to about 0.5 Torr, about 0.4 Torr to about 0.6 Torr, about 0.4 Torr to about 0.7 Torr, about 0.4 Torr to about 0.8 Torr, about 0.4 Torr to about 0.9 Torr, about 0.5 Torr to about 0.6 Torr, about 0.5 Torr to about 0.7 Torr, about 0.5 Torr to about 0.8 Torr, about 0.5 Torr to about 0.9 Torr, about 0.5 Torr to about 1 Torr, about 0.6 Torr to about 0.7 Torr, about 0.6 Torr to about 0.8 Torr, about 0.6 Torr to about 0.9 Torr, about 0.6 Torr to about 1 Torr, about 0.7 Torr to about 0.8 Torr, about 0.7 Torr to about 0.9 Torr, about 0.7 Torr to about 1 Torr, about 0.8 Torr to about 0.9 Torr, about 0.8 Torr to about 1 Torr, or about 0.9 Torr to about 1 Torr.

[0297] In some embodiments, the fraction is collected at vacuum.

[0298] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 70% purity.

[0299] In another embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 50% purity.Attorney Docket No: 148232.001602

[0300] In another embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 40% purity.

[0301] In another embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 20% purity.

[0302] In one embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 10% to about 20%, about 20 to about 50%, or about 50% to about 70%.

[0303] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 85%, less than about 80%, less than about 73%, less than about 70%, less than about 65%, less than about 60%, less than about 53%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 27%, less than about 20%, less than about 12%, less than about 10%, or less than about 5%.

[0304] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 85% to about 80%, about 85% to about 73%, about 85% to about 70%, about 85% to about 65%, about 85% to about 60%, about 85% to about 53%, about 85% to about 50%, about 85% to about 45%, about 85% to about 40%, about 85% to about 35%, about 85% to about 30%, about 85% to about 27%, about 85% to about 20%, about 85% to about 12%, about 85% to about 10%, about 85% to about 5%, about 80% to about 73%, about 80% to about 70%, about 80% to about 65%, about 80% to about 60%, about 80% to about 53%, about 80% to about 50%, about 80% to about 45%, about 80% to about 40%, about 80% to about 35%, about 80% to about 30%, about 80% to about 27%, about 80% to about 20%, about 80% to about 12%, about 80% to about 10%, about 80% to about 5%, about 73% to about 70%, about 73% to about 65%, about 73% to about 60%, about 73% to about 53%, about 73% to about 50%, about 73% to about 45%, about 73% to about 40%, about 73% to about 35%, about 73% to about 30%, about 73% to about 27%, about 73% to about 20%, about 73% to about 12%, about 73% to about 10%, about 73% to about 5%, about 70% to about 65%, about 70% to about 60%, about 70% to about 53%, about 70% to about 50%, about 70% to about 45%, about 70% to about 40%, about 70% to about 35%, about 70% to about 30%, about 70% to about 27%, about 70% to about 20%, about 70% to about 12%, about 70% to about 10%, about 70% to about 5%, about 65% to about 60%, about 65% to about 53%, about 65% to about 50%, about 65% to about 45%, about 65% toAttorney Docket No: 148232.001602 about 40%, about 65% to about 35%, about 65% to about 30%, about 65% to about 27%, about 65% to about 20%, about 65% to about 12%, about 65% to about 10%, about 65% to about 5%, about 60% to about 53%, about 60% to about 50%, about 60% to about 45%, about 60% to about 40%, about 60% to about 35%, about 60% to about 30%, about 60% to about 27%, about 60% to about 20%, about 60% to about 12%, about 60% to about 10%, about 60% to about 5%, about 53% to about 50%, about 53% to about 45%, about 53% to about 40%, about 53% to about 35%, about 53% to about 30%, about 53% to about 27%, about 53% to about 20%, about 53% to about 12%, about 53% to about 10%, about 53% to about 5%, about 50% to about 45%, about 50% to about 40%, about 50% to about 35%, about 50% to about 30%, about 50% to about 27%, about 50% to about 20%, about 50% to about 12%, about 50% to about 10%, about 50% to about 5%, about 45% to about 40%, about 45% to about 35%, about 45% to about 30%, about 45% to about 27%, about 45% to about 20%, about 45% to about 12%, about 45% to about 10%, about 45% to about 5%, about 40% to about 35%, about 40% to about 30%, about 40% to about 27%, about 40% to about 20%, about 40% to about 12%, about 40% to about 10%, about 40% to about 5%, about 35% to about 30%, about 35% to about 27%, about 35% to about 20%, about 35% to about 12%, about 35% to about 10%, about 35% to about 5%, about 30% to about 27%, about 30% to about 20%, about 30% to about 12%, about 30% to about 10%, about 30% to about 5%, about 27% to about 20%, about 27% to about 12%, about 27% to about 10%, about 27% to about 5%, about 20% to about 12%, about 20% to about 10%, about 20% to about 5%, about 12% to about 10%, about 12% to about 5%, or about 10% to about 5%.

[0305] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 85%, about 80%, about 73%, about 70%, about 65%, about 60%, about 53%, about 50%, about 45%, about 40%, about 35%, about 30%, about 27%, about 20%, about 12%, about 10%, or about 5%.

[0306] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 85% to about 80%, about 85% to about 73%, about 85% to about 70%, about 85% to about 65%, about 85% to about 60%, about 85% to about 53%, about 85% to about 50%, about 85% to about 45%, about 85% to about 40%, about 85% to about 35%, about 85% to about 30%, about 85% to about 27%, about 85% to about 20%, about 85% to about 12%, about 85% to about 10%, about 85% to about 5%, about 80% to about 73%, about 80% to about 70%, about 80% to about 65%, about 80% to about 60%, about 80% to about 53%, aboutAttorney Docket No: 148232.001602 80% to about 50%, about 80% to about 45%, about 80% to about 40%, about 80% to about 35%, about 80% to about 30%, about 80% to about 27%, about 80% to about 20%, about 80% to about 12%, about 80% to about 10%, about 80% to about 5%, about 73% to about 70%, about 73% to about 65%, about 73% to about 60%, about 73% to about 53%, about 73% to about 50%, about 73% to about 45%, about 73% to about 40%, about 73% to about 35%, about 73% to about 30%, about 73% to about 27%, about 73% to about 20%, about 73% to about 12%, about 73% to about 10%, about 73% to about 5%, about 70% to about 65%, about 70% to about 60%, about 70% to about 53%, about 70% to about 50%, about 70% to about 45%, about 70% to about 40%, about 70% to about 35%, about 70% to about 30%, about 70% to about 27%, about 70% to about 20%, about 70% to about 12%, about 70% to about 10%, about 70% to about 5%, about 65% to about 60%, about 65% to about 53%, about 65% to about 50%, about 65% to about 45%, about 65% to about 40%, about 65% to about 35%, about 65% to about 30%, about 65% to about 27%, about 65% to about 20%, about 65% to about 12%, about 65% to about 10%, about 65% to about 5%, about 60% to about 53%, about 60% to about 50%, about 60% to about 45%, about 60% to about 40%, about 60% to about 35%, about 60% to about 30%, about 60% to about 27%, about 60% to about 20%, about 60% to about 12%, about 60% to about 10%, about 60% to about 5%, about 53% to about 50%, about 53% to about 45%, about 53% to about 40%, about 53% to about 35%, about 53% to about 30%, about 53% to about 27%, about 53% to about 20%, about 53% to about 12%, about 53% to about 10%, about 53% to about 5%, about 50% to about 45%, about 50% to about 40%, about 50% to about 35%, about 50% to about 30%, about 50% to about 27%, about 50% to about 20%, about 50% to about 12%, about 50% to about 10%, about 50% to about 5%, about 45% to about 40%, about 45% to about 35%, about 45% to about 30%, about 45% to about 27%, about 45% to about 20%, about 45% to about 12%, about 45% to about 10%, about 45% to about 5%, about 40% to about 35%, about 40% to about 30%, about 40% to about 27%, about 40% to about 20%, about 40% to about 12%, about 40% to about 10%, about 40% to about 5%, about 35% to about 30%, about 35% to about 27%, about 35% to about 20%, about 35% to about 12%, about 35% to about 10%, about 35% to about 5%, about 30% to about 27%, about 30% to about 20%, about 30% to about 12%, about 30% to about 10%, about 30% to about 5%, about 27% to about 20%, about 27% to about 12%, about 27% to about 10%, about 27% to about 5%, about 20% to about 12%, about 20% to about 10%, about 20% to about 5%, about 12% to about 10%, about 12% to about 5%, or about 10% to about 5%.Attorney Docket No: 148232.001602

[0307] In some embodiments, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 4% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0308] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 4% to about 20%, about 10% to about 50%, about 10% to about 30%, about 15% to about 25%, about 15% to about 80%, about 10% to about 80%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0309] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 14%, 16%, 19%, or 21% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0310] In another embodiment, the purity of delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 10% to about 30% greater than the purity of delta- tocotrienol in the composition comprising low purity tocotrienol in step a).

[0311] In another embodiment, the purity of delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 20% greater than the purity of delta-tocotrienol in the composition comprising low purity tocotrienol in step a).

[0312] In another embodiment, the purity of delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 10% to about 90% greater than the purity of delta- tocotrienol in the composition comprising low purity tocotrienol in step a).

[0313] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 4% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0314] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 30% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0315] In some embodiments, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1% greater, about 2% greater, about 3% greater, about 4% greater, about 5% greater, about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75%Attorney Docket No: 148232.001602 greater, about 80% greater, about 85% greater, about 90% greater, about 95% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0316] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 40%.

[0317] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 70%.

[0318] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 70% to about 90%.

[0319] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 80%.

[0320] In another embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 90%.

[0321] In one embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 95%.

[0322] In some embodiments, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99%.

[0323] In some embodiments, the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 30% to at least about 40%, at least about 30% to at least about 50%, at least about 30% to at least about 60%, at least about 30% to at least about 70%, at least about 30% to at least about 75%, at least about 30% to at least about 80%, at least about 30% to at least about 85%, at least about 30% to at least about 90%, at least about 30% to at least about 92%, at least about 30% to at least about 95%, at least about 30% to at least about 97%, at least about 30% to at least about 99%, at least about 40% to at least about 50%, at least about 40% to at least about 60%, at least about 40% to at least about 70%, at least about 40% to at least about 75%, at least about 40% to at least about 80%, at least about 40% to at least about 85%, at least about 40% to at least about 90%, at least about 40% to at least about 92%, at least about 40% to at least about 95%, at least about 40% to at least about 97%, at least about 40% to at least about 99%, at least about 50% to about 60%, at least about 50% to about 70%, at leastAttorney Docket No: 148232.001602 about 50% to about 75%, at least about 50% to about 80%, at least about 50% to about 85%, at least about 50% to about 90%, at least about 50% to about 92%, at least about 50% to about 95%, at least about 50% to about 97%, at least about 50% to about 99%, at least about 60% to about 70%, at least about 60% to about 75%, at least about 60% to about 80%, at least about 60% to about 85%, at least about 60% to about 90%, at least about 60% to about 92%, at least about 60% to about 95%, at least about 60% to about 97%, at least about 60% to about 99%, at least about 70% to about 75%, at least about 70% to about 80%, at least about 70% to about 85%, at least about 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 80%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 80% to about 85%, at least about 80% to about 90%, at least about 80% to about 92%, at least about 80% to about 95%, at least about 80% to about 97%, at least about 80% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% to about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99%.

[0324] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% to about 90% delta-tocotrienol by weight.

[0325] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% or about 90% delta-tocotrienol by weight.

[0326] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% delta-tocotrienol by weight.

[0327] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 5% to about 95%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, aboutAttorney Docket No: 148232.001602 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 95%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 95%, about 70% to about 80%, about 70% to about 90%, about 70% to about 95%, about 80% to about 90%, about 80% to about 95%, or about 90% to about 95% delta- tocotrienol by weight.

[0328] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% to about 90% gamma-tocotrienol by weight.

[0329] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% or about 90% gamma-tocotrienol by weight.

[0330] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% gamma-tocotrienol by weight.

[0331] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 5% to about 95%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 95%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 95%, about 50% toAttorney Docket No: 148232.001602 about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 95%, about 70% to about 80%, about 70% to about 90%, about 70% to about 95%, about 80% to about 90%, about 80% to about 95%, or about 90% to about 95% gamma- tocotrienol by weight.

[0332] In some embodiments, the tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

[0333] In some embodiments, the tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight, about 5% gamma-tocotrienol and about 95% delta-tocotrienol by weight, about 15% gamma-tocotrienol and about 85% delta-tocotrienol by weight, about 20% gamma-tocotrienol and about 80% delta-tocotrienol by weight, about 25% gamma-tocotrienol and about 75% delta- tocotrienol by weight, about 30% gamma-tocotrienol and about 70% delta-tocotrienol by weight, about 35% gamma-tocotrienol and about 65% delta-tocotrienol by weight, or about 40% gamma- tocotrienol and about 60% delta-tocotrienol by weight.

[0334] In some embodiments, the tocotrienol in the composition comprising high purity tocotrienol in step c) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

[0335] In some embodiments, the tocotrienol in the composition comprising high purity tocotrienol in step c) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight, about 5% gamma-tocotrienol and about 95% delta-tocotrienol by weight, about 15% gamma-tocotrienol and about 85% delta-tocotrienol by weight, about 20% gamma-tocotrienol and about 80% delta-tocotrienol by weight, about 25% gamma-tocotrienol and about 75% delta- tocotrienol by weight, about 30% gamma-tocotrienol and about 70% delta-tocotrienol by weight, about 35% gamma-tocotrienol and about 65% delta-tocotrienol by weight, or about 40% gamma- tocotrienol and about 60% delta-tocotrienol by weight.

[0336] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:9 to about 9:1.

[0337] In an additional embodiment, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:9.Attorney Docket No: 148232.001602

[0338] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 0.5:9.5, about 1:9, about 2:8, about 3:7, about 4:6, about 5:5, about 6:4, about 7:3, about 8:2, about 9:1, or about 9.5:0.5.

[0339] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is less than about 1: 9. In some embodiments, the weight ratio of gamma- tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is up to about 20: 80. In some embodiments, the weight ratio of gamma-tocotrienol to delta- tocotrienol in the composition comprising high purity tocotrienol in step c) is up to about 5: 95. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is up to about 1: 99. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1:99 to about 5:95 or about 5:95 to about 1:9. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1:99 to about 1:9.

[0340] In some embodiments, the composition is obtained from palm oil extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1:9 to about 9:1. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 20:80 to about 9:1. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 5:95 to about 9:1. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1:99 to about 9:1.

[0341] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 0.5:9.5 to about 1:9, about 0.5:9.5 to about 2:8, about 0.5:9.5 to about 3:7, about 0.5:9.5 to about 4:6, about 0.5:9.5 to about 5:5, about 0.5:9.5 to about 6:4, about 0.5:9.5 to about 7:3, about 0.5:9.5 to about 8:2, about 0.5:9.5 to about 9:1, about 0.5:9.5 to about 9.5:0.5, about 1:9 to about 2:8, about 1:9 to about 3:7, about 1:9 to about 4:6, about 1:9 to about 5:5, about 1:9 to about 6:4, about 1:9 to about 7:3,Attorney Docket No: 148232.001602 about 1:9 to about 8:2, about 1:9 to about 9:1, about 1:9 to about 9.5:0.5, about 2:8 to about 3:7, about 2:8 to about 4:6, about 2:8 to about 5:5, about 2:8 to about 6:4, about 2:8 to about 7:3, about 2:8 to about 8:2, about 2:8 to about 9:1, about 2:8 to about 9.5:0.5, about 3:7 to about 4:6, about 3:7 to about 5:5, about 3:7 to about 6:4, about 3:7 to about 7:3, about 3:7 to about 8:2, about 3:7 to about 9:1, about 3:7 to about 9.5:0.5, about 4:6 to about 5:5, about 4:6 to about 6:4, about 4:6 to about 7:3, about 4:6 to about 8:2, about 4:6 to about 9:1, about 4:6 to about 9.5:0.5, about 5:5 to about 6:4, about 5:5 to about 7:3, about 5:5 to about 8:2, about 5:5 to about 9:1, about 5:5 to about 9.5:0.5, about 6:4 to about 7:3, about 6:4 to about 8:2, about 6:4 to about 9:1, about 6:4 to about 9.5:0.5, about 7:3 to about 8:2, about 7:3 to about 9:1, about 7:3 to about 9.5:0.5, about 8:2 to about 9:1, about 8:2 to about 9.5:0.5, or about 9:1 to about 9.5:0.5.

[0342] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1:9 to about 9:1.

[0343] In an additional embodiment, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1:9.

[0344] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 0.5:9.5, about 1:9, about 2:8, about 3:7, about 4:6, about 5:5, about 6:4, about 7:3, about 8:2, about 9:1, or about 9.5:0.5.

[0345] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of delta-tocotrienol to gamma-tocotrienol in the composition comprising high purity tocotrienol is at least about 80:20, at least about 90:10, or at least about 95: 5, or at least about 99:1, or at least about 99.9 to 0.1.

[0346] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 1:99 to about 1:9 or about 5:95 to about 1:9.

[0347] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 20:80 to about 9:1, about 1:9 to about 9:1, about 5:95 to about 9:1, or about 1:99 to about 9:1.Attorney Docket No: 148232.001602

[0348] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 0.5:9.5 to about 1:9, about 0.5:9.5 to about 2:8, about 0.5:9.5 to about 3:7, about 0.5:9.5 to about 4:6, about 0.5:9.5 to about 5:5, about 0.5:9.5 to about 6:4, about 0.5:9.5 to about 7:3, about 0.5:9.5 to about 8:2, about 0.5:9.5 to about 9:1, about 0.5:9.5 to about 9.5:0.5, about 1:9 to about 2:8, about 1:9 to about 3:7, about 1:9 to about 4:6, about 1:9 to about 5:5, about 1:9 to about 6:4, about 1:9 to about 7:3, about 1:9 to about 8:2, about 1:9 to about 9:1, about 1:9 to about 9.5:0.5, about 2:8 to about 3:7, about 2:8 to about 4:6, about 2:8 to about 5:5, about 2:8 to about 6:4, about 2:8 to about 7:3, about 2:8 to about 8:2, about 2:8 to about 9:1, about 2:8 to about 9.5:0.5, about 3:7 to about 4:6, about 3:7 to about 5:5, about 3:7 to about 6:4, about 3:7 to about 7:3, about 3:7 to about 8:2, about 3:7 to about 9:1, about 3:7 to about 9.5:0.5, about 4:6 to about 5:5, about 4:6 to about 6:4, about 4:6 to about 7:3, about 4:6 to about 8:2, about 4:6 to about 9:1, about 4:6 to about 9.5:0.5, about 5:5 to about 6:4, about 5:5 to about 7:3, about 5:5 to about 8:2, about 5:5 to about 9:1, about 5:5 to about 9.5:0.5, about 6:4 to about 7:3, about 6:4 to about 8:2, about 6:4 to about 9:1, about 6:4 to about 9.5:0.5, about 7:3 to about 8:2, about 7:3 to about 9:1, about 7:3 to about 9.5:0.5, about 8:2 to about 9:1, about 8:2 to about 9.5:0.5, or about 9:1 to about 9.5:0.5.

[0349] In some embodiments, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 63% purity.

[0350] In an additional embodiment, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 45% purity.

[0351] In an additional embodiment, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 18% purity.

[0352] In some embodiments, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 85%, less than about 80%, less than about 73%, less than about 70%, less than about 63%, less than about 60%, less than about 53%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 27%, less than about 20%, less than about 18%, less than about 10%, or less than about 5% purity.

[0353] In some embodiments, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of about 85% to about 80%, about 85% to about 73%, about 85% to about 70%, about 85% to about 63%, about 85% to about 60%, about 85% to about 53%, aboutAttorney Docket No: 148232.001602 85% to about 50%, about 85% to about 45%, about 85% to about 40%, about 85% to about 35%, about 85% to about 30%, about 85% to about 27%, about 85% to about 20%, about 85% to about 18%, about 85% to about 10%, about 85% to about 5%, about 80% to about 73%, about 80% to about 70%, about 80% to about 63%, about 80% to about 60%, about 80% to about 53%, about 80% to about 50%, about 80% to about 45%, about 80% to about 40%, about 80% to about 35%, about 80% to about 30%, about 80% to about 27%, about 80% to about 20%, about 80% to about 18%, about 80% to about 10%, about 80% to about 5%, about 73% to about 70%, about 73% to about 63%, about 73% to about 60%, about 73% to about 53%, about 73% to about 50%, about 73% to about 45%, about 73% to about 40%, about 73% to about 35%, about 73% to about 30%, about 73% to about 27%, about 73% to about 20%, about 73% to about 18%, about 73% to about 10%, about 73% to about 5%, about 70% to about 63%, about 70% to about 60%, about 70% to about 53%, about 70% to about 50%, about 70% to about 45%, about 70% to about 40%, about 70% to about 35%, about 70% to about 30%, about 70% to about 27%, about 70% to about 20%, about 70% to about 18%, about 70% to about 10%, about 70% to about 5%, about 63% to about 60%, about 63% to about 53%, about 63% to about 50%, about 63% to about 45%, about 63% to about 40%, about 63% to about 35%, about 63% to about 30%, about 63% to about 27%, about 63% to about 20%, about 63% to about 18%, about 63% to about 10%, about 63% to about 5%, about 60% to about 53%, about 60% to about 50%, about 60% to about 45%, about 60% to about 40%, about 60% to about 35%, about 60% to about 30%, about 60% to about 27%, about 60% to about 20%, about 60% to about 18%, about 60% to about 10%, about 60% to about 5%, about 53% to about 50%, about 53% to about 45%, about 53% to about 40%, about 53% to about 35%, about 53% to about 30%, about 53% to about 27%, about 53% to about 20%, about 53% to about 18%, about 53% to about 10%, about 53% to about 5%, about 50% to about 45%, about 50% to about 40%, about 50% to about 35%, about 50% to about 30%, about 50% to about 27%, about 50% to about 20%, about 50% to about 18%, about 50% to about 10%, about 50% to about 5%, about 45% to about 40%, about 45% to about 35%, about 45% to about 30%, about 45% to about 27%, about 45% to about 20%, about 45% to about 18%, about 45% to about 10%, about 45% to about 5%, about 40% to about 35%, about 40% to about 30%, about 40% to about 27%, about 40% to about 20%, about 40% to about 18%, about 40% to about 10%, about 40% to about 5%, about 35% to about 30%, about 35% to about 27%, about 35% to about 20%, about 35% to about 18%, about 35% to about 10%, about 35% to about 5%, about 30% to about 27%, about 30% toAttorney Docket No: 148232.001602 about 20%, about 30% to about 18%, about 30% to about 10%, about 30% to about 5%, about 27% to about 20%, about 27% to about 18%, about 27% to about 10%, about 27% to about 5%, about 20% to about 18%, about 20% to about 10%, about 20% to about 5%, about 18% to about 10%, about 18% to about 5%, or about 10% to about 5% purity.

[0354] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 63% purity.

[0355] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 90% purity.

[0356] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 90% purity.

[0357] In an additional embodiment, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of about 63% to about 81% purity.

[0358] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 63%, at least about 70%, at least about 75%, at least about 81%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% purity.

[0359] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 30% to at least about 40%, at least about 30% to at least about 50%, at least about 30% to at least about 60%, at least about 30% to at least about 63%, at least about 30% to at least about 70%, at least about 30% to at least about 75%, at least about 30% to at least about 81%, at least about 30% to at least about 85%, at least about 30% to at least about 90%, at least about 30% to at least about 92%, at least about 30% to at least about 95%, at least about 30% to at least about 97%, at least about 30% to at least about 99%, at least about 40% to at least about 50%, at least about 40% to at least about 60%, at least about 40% to at least about 63%, at least about 40% to at least about 70%, at least about 40% to at least about 75%, at least about 40% to at least about 81%, at least about 40% to at least about 85%, at least about 40% to at least about 90%, at least about 40% to at least about 92%, at least about 40% to at least about 95%, at least about 40% to at least about 97%, at least about 40% to at least about 99%, at least about 50% to about 60%, at least about 50% to about 63%, at least about 50% to about 70%, at least about 50% to about 75%, at least about 50% to about 81%, at least aboutAttorney Docket No: 148232.001602 50% to about 85%, at least about 50% to about 90%, at least about 50% to about 92%, at least about 50% to about 95%, at least about 50% to about 97%, at least about 50% to about 99%, at least about 60% to about 63%, at least about 60% to about 70%, at least about 60% to about 75%, at least about 60% to about 81%, at least about 60% to about 85%, at least about 60% to about 90%, at least about 60% to about 92%, at least about 60% to about 95%, at least about 60% to about 97%, at least about 60% to about 99%, at least about 63% to about 70%, at least about 63% to about 75%, at least about 63% to about 81%, at least about 63% to about 85%, at least about 63% to about 90%, at least about 63% to about 92%, at least about 63% to about 95%, at least about 63% to about 97%, at least about 63% to about 99%, at least about 70% to about 75%, at least about 70% to about 81%, at least about 70% to about 85%, at least about 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 81%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 81% to about 85%, at least about 81% to about 90%, at least about 81% to about 92%, at least about 81% to about 95%, at least about 81% to about 97%, at least about 81% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% to about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99% purity.

[0360] In an additional embodiment, the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of about 7% to about 10% purity.

[0361] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of about 2%, about 4%, about 5%, about 7%, about 8%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, or about 30% purity.

[0362] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of about 2% to about 4%, about 2% to about 5%, about 2% to about 7%, about 2% to about 8%, about 2% to about 9%, about 2% to about 10%, about 2% to about 12%, about 2% to about 15%, about 2% to about 20%, about 2% to about 25%, about 2%Attorney Docket No: 148232.001602 to about 30%, about 4% to about 5%, about 4% to about 7%, about 4% to about 8%, about 4% to about 9%, about 4% to about 10%, about 4% to about 12%, about 4% to about 15%, about 4% to about 20%, about 4% to about 25%, about 4% to about 30%, about 5% to about 7%, about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 12%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 7% to about 8%, about 7% to about 9%, about 7% to about 10%, about 7% to about 12%, about 7% to about 15%, about 7% to about 20%, about 7% to about 25%, about 7% to about 30%, about 8% to about 9%, about 8% to about 10%, about 8% to about 12%, about 8% to about 15%, about 8% to about 20%, about 8% to about 25%, about 8% to about 30%, about 9% to about 10%, about 9% to about 12%, about 9% to about 15%, about 9% to about 20%, about 9% to about 25%, about 9% to about 30%, about 10% to about 12%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 12% to about 15%, about 12% to about 20%, about 12% to about 25%, about 12% to about 30%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 20% to about 25%, about 20% to about 30%, or about 25% to about 30% purity.

[0363] In some embodiments, the yield of tocotrienol is at least 30% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0364] In some embodiments, the yield of tocotrienol is at least 15% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0365] In some embodiments, the yield of tocotrienol is at least 20% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0366] In some embodiments, the yield of tocotrienol is at least 25% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).Attorney Docket No: 148232.001602

[0367] In some embodiments, the yield of tocotrienol is at least 35% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0368] In some embodiments, the yield of tocotrienol is at least 40% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0369] In some embodiments, the yield of tocotrienol is at least 45% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0370] In some embodiments, the yield of tocotrienol is at least 50% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0371] In some embodiments, the yield of tocotrienol is at least 60% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0372] In some embodiments, the yield of tocotrienol is at least 70% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a). Methods of Preparations of High Purity Tocotrienol Compositions Using Liquid-Solid Extraction (in a Container or in Column Chromatography)

[0373] Provided herein is a method of preparing a composition comprising high purity tocotrienol, said method comprising: a) providing a composition comprising low purity tocotrienol; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase;Attorney Docket No: 148232.001602 c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with tocotrienol; d) contacting the absorbent bonded with tocotrienol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising tocotrienol; and f) concentrating the filtrate to obtain the composition comprising high purity tocotrienol with increased purity as compared to the composition comprising the low purity tocotrienol in step a).

[0374] The steps can be repeated to continuously increase the purity of tocotrienol or the purity of delta-tocotrienol to above about 99%, and the weight ratio of delta-tocotrienol to gamma-tocotrienol to above 99:1 or even above 99.9:0.1.

[0375] In some embodiments, the composition in step a) comprises alpha-tocotrienol, beta- tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol, beta-tocopherol, delta- tocopherol, gamma-tocopherol, or any of the combinations thereof.

[0376] In some embodiments, the obtained high purity tocotrienol in the last step consists essentially of delta-tocotrienol.

[0377] In some embodiments, the obtained high purity tocotrienol in the last step consists essentially of gamma-tocotrienol.

[0378] In some embodiments, the obtained composition in the last step is free of alpha- tocopherol, or the obtained composition in the last step has substantially less alpha-tocopherol as compared to the amount of alpha-tocopherol in the composition in step a).

[0379] Provided herein is a method of preparing a composition comprising high purity delta- tocotrienol, said method comprising: a) providing a composition comprising low purity delta-tocotrienol, optionally wherein the composition comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma- tocotrienol, alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with delta-tocotrienol;Attorney Docket No: 148232.001602 d) contacting the absorbent bonded with delta-tocotrienol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising delta-tocotrienol; and f) concentrating the filtrate to obtain the composition comprising high purity delta- tocotrienol with increased purity as compared to the composition comprising the low purity delta-tocotrienol in step a), optionally wherein the obtained composition consists essentially of delta-tocotrienol.

[0380] Provided herein is a method of preparing a composition comprising high purity gamma- tocotrienol, said method comprising: a) providing a composition comprising low purity gamma-tocotrienol, optionally wherein the composition comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma- tocotrienol, alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with gamma-tocotrienol; d) contacting the absorbent bonded with gamma-tocotrienol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising gamma-tocotrienol; and f) concentrating the filtrate to obtain the composition comprising high purity gamma- tocotrienol with increased purity as compared to the composition comprising the low purity gamma-tocotrienol in step a), optionally wherein the obtained composition consists essentially of gamma-tocotrienol.

[0381] In some embodiments, step b) further comprises stirring the first mixture for at least about 5 minutes.

[0382] In an additional embodiment, step b) further comprises stirring the first mixture for at least about 1 hour.

[0383] In some embodiments, step b) further comprises stirring the first mixture for at least about 1 minute, at least about 2 minutes, at least about 4 minutes, at least about 5 minutes, at least about 8 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20Attorney Docket No: 148232.001602 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 3 hours.

[0384] In some embodiments, step c) further comprises rinsing the first mixture with the non- polar solvent at filtration.

[0385] In some embodiments, step d) further comprises stirring the second mixture for at least about 5 minutes.

[0386] In an additional embodiment, step d) further comprises stirring the second mixture for at least about 1 hour.

[0387] In some embodiments, step d) further comprises stirring the second mixture for at least about 1 minute, at least about 2 minutes, at least about 4 minutes, at least about 5 minutes, at least about 8 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 3 hours.

[0388] In some embodiments, step e) further comprises rinsing the second mixture with the polar solvent at filtration.

[0389] In some embodiments, step f) further comprises using a rotary evaporator to remove the solvent.

[0390] In some embodiments, the method further comprises repeating steps a)-f) to increase the purity of tocotrienol.

[0391] Provided herein is a method of preparing a composition comprising high purity tocotrienol, said method comprising: a) loading a composition comprising low purity tocotrienol and other components onto a column packed with an absorbent; b) separating tocotrienol from other components by column chromatography; and c) obtaining a composition comprising high purity tocotrienol with increased purity of tocotrienol as compared to the composition comprising the low purity tocotrienol in step a).Attorney Docket No: 148232.001602

[0392] In some embodiments, the composition in step a) comprises alpha-tocotrienol, beta- tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol, beta-tocopherol, delta- tocopherol, gamma-tocopherol, or any of the combinations thereof.

[0393] In some embodiments, the obtained high purity tocotrienol consists essentially of delta- tocotrienol.

[0394] In some embodiments, the obtained high purity tocotrienol consists essentially of gamma-tocotrienol.

[0395] In some embodiments, the obtained composition in step c) is free of alpha-tocopherol, or the obtained composition in step c) has substantially less alpha-tocopherol as compared to the amount of alpha-tocopherol in the composition in step a).

[0396] Provided herein is a method of preparing a composition comprising high purity delta- tocotrienol, said method comprising: a) loading a composition comprising low purity delta-tocotrienol and other components onto a column packed with an absorbent, optionally wherein the composition comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha- tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof; b) separating delta-tocotrienol from other components by column chromatography; and c) obtaining a composition comprising high purity delta-tocotrienol with increased purity of delta-tocotrienol as compared to the composition comprising the low purity delta- tocotrienol in step a), optionally wherein the obtained composition consists essentially of delta-tocotrienol.

[0397] Provided herein is a method of preparing a composition comprising high purity gamma- tocotrienol, said method comprising: a) loading a composition comprising low purity gamma-tocotrienol and other components onto a column packed with an absorbent, optionally wherein the composition comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha- tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof; b) separating gamma-tocotrienol from other components by column chromatography; andAttorney Docket No: 148232.001602 c) obtaining a composition comprising high purity gamma-tocotrienol with increased purity of gamma-tocotrienol as compared to the composition comprising the low purity gamma-tocotrienol in step a), optionally wherein the obtained composition consists essentially of gamma-tocotrienol.

[0398] In some embodiments, step b) further comprises: i. eluting the column with a non-polar solvent and then a polar solvent; ii. eluting the column with a non-polar solvent and then a mixture of non-polar and polar solvents; or iii. eluting the column with a gradient mobile phase that is a mixture of non-polar and polar solvents with an increased ratio of the polar solvent to the non-polar solvent over time.

[0399] In one embodiment, the adsorbent or stationary phase of column chromatography is regenerative.

[0400] In some embodiments, step b) further comprises using a rotary evaporator to remove the solvent.

[0401] In some embodiments, the method further comprises repeating steps a)-c) to increase the purity of tocotrienol or delta-tocotrienol.

[0402] The fractional distillation or liquid-solid extraction can be combined in any of the combinations thereof. In one embodiment, the product from one method is subsequently provided as the start material of a different method. In one embodiment, the product from one method is subsequently provided as the start material of the same method.

[0403] In some embodiments, the composition in step a) comprises alpha-tocopherol, alpha- tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, or any of the combinations thereof.

[0404] In some embodiments, the composition in step a) comprises alpha-tocotrienol, beta- tocotrienol, delta-tocotrienol, gamma-tocotrienol, or any of the combinations thereof.

[0405] In an additional embodiment, the composition in step a) comprises delta-tocotrienol, gamma-tocotrienol, or a combination thereof.

[0406] In an additional embodiment, the composition in step a) comprises delta-tocotrienol and gamma-tocotrienol.Attorney Docket No: 148232.001602

[0407] In one embodiment, the method prepares high purity delta-tocotrienol, high purity gamma-tocotrienol, or a combination thereof.

[0408] In some embodiments, the method as described herein, wherein: the method prepares high purity delta-tocotrienol; the composition comprising low purity tocotrienol in step a) is a composition comprising low purity delta-tocotrienol; and the composition comprising high purity tocotrienol is a composition comprising high purity delta-tocotrienol with increased purity of delta-tocotrienol as compared to the composition comprising the low purity delta- tocotrienol in step a).

[0409] In some embodiments, high purity tocotrienol consists essentially of delta-tocotrienol.

[0410] In some embodiments, the non-polar solvent is a C3 to C12 alkane, a C3 to C12 alkene, a C3 to C12 alkyne, a C6 to C12 arene, or any of the combinations thereof.

[0411] In an additional embodiment, the non-polar solvent is a C3 to C12 alkane.

[0412] In one embodiment, the C3 to C12 alkane is pentane, hexane, heptane, or any of the combinations thereof.

[0413] In one embodiment, the C3 to C12 alkane is hexane.

[0414] In an additional embodiment, the non-polar solvent is a C3 to C12 alkene.

[0415] In one embodiment, the C3 to C12 alkene is limonene.

[0416] In an additional embodiment, the non-polar solvent is a C3to C12arene.

[0417] In one embodiment, the C3to C12arene is benzene, toluene, xylene, or any of the combinations thereof.

[0418] In some embodiments, the absorbent comprises alumina, aluminum oxide, silica, silicon dioxide (SiO2), or a combination thereof.

[0419] In an additional embodiment, the absorbent comprises aluminum oxide.

[0420] In one embodiment, the aluminum oxide is acidic, basic, or neutral.

[0421] In one embodiment, the aluminum oxide is basic.

[0422] In an additional embodiment, the absorbent comprises SiO2.

[0423] In an additional embodiment, the absorbent is silica gel or silica.

[0424] In some embodiments, the polar solvent comprises a C1 to C10 alkyl alcohol, water, acetic acid, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran (THF),Attorney Docket No: 148232.001602 dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, hexamethyl phosphoric triamide (HMPT), or any of combinations thereof.

[0425] In one embodiment, the C1to C10alkyl alcohol is ethanol. In one embodiment, the C1to C10alkyl alcohol is methanol. In one embodiment, the C1to C10alkyl alcohol is propanol.

[0426] In one embodiment, the polar solvent comprises ethyl acetate.

[0427] In an additional embodiment, the polar solvent comprises a mixture of ethanol and water.

[0428] In some embodiments, the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane and ethyl acetate.

[0429] In some embodiments, the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane, water, and ethanol.

[0430] In some embodiments, the polar solvent comprises a mixture of ethanol and water, and ethanol is at least 35% by volume over the total volume of ethanol and water.

[0431] In an additional embodiment, the polar solvent comprises a mixture of ethanol and water, and ethanol is about 35% to about 95% by volume over the total volume of ethanol and water.

[0432] In some embodiments, the polar solvent comprises a mixture of ethanol and water, and ethanol is at least about 10%, at least about 20%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% by volume over the total volume of ethanol and water.

[0433] In some embodiments, the polar solvent comprises a mixture of ethanol and water, and ethanol is about 10% to about 20%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 55%, about 10% to about 60%, about 10% to about 65%, about 10% to about 70%, about 10% to about 75%, about 10% to about 80%, about 10% to about 85%, about 10% to about 90%, about 10% to about 95%, about 10% to about 99%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 55%, about 20% to about 60%, about 20% to about 65%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 20% to about 85%, about 20% to about 90%, about 20% toAttorney Docket No: 148232.001602 about 95%, about 20% to about 99%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55%, about 30% to about 60%, about 30% to about 65%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 30% to about 85%, about 30% to about 90%, about 30% to about 95%, about 30% to about 99%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55%, about 35% to about 60%, about 35% to about 65%, about 35% to about 70%, about 35% to about 75%, about 35% to about 80%, about 35% to about 85%, about 35% to about 90%, about 35% to about 95%, about 35% to about 99%, about 40% to about 45%, about 40% to about 50%, about 40% to about 55%, about 40% to about 60%, about 40% to about 65%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 40% to about 85%, about 40% to about 90%, about 40% to about 95%, about 40% to about 99%, about 45% to about 50%, about 45% to about 55%, about 45% to about 60%, about 45% to about 65%, about 45% to about 70%, about 45% to about 75%, about 45% to about 80%, about 45% to about 85%, about 45% to about 90%, about 45% to about 95%, about 45% to about 99%, about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 50% to about 95%, about 50% to about 99%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 55% to about 75%, about 55% to about 80%, about 55% to about 85%, about 55% to about 90%, about 55% to about 95%, about 55% to about 99%, about 60% to about 65%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 60% to about 85%, about 60% to about 90%, about 60% to about 95%, about 60% to about 99%, about 65% to about 70%, about 65% to about 75%, about 65% to about 80%, about 65% to about 85%, about 65% to about 90%, about 65% to about 95%, about 65% to about 99%, about 70% to about 75%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 70% to about 95%, about 70% to about 99%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 75% to about 95%, about 75% to about 99%, about 80% to about 85%, about 80% to about 90%, about 80% to about 95%, about 80% to about 99%, about 85% to about 90%, about 85% to about 95%, about 85% to about 99%, about 90% to about 95%, about 90% to about 99%, or about 95% to about 99% by volume over the total volume of ethanol and water.

[0434] In some embodiments, the mixture of non-polar and polar solvents comprises hexane and ethyl acetate at a ratio of about 0.5:1 to about 3:1 by volume.Attorney Docket No: 148232.001602

[0435] In some embodiments, the mixture of non-polar and polar solvents comprises hexane and ethyl acetate, optionally at a ratio of about 0.25:1, about 0.5:1, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, or about 9:1 by volume.

[0436] In some embodiments, the mixture of non-polar and polar solvents comprises hexane and ethyl acetate, optionally at a ratio of about 0.25:1 to about 0.5:1, about 0.25:1 to about 1:1, about 0.25:1 to about 2:1, about 0.25:1 to about 3:1, about 0.25:1 to about 4:1, about 0.25:1 to about 5:1, about 0.25:1 to about 6:1, about 0.25:1 to about 7:1, about 0.25:1 to about 8:1, about 0.25:1 to about 9:1, about 0.5:1 to about 1:1, about 0.5:1 to about 2:1, about 0.5:1 to about 3:1, about 0.5:1 to about 4:1, about 0.5:1 to about 5:1, about 0.5:1 to about 6:1, about 0.5:1 to about 7:1, about 0.5:1 to about 8:1, about 0.5:1 to about 9:1, about 1:1 to about 2:1, about 1:1 to about 3:1, about 1:1 to about 4:1, about 1:1 to about 5:1, about 1:1 to about 6:1, about 1:1 to about 7:1, about 1:1 to about 8:1, about 1:1 to about 9:1, about 2:1 to about 3:1, about 2:1 to about 4:1, about 2:1 to about 5:1, about 2:1 to about 6:1, about 2:1 to about 7:1, about 2:1 to about 8:1, about 2:1 to about 9:1, about 3:1 to about 4:1, about 3:1 to about 5:1, about 3:1 to about 6:1, about 3:1 to about 7:1, about 3:1 to about 8:1, about 3:1 to about 9:1, about 4:1 to about 5:1, about 4:1 to about 6:1, about 4:1 to about 7:1, about 4:1 to about 8:1, about 4:1 to about 9:1, about 5:1 to about 6:1, about 5:1 to about 7:1, about 5:1 to about 8:1, about 5:1 to about 9:1, about 6:1 to about 7:1, about 6:1 to about 8:1, about 6:1 to about 9:1, about 7:1 to about 8:1, about 7:1 to about 9:1, about 8:1 to about 9:1, or about 8:1 to about 9:1 by volume.

[0437] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 70% purity.

[0438] In an additional embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 50% purity.

[0439] In an additional embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 40% purity.

[0440] In an additional embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 20% purity.

[0441] In one embodiment, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 10% to about 20%, about 20 to about 50%, or about 50% to about 70%.Attorney Docket No: 148232.001602

[0442] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 10%, is less than about 20%, is less than about 25%, is less than about 30%, is less than about 35%, is less than about 40%, is less than about 45%, is less than about 50%, is less than about 60%, is less than about 70%, is less than about 75%, or is less than about 80%.

[0443] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 75%, about 10% to about 80%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 60%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 60%, about 35% to about 70%, about 35% to about 75%, about 35% to about 80%, about 40% to about 45%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 45% to about 50%, about 45% to about 60%, about 45% to about 70%, about 45% to about 75%, about 45% to about 80%, about 50% to about 60%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 70% to about 75%, about 70% to about 80%, or about 75% to about 80%.

[0444] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 75%, or about 80%.

[0445] In some embodiments, the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 75%,Attorney Docket No: 148232.001602 about 10% to about 80%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 60%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 60%, about 35% to about 70%, about 35% to about 75%, about 35% to about 80%, about 40% to about 45%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 45% to about 50%, about 45% to about 60%, about 45% to about 70%, about 45% to about 75%, about 45% to about 80%, about 50% to about 60%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 70% to about 75%, about 70% to about 80%, or about 75% to about 80%.

[0446] In some embodiments, the purity of tocotrienol in the composition comprising high purity tocotrienol is at least about 4% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0447] In an additional embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol is about 4% to about 20%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0448] In an additional embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol is about 4% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0449] In an additional embodiment, the purity of tocotrienol in the composition comprising high purity tocotrienol is about 30% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0450] In some embodiments, the purity of tocotrienol in the composition comprising high purity tocotrienol is about 1% greater, about 2% greater, about 3% greater, about 4% greater, about 5% greater, about 7% greater, about 10% greater, about 15% greater, about 20% greater,Attorney Docket No: 148232.001602 about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, about 95% greater, about 100% greater, about 110% greater, about 120% greater, about 140% greater, about 160% greater, about 180% greater, or about 200% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

[0451] In some embodiments, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 40%.

[0452] In some embodiments, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 70%.

[0453] In an additional embodiment, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is about 70% to about 90%.

[0454] In an additional embodiment, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 80%.

[0455] In an additional embodiment, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 90%.

[0456] In one embodiment, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 95%.

[0457] In some embodiments, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99%.

[0458] In some embodiments, the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 30% to at least about 40%, at least about 30% to at least about 50%, at least about 30% to at least about 60%, at least about 30% to at least about 70%, at least about 30% to at least about 75%, at least about 30% to at least about 80%, at least about 30% to at least about 85%, at least about 30% to at least about 90%, at least about 30% to at least about 92%, at least about 30% to at least about 95%, at least about 30% to at least about 97%, at least about 30% to at least about 99%, at least about 40% to at least about 50%, at least about 40% to at least about 60%, at least about 40% to at least about 70%, at least aboutAttorney Docket No: 148232.001602 40% to at least about 75%, at least about 40% to at least about 80%, at least about 40% to at least about 85%, at least about 40% to at least about 90%, at least about 40% to at least about 92%, at least about 40% to at least about 95%, at least about 40% to at least about 97%, at least about 40% to at least about 99%, at least about 50% to about 60%, at least about 50% to about 70%, at least about 50% to about 75%, at least about 50% to about 80%, at least about 50% to about 85%, at least about 50% to about 90%, at least about 50% to about 92%, at least about 50% to about 95%, at least about 50% to about 97%, at least about 50% to about 99%, at least about 60% to about 70%, at least about 60% to about 75%, at least about 60% to about 80%, at least about 60% to about 85%, at least about 60% to about 90%, at least about 60% to about 92%, at least about 60% to about 95%, at least about 60% to about 97%, at least about 60% to about 99%, at least about 70% to about 75%, at least about 70% to about 80%, at least about 70% to about 85%, at least about 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 80%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 80% to about 85%, at least about 80% to about 90%, at least about 80% to about 92%, at least about 80% to about 95%, at least about 80% to about 97%, at least about 80% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% to about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99%.

[0459] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% to 90% delta-tocotrienol by weight.

[0460] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% or about 90% delta-tocotrienol by weight.

[0461] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% delta-tocotrienol by weight.Attorney Docket No: 148232.001602

[0462] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 5% to about 95%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 95%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 95%, about 70% to about 80%, about 70% to about 90%, about 70% to about 95%, about 80% to about 90%, about 80% to about 95%, or about 90% to about 95% delta- tocotrienol by weight.

[0463] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% to about 90% gamma-tocotrienol by weight.

[0464] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% or about 90% gamma-tocotrienol by weight.

[0465] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% gamma-tocotrienol by weight.

[0466] In some embodiments, tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 5% to about 95%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 95%, about 20% to about 30%, about 20% to about 40%, about 20% to aboutAttorney Docket No: 148232.001602 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 95%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 95%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 95%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 95%, about 70% to about 80%, about 70% to about 90%, about 70% to about 95%, about 80% to about 90%, about 80% to about 95%, or about 90% to about 95% gamma- tocotrienol by weight.

[0467] In some embodiments, the tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

[0468] In some embodiments, the tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight, about 5% gamma-tocotrienol and about 95% delta-tocotrienol by weight, about 15% gamma-tocotrienol and about 85% delta-tocotrienol by weight, about 20% gamma-tocotrienol and about 80% delta-tocotrienol by weight, about 25% gamma-tocotrienol and about 75% delta- tocotrienol by weight, about 30% gamma-tocotrienol and about 70% delta-tocotrienol by weight, about 35% gamma-tocotrienol and about 65% delta-tocotrienol by weight, or about 40% gamma- tocotrienol and about 60% delta-tocotrienol by weight.

[0469] In some embodiments, the tocotrienol in the composition comprising high purity tocotrienol comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

[0470] In some embodiments, the tocotrienol in the composition comprising high purity tocotrienol in step c) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight, about 5% gamma-tocotrienol and about 95% delta-tocotrienol by weight, about 15% gamma-tocotrienol and about 85% delta-tocotrienol by weight, about 20% gamma-tocotrienol and about 80% delta-tocotrienol by weight, about 25% gamma-tocotrienol and about 75% delta- tocotrienol by weight, about 30% gamma-tocotrienol and about 70% delta-tocotrienol by weight, about 35% gamma-tocotrienol and about 65% delta-tocotrienol by weight, or about 40% gamma- tocotrienol and about 60% delta-tocotrienol by weight.Attorney Docket No: 148232.001602

[0471] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:9 to about 9:1.

[0472] In an additional embodiment, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:9.

[0473] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 0.5:9.5, about 1:9, about 2:8, about 3:7, about 4:6, about 5:5, about 6:4, about 7:3, about 8:2, about 9:1, or about 9.5:0.5.

[0474] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 0.5:9.5 to about 1:9, about 0.5:9.5 to about 2:8, about 0.5:9.5 to about 3:7, about 0.5:9.5 to about 4:6, about 0.5:9.5 to about 5:5, about 0.5:9.5 to about 6:4, about 0.5:9.5 to about 7:3, about 0.5:9.5 to about 8:2, about 0.5:9.5 to about 9:1, about 0.5:9.5 to about 9.5:0.5, about 1:9 to about 2:8, about 1:9 to about 3:7, about 1:9 to about 4:6, about 1:9 to about 5:5, about 1:9 to about 6:4, about 1:9 to about 7:3, about 1:9 to about 8:2, about 1:9 to about 9:1, about 1:9 to about 9.5:0.5, about 2:8 to about 3:7, about 2:8 to about 4:6, about 2:8 to about 5:5, about 2:8 to about 6:4, about 2:8 to about 7:3, about 2:8 to about 8:2, about 2:8 to about 9:1, about 2:8 to about 9.5:0.5, about 3:7 to about 4:6, about 3:7 to about 5:5, about 3:7 to about 6:4, about 3:7 to about 7:3, about 3:7 to about 8:2, about 3:7 to about 9:1, about 3:7 to about 9.5:0.5, about 4:6 to about 5:5, about 4:6 to about 6:4, about 4:6 to about 7:3, about 4:6 to about 8:2, about 4:6 to about 9:1, about 4:6 to about 9.5:0.5, about 5:5 to about 6:4, about 5:5 to about 7:3, about 5:5 to about 8:2, about 5:5 to about 9:1, about 5:5 to about 9.5:0.5, about 6:4 to about 7:3, about 6:4 to about 8:2, about 6:4 to about 9:1, about 6:4 to about 9.5:0.5, about 7:3 to about 8:2, about 7:3 to about 9:1, about 7:3 to about 9.5:0.5, about 8:2 to about 9:1, about 8:2 to about 9.5:0.5, or about 9:1 to about 9.5:0.5.

[0475] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is less than about 1: 9. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is up to about 20: 80. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is up to about 5: 95. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purityAttorney Docket No: 148232.001602 tocotrienol is up to about 1: 99. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 5:95 to about 1:9. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 1:99 to about 1:9.

[0476] In some embodiments, the composition is obtained from palm oil extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 1:9 to about 9:1. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 20:80 to about 9:1. In some embodiments, the weight ratio of gamma- tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 5:95 to about 9:1. In some embodiments, the weight ratio of gamma-tocotrienol to delta- tocotrienol in the composition comprising high purity tocotrienol is about 1:99 to about 9:1.

[0477] In an additional embodiment, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in is about 1:9 to about 9:1.

[0478] In one embodiment, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 1:9.

[0479] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 0.5:9.5, about 1:9, about 2:8, about 3:7, about 4:6, about 5:5, about 6:4, about 7:3, about 8:2, about 9:1, or about 9.5:0.5.

[0480] In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 0.5:9.5 to about 1:9, about 0.5:9.5 to about 2:8, about 0.5:9.5 to about 3:7, about 0.5:9.5 to about 4:6, about 0.5:9.5 to about 5:5, about 0.5:9.5 to about 6:4, about 0.5:9.5 to about 7:3, about 0.5:9.5 to about 8:2, about 0.5:9.5 to about 9:1, about 0.5:9.5 to about 9.5:0.5, about 1:9 to about 2:8, about 1:9 to about 3:7, about 1:9 to about 4:6, about 1:9 to about 5:5, about 1:9 to about 6:4, about 1:9 to about 7:3, about 1:9 to about 8:2, about 1:9 to about 9:1, about 1:9 to about 9.5:0.5, about 2:8 to about 3:7, about 2:8 to about 4:6, about 2:8 to about 5:5, about 2:8 to about 6:4, about 2:8 to about 7:3, about 2:8 to about 8:2, about 2:8 to about 9:1, about 2:8 to about 9.5:0.5, about 3:7 to about 4:6, about 3:7 to about 5:5, about 3:7 to about 6:4, about 3:7 to about 7:3, about 3:7 to about 8:2, about 3:7 to about 9:1, about 3:7 to about 9.5:0.5, about 4:6 to about 5:5, about 4:6 to about 6:4, about 4:6 to about 7:3, about 4:6 to about 8:2, about 4:6 to about 9:1, about 4:6 to about 9.5:0.5,Attorney Docket No: 148232.001602 about 5:5 to about 6:4, about 5:5 to about 7:3, about 5:5 to about 8:2, about 5:5 to about 9:1, about 5:5 to about 9.5:0.5, about 6:4 to about 7:3, about 6:4 to about 8:2, about 6:4 to about 9:1, about 6:4 to about 9.5:0.5, about 7:3 to about 8:2, about 7:3 to about 9:1, about 7:3 to about 9.5:0.5, about 8:2 to about 9:1, about 8:2 to about 9.5:0.5, or about 9:1 to about 9.5:0.5.

[0481] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of delta-tocotrienol to gamma-tocotrienol in the composition comprising high purity tocotrienol is at least about 80:20, at least about 90 to 10, or at least about 95 to 5, or at least about 99:1, or at least about 99.9 to 0.1.

[0482] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 1:99 to about 1:9, about 5:95 to about 1:9, or about 1:9 to about 1:9.

[0483] In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts. In some embodiments, the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 20:80 to about 9:1, about 1:9 to about 9:1, about 5:95 to about 9:1, or about 1:99 to about 9:1.

[0484] In some embodiments, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 63% purity.

[0485] In an additional embodiment, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 45% purity.

[0486] In an additional embodiment, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 18% purity.

[0487] In some embodiments, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 85%, less than about 80%, less than about 73%, less than about 70%, less than about 63%, less than about 60%, less than about 53%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 27%, less than about 20%, less than about 18%, less than about 10%, or less than about 5% purity.Attorney Docket No: 148232.001602

[0488] In some embodiments, the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 85% to about 80%, less than about 85% to about 73%, less than about 85% to about 70%, less than about 85% to about 63%, less than about 85% to about 60%, less than about 85% to about 53%, less than about 85% to about 50%, less than about 85% to about 45%, less than about 85% to about 40%, less than about 85% to about 35%, less than about 85% to about 30%, less than about 85% to about 27%, less than about 85% to about 20%, less than about 85% to about 18%, less than about 85% to about 10%, less than about 85% to about 5%, less than about 80% to about 73%, less than about 80% to about 70%, less than about 80% to about 63%, less than about 80% to about 60%, less than about 80% to about 53%, less than about 80% to about 50%, less than about 80% to about 45%, less than about 80% to about 40%, less than about 80% to about 35%, less than about 80% to about 30%, less than about 80% to about 27%, less than about 80% to about 20%, less than about 80% to about 18%, less than about 80% to about 10%, less than about 80% to about 5%, less than about 73% to about 70%, less than about 73% to about 63%, less than about 73% to about 60%, less than about 73% to about 53%, less than about 73% to about 50%, less than about 73% to about 45%, less than about 73% to about 40%, less than about 73% to about 35%, less than about 73% to about 30%, less than about 73% to about 27%, less than about 73% to about 20%, less than about 73% to about 18%, less than about 73% to about 10%, less than about 73% to about 5%, less than about 70% to about 63%, less than about 70% to about 60%, less than about 70% to about 53%, less than about 70% to about 50%, less than about 70% to about 45%, less than about 70% to about 40%, less than about 70% to about 35%, less than about 70% to about 30%, less than about 70% to about 27%, less than about 70% to about 20%, less than about 70% to about 18%, less than about 70% to about 10%, less than about 70% to about 5%, less than about 63% to about 60%, less than about 63% to about 53%, less than about 63% to about 50%, less than about 63% to about 45%, less than about 63% to about 40%, less than about 63% to about 35%, less than about 63% to about 30%, less than about 63% to about 27%, less than about 63% to about 20%, less than about 63% to about 18%, less than about 63% to about 10%, less than about 63% to about 5%, less than about 60% to about 53%, less than about 60% to about 50%, less than about 60% to about 45%, less than about 60% to about 40%, less than about 60% to about 35%, less than about 60% to about 30%, less than about 60% to about 27%, less than about 60% to about 20%, less than about 60% to about 18%, less than about 60% to about 10%, less than about 60%Attorney Docket No: 148232.001602 to about 5%, less than about 53% to about 50%, less than about 53% to about 45%, less than about 53% to about 40%, less than about 53% to about 35%, less than about 53% to about 30%, less than about 53% to about 27%, less than about 53% to about 20%, less than about 53% to about 18%, less than about 53% to about 10%, less than about 53% to about 5%, less than about 50% to about 45%, less than about 50% to about 40%, less than about 50% to about 35%, less than about 50% to about 30%, less than about 50% to about 27%, less than about 50% to about 20%, less than about 50% to about 18%, less than about 50% to about 10%, less than about 50% to about 5%, less than about 45% to about 40%, less than about 45% to about 35%, less than about 45% to about 30%, less than about 45% to about 27%, less than about 45% to about 20%, less than about 45% to about 18%, less than about 45% to about 10%, less than about 45% to about 5%, less than about 40% to about 35%, less than about 40% to about 30%, less than about 40% to about 27%, less than about 40% to about 20%, less than about 40% to about 18%, less than about 40% to about 10%, less than about 40% to about 5%, less than about 35% to about 30%, less than about 35% to about 27%, less than about 35% to about 20%, less than about 35% to about 18%, less than about 35% to about 10%, less than about 35% to about 5%, less than about 30% to about 27%, less than about 30% to about 20%, less than about 30% to about 18%, less than about 30% to about 10%, less than about 30% to about 5%, less than about 27% to about 20%, less than about 27% to about 18%, less than about 27% to about 10%, less than about 27% to about 5%, less than about 20% to about 18%, less than about 20% to about 10%, less than about 20% to about 5%, less than about 18% to about 10%, less than about 18% to about 5%, or less than about 10% to about 5% purity.

[0489] In some embodiments, the composition comprising high purity tocotrienol comprises delta-tocotrienol of at least about 63% purity.

[0490] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 90% purity.

[0491] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of at least about 90% purity.

[0492] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 95% purity.

[0493] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of at least about 95% purity.Attorney Docket No: 148232.001602

[0494] In an additional embodiment, the composition comprising high purity tocotrienol comprises delta-tocotrienol of about 63% to about 81% purity.

[0495] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 63%, at least about 70%, at least about 75%, at least about 81%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% purity.

[0496] In some embodiments, the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 30% to at least about 40%, at least about 30% to at least about 50%, at least about 30% to at least about 60%, at least about 30% to at least about 63%, at least about 30% to at least about 70%, at least about 30% to at least about 75%, at least about 30% to at least about 81%, at least about 30% to at least about 85%, at least about 30% to at least about 90%, at least about 30% to at least about 92%, at least about 30% to at least about 95%, at least about 30% to at least about 97%, at least about 30% to at least about 99%, at least about 40% to at least about 50%, at least about 40% to at least about 60%, at least about 40% to at least about 63%, at least about 40% to at least about 70%, at least about 40% to at least about 75%, at least about 40% to at least about 81%, at least about 40% to at least about 85%, at least about 40% to at least about 90%, at least about 40% to at least about 92%, at least about 40% to at least about 95%, at least about 40% to at least about 97%, at least about 40% to at least about 99%, at least about 50% to about 60%, at least about 50% to about 63%, at least about 50% to about 70%, at least about 50% to about 75%, at least about 50% to about 81%, at least about 50% to about 85%, at least about 50% to about 90%, at least about 50% to about 92%, at least about 50% to about 95%, at least about 50% to about 97%, at least about 50% to about 99%, at least about 60% to about 63%, at least about 60% to about 70%, at least about 60% to about 75%, at least about 60% to about 81%, at least about 60% to about 85%, at least about 60% to about 90%, at least about 60% to about 92%, at least about 60% to about 95%, at least about 60% to about 97%, at least about 60% to about 99%, at least about 63% to about 70%, at least about 63% to about 75%, at least about 63% to about 81%, at least about 63% to about 85%, at least about 63% to about 90%, at least about 63% to about 92%, at least about 63% to about 95%, at least about 63% to about 97%, at least about 63% to about 99%, at least about 70% to about 75%, at least about 70% to about 81%, at least about 70% to about 85%, at least aboutAttorney Docket No: 148232.001602 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 81%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 81% to about 85%, at least about 81% to about 90%, at least about 81% to about 92%, at least about 81% to about 95%, at least about 81% to about 97%, at least about 81% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% to about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99% purity.

[0497] In an additional embodiment, the composition comprising high purity tocotrienol comprises gamma-tocotrienol of about 7% to about 10% purity.

[0498] In some embodiments, the composition comprising high purity tocotrienol comprises gamma-tocotrienol of about 2%, about 4%, about 5%, about 7%, about 8%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, or about 30% purity.

[0499] In some embodiments, the composition comprising high purity tocotrienol comprises gamma-tocotrienol of about 2% to about 4%, about 2% to about 5%, about 2% to about 7%, about 2% to about 8%, about 2% to about 9%, about 2% to about 10%, about 2% to about 12%, about 2% to about 15%, about 2% to about 20%, about 2% to about 25%, about 2% to about 30%, about 4% to about 5%, about 4% to about 7%, about 4% to about 8%, about 4% to about 9%, about 4% to about 10%, about 4% to about 12%, about 4% to about 15%, about 4% to about 20%, about 4% to about 25%, about 4% to about 30%, about 5% to about 7%, about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 12%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 7% to about 8%, about 7% to about 9%, about 7% to about 10%, about 7% to about 12%, about 7% to about 15%, about 7% to about 20%, about 7% to about 25%, about 7% to about 30%, about 8% to about 9%, about 8% to about 10%, about 8% to about 12%, about 8% to about 15%, about 8% to about 20%, about 8% to about 25%, about 8% to about 30%, about 9% to about 10%, about 9% to about 12%, about 9% to about 15%, about 9% to about 20%, about 9% to about 25%,Attorney Docket No: 148232.001602 about 9% to about 30%, about 10% to about 12%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 12% to about 15%, about 12% to about 20%, about 12% to about 25%, about 12% to about 30%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 20% to about 25%, about 20% to about 30%, or about 25% to about 30% purity.

[0500] In some embodiments, the yield of tocotrienol is at least 30% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0501] In some embodiments, the yield of tocotrienol is at least 15% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0502] In some embodiments, the yield of tocotrienol is at least 20% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0503] In some embodiments, the yield of tocotrienol is at least 25% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0504] In some embodiments, the yield of tocotrienol is at least 35% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0505] In some embodiments, the yield of tocotrienol is at least 40% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0506] In some embodiments, the yield of tocotrienol is at least 45% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the compositionAttorney Docket No: 148232.001602 comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0507] In some embodiments, the yield of tocotrienol is at least 50% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0508] In some embodiments, the yield of tocotrienol is at least 60% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0509] In some embodiments, the yield of tocotrienol is at least 70% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

[0510] In some embodiments, the weight ratio of tocotrienol to the absorbent is about 1:1 to about 1:100.

[0511] In an additional embodiment, the weight ratio of tocotrienol to the absorbent is about 1:1 to about 1:10.

[0512] In an additional embodiment, the weight ratio of tocotrienol to aluminum oxide or silica gel is about 1:1, 1:3, 1:4, or 1:6.

[0513] In one embodiment, the weight ratio of tocotrienol to aluminum oxide or silica gel is about 1:4.

[0514] In some embodiments, the weight ratio of tocotrienol to the absorbent is about 1:0.5, about 1:0.75, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:50, about 1:70, about 1:90, about 1:100, about 1:120, about 1:150, or about 1:200.

[0515] In some embodiments, the weight ratio of tocotrienol to the absorbent is about 1:0.5 to about 1:0.75, about 1:0.5 to about 1:1, about 1:0.5 to about 1:2, about 1:0.5 to about 1:3, about 1:0.5 to about 1:4, about 1:0.5 to about 1:5, about 1:0.5 to about 1:6, about 1:0.5 to about 1:7, about 1:0.5 to about 1:8, about 1:0.5 to about 1:9, about 1:0.5 to about 1:10, about 1:0.5 to about 1:15, about 1:0.5 to about 1:20, about 1:0.5 to about 1:30, about 1:0.5 to about 1:50, about 1:0.5Attorney Docket No: 148232.001602 to about 1:70, about 1:0.5 to about 1:90, about 1:0.5 to about 1:100, about 1:0.5 to about 1:120, about 1:0.5 to about 1:150, about 1:0.5 to about 1:200, about 1:0.75 to about 1:1, about 1:0.75 to about 1:2, about 1:0.75 to about 1:3, about 1:0.75 to about 1:4, about 1:0.75 to about 1:5, about 1:0.75 to about 1:6, about 1:0.75 to about 1:7, about 1:0.75 to about 1:8, about 1:0.75 to about 1:9, about 1:0.75 to about 1:10, about 1:0.75 to about 1:15, about 1:0.75 to about 1:20, about 1:0.75 to about 1:30, about 1:0.75 to about 1:50, about 1:0.75 to about 1:70, about 1:0.75 to about 1:90, about 1:0.75 to about 1:100, about 1:0.75 to about 1:120, about 1:0.75 to about 1:150, about 1:0.75 to about 1:200, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1 to about 1:4, about 1:1 to about 1:5, about 1:1 to about 1:6, about 1:1 to about 1:7, about 1:1 to about 1:8, about 1:1 to about 1:9, about 1:1 to about 1:10, about 1:1 to about 1:15, about 1:1 to about 1:20, about 1:1 to about 1:30, about 1:1 to about 1:50, about 1:1 to about 1:70, about 1:1 to about 1:90, about 1:1 to about 1:100, about 1:1 to about 1:120, about 1:1 to about 1:150, about 1:1 to about 1:200, about 1:2 to about 1:3, about 1:2 to about 1:4, about 1:2 to about 1:5, about 1:2 to about 1:6, about 1:2 to about 1:7, about 1:2 to about 1:8, about 1:2 to about 1:9, about 1:2 to about 1:10, about 1:2 to about 1:15, about 1:2 to about 1:20, about 1:2 to about 1:30, about 1:2 to about 1:50, about 1:2 to about 1:70, about 1:2 to about 1:90, about 1:2 to about 1:100, about 1:2 to about 1:120, about 1:2 to about 1:150, about 1:2 to about 1:200, about 1:3 to about 1:4, about 1:3 to about 1:5, about 1:3 to about 1:6, about 1:3 to about 1:7, about 1:3 to about 1:8, about 1:3 to about 1:9, about 1:3 to about 1:10, about 1:3 to about 1:15, about 1:3 to about 1:20, about 1:3 to about 1:30, about 1:3 to about 1:50, about 1:3 to about 1:70, about 1:3 to about 1:90, about 1:3 to about 1:100, about 1:3 to about 1:120, about 1:3 to about 1:150, about 1:3 to about 1:200, about 1:4 to about 1:5, about 1:4 to about 1:6, about 1:4 to about 1:7, about 1:4 to about 1:8, about 1:4 to about 1:9, about 1:4 to about 1:10, about 1:4 to about 1:15, about 1:4 to about 1:20, about 1:4 to about 1:30, about 1:4 to about 1:50, about 1:4 to about 1:70, about 1:4 to about 1:90, about 1:4 to about 1:100, about 1:4 to about 1:120, about 1:4 to about 1:150, about 1:4 to about 1:200, about 1:5 to about 1:6, about 1:5 to about 1:7, about 1:5 to about 1:8, about 1:5 to about 1:9, about 1:5 to about 1:10, about 1:5 to about 1:15, about 1:5 to about 1:20, about 1:5 to about 1:30, about 1:5 to about 1:50, about 1:5 to about 1:70, about 1:5 to about 1:90, about 1:5 to about 1:100, about 1:5 to about 1:120, about 1:5 to about 1:150, about 1:5 to about 1:200, about 1:6 to about 1:7, about 1:6 to about 1:8, about 1:6 to about 1:9, about 1:6 to about 1:10, about 1:6 to about 1:15, about 1:6 to about 1:20, about 1:6 to about 1:30, about 1:6 to about 1:50, about 1:6Attorney Docket No: 148232.001602 to about 1:70, about 1:6 to about 1:90, about 1:6 to about 1:100, about 1:6 to about 1:120, about 1:6 to about 1:150, about 1:6 to about 1:200, about 1:7 to about 1:8, about 1:7 to about 1:9, about 1:7 to about 1:10, about 1:7 to about 1:15, about 1:7 to about 1:20, about 1:7 to about 1:30, about 1:7 to about 1:50, about 1:7 to about 1:70, about 1:7 to about 1:90, about 1:7 to about 1:100, about 1:7 to about 1:120, about 1:7 to about 1:150, about 1:7 to about 1:200, about 1:8 to about 1:9, about 1:8 to about 1:10, about 1:8 to about 1:15, about 1:8 to about 1:20, about 1:8 to about 1:30, about 1:8 to about 1:50, about 1:8 to about 1:70, about 1:8 to about 1:90, about 1:8 to about 1:100, about 1:8 to about 1:120, about 1:8 to about 1:150, about 1:8 to about 1:200, about 1:9 to about 1:10, about 1:9 to about 1:15, about 1:9 to about 1:20, about 1:9 to about 1:30, about 1:9 to about 1:50, about 1:9 to about 1:70, about 1:9 to about 1:90, about 1:9 to about 1:100, about 1:9 to about 1:120, about 1:9 to about 1:150, about 1:9 to about 1:200, about 1:10 to about 1:15, about 1:10 to about 1:20, about 1:10 to about 1:30, about 1:10 to about 1:50, about 1:10 to about 1:70, about 1:10 to about 1:90, about 1:10 to about 1:100, about 1:10 to about 1:120, about 1:10 to about 1:150, about 1:10 to about 1:200, about 1:15 to about 1:20, about 1:15 to about 1:30, about 1:15 to about 1:50, about 1:15 to about 1:70, about 1:15 to about 1:90, about 1:15 to about 1:100, about 1:15 to about 1:120, about 1:15 to about 1:150, about 1:15 to about 1:200, about 1:20 to about 1:30, about 1:20 to about 1:50, about 1:20 to about 1:70, about 1:20 to about 1:90, about 1:20 to about 1:100, about 1:20 to about 1:120, about 1:20 to about 1:150, about 1:20 to about 1:200, about 1:30 to about 1:50, about 1:30 to about 1:70, about 1:30 to about 1:90, about 1:30 to about 1:100, about 1:30 to about 1:120, about 1:30 to about 1:150, about 1:30 to about 1:200, about 1:50 to about 1:70, about 1:50 to about 1:90, about 1:50 to about 1:100, about 1:50 to about 1:120, about 1:50 to about 1:150, about 1:50 to about 1:200, about 1:70 to about 1:90, about 1:70 to about 1:100, about 1:70 to about 1:120, about 1:70 to about 1:150, about 1:70 to about 1:200, about 1:90 to about 1:100, about 1:90 to about 1:120, about 1:90 to about 1:150, about 1:90 to about 1:200, about 1:100 to about 1:120, about 1:100 to about 1:150, about 1:100 to about 1:200, about 1:120 to about 1:150, about 1:120 to about 1:200, or about 1:150 to about 1:200.

[0516] In some embodiments, the purity of tocotrienol is measured by gas chromatography based on the ratio of the peak area of tocotrienol over the total area of all peaks.

[0517] In some embodiments, the composition comprising low purity tocotrienol in step a) is obtained from extracts of Bixa orellana seed components.Attorney Docket No: 148232.001602

[0518] In some embodiments, the composition comprising low purity tocotrienol is obtained from extracts of vegetable oil.

[0519] In an additional embodiment, the vegetable oil is rice bran, soybean, sesame, or palm oil. Compositions of High Purity Tocotrienol

[0520] Provided herein is a composition comprising high purity tocotrienol prepared by the any one of the methods as described herein.

[0521] In some embodiments, the composition further comprises limonene and / or geranylgeraniol.

[0522] In some embodiments, the composition is free of ethanol.

[0523] Provided herein is a composition comprising tocotrienol of at least about 40% purity.

[0524] In some embodiments, the composition comprises tocotrienol of at least about 70% purity.

[0525] In some embodiments, the composition comprises tocotrienol of at least about 80% purity.

[0526] In some embodiments, the composition comprises tocotrienol of at least about 90% purity.

[0527] In some embodiments, the composition comprises tocotrienol of at least about 95% purity.

[0528] In some embodiments, the composition comprises tocotrienol of at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% purity.

[0529] In some embodiments, the composition comprises tocotrienol of at least about 30% to at least about 40%, at least about 30% to at least about 50%, at least about 30% to at least about 60%, at least about 30% to at least about 70%, at least about 30% to at least about 75%, at least about 30% to at least about 80%, at least about 30% to at least about 85%, at least about 30% to at least about 90%, at least about 30% to at least about 92%, at least about 30% to at least about 95%, at least about 30% to at least about 97%, at least about 30% to at least about 99%, at least about 40% to at least about 50%, at least about 40% to at least about 60%, at least about 40% to at least about 70%, at least about 40% to at least about 75%, at least about 40% to at least aboutAttorney Docket No: 148232.001602 80%, at least about 40% to at least about 85%, at least about 40% to at least about 90%, at least about 40% to at least about 92%, at least about 40% to at least about 95%, at least about 40% to at least about 97%, at least about 40% to at least about 99%, at least about 50% to about 60%, at least about 50% to about 70%, at least about 50% to about 75%, at least about 50% to about 80%, at least about 50% to about 85%, at least about 50% to about 90%, at least about 50% to about 92%, at least about 50% to about 95%, at least about 50% to about 97%, at least about 50% to about 99%, at least about 60% to about 70%, at least about 60% to about 75%, at least about 60% to about 80%, at least about 60% to about 85%, at least about 60% to about 90%, at least about 60% to about 92%, at least about 60% to about 95%, at least about 60% to about 97%, at least about 60% to about 99%, at least about 70% to about 75%, at least about 70% to about 80%, at least about 70% to about 85%, at least about 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 80%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 80% to about 85%, at least about 80% to about 90%, at least about 80% to about 92%, at least about 80% to about 95%, at least about 80% to about 97%, at least about 80% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% to about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99% purity.

[0530] In some embodiments, the tocotrienol comprises delta-tocotrienol, gamma-tocotrienol, or a combination thereof.

[0531] In some embodiments, the tocotrienol comprises delta-tocotrienol and gamma- tocotrienol at a ratio of about 9:1.

[0532] In some embodiments, the tocotrienol comprises delta-tocotrienol and gamma- tocotrienol at a ratio of about 0.5:9.5, about 1:9, about 2:8, about 3:7, about 4:6, about 5:5, about 6:4, about 7:3, about 8:2, about 9:1, or about 9.5:0.5.Attorney Docket No: 148232.001602

[0533] In some embodiments, the tocotrienol comprises delta-tocotrienol and gamma- tocotrienol at a ratio of about 0.5:9.5 to about 1:9, about 0.5:9.5 to about 2:8, about 0.5:9.5 to about 3:7, about 0.5:9.5 to about 4:6, about 0.5:9.5 to about 5:5, about 0.5:9.5 to about 6:4, about 0.5:9.5 to about 7:3, about 0.5:9.5 to about 8:2, about 0.5:9.5 to about 9:1, about 0.5:9.5 to about 9.5:0.5, about 1:9 to about 2:8, about 1:9 to about 3:7, about 1:9 to about 4:6, about 1:9 to about 5:5, about 1:9 to about 6:4, about 1:9 to about 7:3, about 1:9 to about 8:2, about 1:9 to about 9:1, about 1:9 to about 9.5:0.5, about 2:8 to about 3:7, about 2:8 to about 4:6, about 2:8 to about 5:5, about 2:8 to about 6:4, about 2:8 to about 7:3, about 2:8 to about 8:2, about 2:8 to about 9:1, about 2:8 to about 9.5:0.5, about 3:7 to about 4:6, about 3:7 to about 5:5, about 3:7 to about 6:4, about 3:7 to about 7:3, about 3:7 to about 8:2, about 3:7 to about 9:1, about 3:7 to about 9.5:0.5, about 4:6 to about 5:5, about 4:6 to about 6:4, about 4:6 to about 7:3, about 4:6 to about 8:2, about 4:6 to about 9:1, about 4:6 to about 9.5:0.5, about 5:5 to about 6:4, about 5:5 to about 7:3, about 5:5 to about 8:2, about 5:5 to about 9:1, about 5:5 to about 9.5:0.5, about 6:4 to about 7:3, about 6:4 to about 8:2, about 6:4 to about 9:1, about 6:4 to about 9.5:0.5, about 7:3 to about 8:2, about 7:3 to about 9:1, about 7:3 to about 9.5:0.5, about 8:2 to about 9:1, about 8:2 to about 9.5:0.5, or about 9:1 to about 9.5:0.5.

[0534] In some embodiments, the tocotrienol is delta-tocotrienol.

[0535] In some embodiments, the tocotrienol comprises at least about 90% delta-tocotrienol.

[0536] In some embodiments, the tocotrienol comprises at least about 95% delta-tocotrienol.

[0537] In some embodiments, the tocotrienol consists essentially of delta-tocotrienol.

[0538] In some embodiments, the tocotrienol is gamma-tocotrienol.

[0539] In some embodiments, the tocotrienol comprises at least about 90% gamma-tocotrienol.

[0540] In some embodiments, the tocotrienol comprises at least about 95% gamma-tocotrienol.

[0541] In some embodiments, the tocotrienol consists essentially of gamma-tocotrienol.

[0542] In some embodiments, the composition is free of alpha-tocopherol.

[0543] In some embodiments, the composition comprises tocotrienol of at least about 40% purity, and the weight ratio of gamma-tocotrienol to delta-tocotrienol is up to about 1: 9.

[0544] In some embodiments, the composition comprises tocotrienol of at least about 70% purity, and the weight ratio of gamma-tocotrienol to delta-tocotrienol is up to about 1: 9.

[0545] In some embodiments, the composition comprises tocotrienol of at least about 90% purity, and the weight ratio of gamma-tocotrienol to delta-tocotrienol is up to about 1: 9.Attorney Docket No: 148232.001602

[0546] In some embodiments, the composition comprises tocotrienol of at least about 40%, at least about 70%, at least about 80%, at least about 90% purity, and the weight ratio of gamma- tocotrienol to delta-tocotrienol is up to about 20:80, 1:9.5:95, or 1:99.

[0547] In some embodiments, the composition comprises tocotrienol of at least about 40%, at least about 70%, at least about 80%, at least about 90% purity, and the weight ratio of gamma- tocotrienol to delta-tocotrienol is about 0:100 to about 1:9, about 1:99 to about 1:9, about 5:95 to about 1:9, or about 1:99 to about 1:9. In some embodiments, the composition is obtained from annatto extracts. In some embodiments, the composition is obtained from annatto seed extracts.

[0548] In some embodiments, the composition comprises tocotrienol of at least about 40%, at least about 70%, at least about 80%, at least about 90% purity, and the weight ratio of gamma- tocotrienol to delta-tocotrienol is about 20: 80 to about 9:1, about 1:9 to about 9:1, about 5:95 to about 9: 1, about 1:99 to about 9:1, or about 0:100 to about 9:1. In some embodiments, the composition is obtained from palm oil extracts.

[0549] In some embodiments, the tocotrienol comprises at least about 70%, at least about 75%, at least about 81%, at least about 85%, at least about 90%, at least about 92%, at least about 95%, at least about 97%, or at least about 99% delta-tocotrienol.

[0550] In some embodiments, the tocotrienol comprises at least about 70% to about 75%, at least about 70% to about 81%, at least about 70% to about 85%, at least about 70% to about 90%, at least about 70% to about 92%, at least about 70% to about 95%, at least about 70% to about 97%, at least about 70% to about 99%, at least about 75% to about 81%, at least about 75% to about 85%, at least about 75% to about 90%, at least about 75% to about 92%, at least about 75% to about 95%, at least about 75% to about 97%, at least about 75% to about 99%, at least about 81% to about 85%, at least about 81% to about 90%, at least about 81% to about 92%, at least about 81% to about 95%, at least about 81% to about 97%, at least about 81% to about 99%, at least about 85% to about 90%, at least about 85% to about 92%, at least about 85% to about 95%, at least about 85% to about 97%, at least about 85% to about 99%, at least about 90% to about 92%, at least about 90% to about 95%, at least about 90% to about 97%, at least about 90% to about 99%, at least about 92% to about 95%, at least about 92% to about 97%, at least about 92% to about 99%, at least about 95% to about 97%, at least about 95% to about 99%, or at least about 97% to about 99% delta-tocotrienol.Attorney Docket No: 148232.001602

[0551] In some embodiments, the purity of tocotrienol is measured by gas chromatography based on the ratio of the peak area of tocotrienol over the total area of all peaks.

[0552] In some embodiments, the start material is the composition comprising low purity tocotrienol obtained from chemical synthesis, fermentation biosynthesis, or extraction of natural sources.

[0553] In some embodiments, the composition comprising low purity tocotrienol is obtained from the byproduct solution of Bixa orellana seed components.

[0554] In some embodiments, the byproduct solution of Bixa orellana seed components comprises natural annatto extracts.

[0555] In some embodiments, the composition is obtained from annatto extracts.

[0556] In some embodiments, the composition is obtained from extracts of linseed oil, Cedrela toona wood, or palm oil.

[0557] In some embodiments, the start material is the composition comprising low purity tocotrienol obtained from annatto extracts, extracts of linseed oil, Cedrela toona wood, or palm oil, or the further purified composition based on the purification method known in the art or in the present disclosure. In some embodiments, the start material is 0.01-1kg. In some embodiments, the start material is 1-100 kg. In some embodiments, the start material is 100-1000 kg. In some embodiments, the start material is 1000-10000 kg. Compositions of High Purity Tocotrienol and High Purity Geranylgeraniol

[0558] Provided herein is a composition comprising high purity geranylgeraniol prepared by any one of the methods as described herein and high purity tocotrienol prepared by any one of the methods as described herein.

[0559] In some embodiments, high purity geranylgeraniol consists essentially of trans- geranylgeraniol and high purity tocotrienol consists essentially of delta-tocotrienol.

[0560] In some embodiments, high purity geranylgeraniol consists essentially of trans- geranylgeraniol and high purity tocotrienol consists essentially of gamma-tocotrienol.

[0561] In some embodiments, high purity geranylgeraniol consists essentially of cis- geranylgeraniol and high purity tocotrienol consists essentially of delta-tocotrienol.

[0562] In some embodiments, high purity geranylgeraniol consists essentially of cis- geranylgeraniol and high purity tocotrienol consists essentially of gamma-tocotrienol.

[0563] In some embodiments, the composition is free of ethanol.Attorney Docket No: 148232.001602

[0564] In some embodiments, the composition comprises at least about 40%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98% of geranylgeraniol and less than about 1% of tocotrienol. The tocotrienol functions as an antioxidant to stabilize the composition.

[0565] In some embodiments, the composition comprises ultra-high purity of geranylgeraniol, and less than about 1% of tocotrienol.

[0566] In some embodiments, the composition comprises ultra-high purity of geranylgeraniol, and less than about 1% of tocotrienol, wherein the geranylgeraniol consists essentially of trans- geranylgeraniol.

[0567] In some embodiments, the composition comprises at least about 40%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98% of geranylgeraniol and less than about 1% of tocotrienol, wherein the geranylgeraniol consists essentially of trans-geranylgeraniol.

[0568] In some embodiments, the composition comprises at least about 40% of geranylgeraniol and less than about 1% of tocotrienol, wherein the geranylgeraniol consists essentially of trans-geranylgeraniol, wherein the composition further comprises. Uses of Compositions of Tocotrienol

[0569] Provided herein is a method, the method comprising: i. causing an antioxidant, anti-inflammatory, hypolipidemic, or neuroprotective effect; ii. reducing atherogenic apolipoprotein B, lipoprotein(a) (Lpa), triglyceride (TG), and / or low-density lipoprotein (LDL) plasma levels; iii. suppressing cholesterol level; iv. inducing apoptosis of breast cancer cells or prostate cancer cells; v. protecting normal cells in radiation oncology; vi. preventing or treating pre-diabetes, Type 2 diabetes, or metabolic syndrome; vii. preventing or treating ovarian cancer, pancreatic cancer, or colon cancer; viii. preventing or treating a Non-Alcoholic Fatty Liver Disease (NAFLD); ix. preventing or treating genetic, epilepsy, or neurologic disorders; x. preventing or treating brain trauma or strokes; orAttorney Docket No: 148232.001602 xi. preventing or treating inflammation-associated diseases, cardiovascular disease, or cancer, in a subject in need of, comprising administering to the subject in need of the composition comprising high purity tocotrienol as described herein or a composition comprising high purity tocotrienol prepared according to any one of the methods as described herein. Uses of Compositions of Geranylgeraniol

[0570] Provided herein is a method, the method comprising: i. promoting the maintenance and growth of skeletal muscle proteins; ii. preventing or treating Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ); iii. preventing or treating Statin-Associated Muscle Symptoms (SAMS), sarcopenia, preventing loss of muscle, or maintaining muscle mass; iv. promoting or increasing muscle force production and / or energy production; v. promoting or increasing the biosynthesis of CoQ10, MK-4, and / or testosterone; vi. promoting or increasing bone mineralization or density; vii. preventing or treating calcified atherosclerosis, kidney stone, biliary stone, gallstone, osteopenia, or osteoporosis; viii. increasing vitamin K-dependent proteins (VKDP), osteocalcin, Matrix Gla Protein (MGP); ix. reversing depressive symptoms and improving cognitive memory; x. promoting or increasing the conversion of white adipose tissue (WAT) to brown tissue (BAT); xi. maintaining and regulating body temperature and blood sugar; or xii. boosting immunity and reducing pain, in a subject in need of, comprising administering to the subject in need of the composition comprising high purity geranylgeraniol as described herein or a composition comprising high purity geranylgeraniol prepared according to any one of the methods as described herein.Attorney Docket No: 148232.001602 EXAMPLES

[0571] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. Example 1. Determining GG and T3 Concentrations GC-FID, GC / MS, and Relative Response Factor (RRF)

[0572] Relative Response Factors (RRF) are used to calculate the concentration of a compound in a sample. The RRF is determined via gas chromatographs with flame ionization detection '73*694( ?K?IVPGP A?IARI?QGLKP @?PCB LK ?K GKQCOK?I PQ?KB?OB '9<() G+C+) PNR?ICKC 'Y21& <GEJ?() as used herein. Herein, the determination of the RRF of geranylgeraniol (GG), delta-tocotrienol (delta-T3), and gamma-tocotrienol (gamma-T3) are used in calculations of compound concentration in numerous analysis.

[0573] The calculation used to determine the RRF (of a compound) is: ,) G0H +419 (@41 G0H +419 (@41 G-?H ,,) F = / ' ' ? with theRF = response factor = peak area / concentration; X = compound of interest (i.e., GG, delta-T3, gamma-T3, etc.); and Sq = squalene (the internal standard).

[0574] Further, the calculation used to determine the percentage of a component is: +419 (@41 (0) / 4867A (*-) 0& F ,,) ' & ' +B@8AE (*-) ' *- 38:BA8=< 512A=@ +419 (@41(*-) / 4867A(0)with X =and IS = internal standard (i.e., squalene). Determining the GG Concentration

[0575] The experimental protocol to determine the geranylgeraniol concentration using relative response factor is as follows:Attorney Docket No: 148232.001602 1. Three different levels (high, medium, and low) of GG samples were prepared by weighing out 0.0570g, 0.0400g, and 0.0220g GG standard (Sigma’s Spec. >85%, Certificate of Analysis (CoA) 96%) in 10mL volumetric flasks; 2. 1.2500g squalene was weighed out in 25mL hexane (50mg / mL) as internal standard; 3. 1mL squalene as internal standard was added to the samples, and the volume was brought to 10mL; 4. Each level (high, medium, and low) underwent two independently weighed and prepared replicates, and each replicate was injected twice into each GC; 5. The response factors of squalene and GG of each injection were obtained by dividing the peak area by the corresponding concentration; 6. Relative response factors were obtained by dividing the response factor of squalene by the response factor of GG; 7. The relative standard deviation (RSD) was less than 1% between two injections of the same sample, between two replicates of the same level, and amongst the three different levels; 8. Relative response factors were used in the calculation of GG concentration. Determining the T3 Concentration

[0576] Here is the experimental protocol used to determine the tocotrienol and the tocotrienol isomer concentrations using relative response factor: 1. Three different levels (high, medium, and low) of T3 samples were prepared by weighing out 0.1000g, 0.0550g, and 0.0220g T3 standard (delta-T3 = 64.00%, gamma-T3 = 7.26%) in 10mL volumetric flasks; 2. 1.2500g squalene was weighed out in 25mL hexane (50mg / mL) as internal standard; 3. 1mL squalene as internal standard was added to the samples, and the volume was brought to 10mL; 4. Each level (high, medium, and low) underwent two independently weighed and prepared replicates, and each replicate was injected twice into each GC; 5. The response factors of squalene, delta-T3, and gamma-T3 of each injection were obtained by dividing the peak area by the corresponding concentration; 6. Relative response factors were obtained by dividing the response factor of squalene by the response factor of delta-T3 or gamma-T3;Attorney Docket No: 148232.001602 7. The relative standard deviation (RSD) was less than 1% between two injections of the same sample, between two replicates of the same level, and among the three different levels; 8. Relative response factors were used in the calculation of delta-T3 and gamma-T3 concentrations. Example 2. Crude Material

[0577] The GG or T3 compositions used as the start materials herein are annatto extracts obtained from an extraction and purification process from annatto seeds. The extraction and purification processes are described in US 6,350,453 (Tan, B. and Foley, J., 2002), which is incorporated by reference herein in its entirety. The annatto extracts are comprised of trans- geranylgeraniol and delta- / gamma-tocotrienols. A few other components found within the extract are cis-geranylgeraniol isomers, and other terpenoids. The components have boiling points that are close to each other, making separation difficult or impossible when using molecular distillation. For example, the cyclotetradecatriene has a boiling point close to GG; simultaneous extraction of cyclotetradecatriene with GG is an issue when using molecular distillation to obtain GG fractions. The present disclosure addresses this difficulty using the purification processes described below; the end purity of GG or T3 is significantly different and improved from what was disclosed in US 6,350,453. Ultra-high purity can be achieved for the end purity of GG, T3, and any of their isomers. The purification processes in the present disclosure can also be used to refine and purify other oils. Example 3. Purification of GG Example 3.1 Purification of GG by Fractional Distillation

[0578] The fractional distillation setup included a 500mL round-bottomed, three-necked, flask containing the feed material and a small magnetic stir bar that was placed in a heating mantle on top of a magnetic stir plate to create agitation. Connected in the two side necks were two temperature reading devices. One temperature reading device controlled the variable adapter, monitoring the temperature at the bottom of the pot and adjusting the mantle heat as necessary (this temperature reading was used to determine the “Pot Temp”). The other temperature reading device was a thermometer reading the top portion and airspace directly above the material. A vacuum sealed, silvered Vigreux column was attached to the center neck (approximately 15 theoretical plates). At the top of this was attached the distillation head equipped with a coldAttorney Docket No: 148232.001602 finger to condense the distillate, a flask to receive the fractioned material, a vacuum valve to control the removal of the flask, and a thermometer placed at the point where the column and the distillation head meet (this temperature reading was used to determine the “Head Temp”). Vacuum was pulled through the head apparatus and any volatiles not condensed by the cold finger were condensed before entering the vacuum pump by a liquid nitrogen cooled cold trap located at the end of the air line running from the distillation head. All vacuum readings were made at the junction between this cold trap and the hose that led directly into the vacuum pump.

[0579] Different fractions were collected when there was a significant sudden change in the Head Temp (indicating a change of species distilling) or when there was a distinct color change occurred in the distillate. Example 3.1.1 – Purification of a Composition of 12.46% GG purity

[0580] The crude material was obtained according to Example 2. The GG purity in the crude is 12.46%. The 390 g crude is used as the start material. Nine fractions were collected over the course of 705 minutes of run time. Measurements were taken approximately every 15 minutes. Vacuum was maintained at approximately 0.3-0.4 Torr throughout the entire process. It is unexpected to obtain end product of over 70% GG purity and an over 58% purity increase from the start material to end product. Table 1. Fraction collection and conditions in Example 3.1.1 Pot Temp Head Temp Vac Fraction GG% (°C) (°C) (T rr)Attorney Docket No: 148232.001602 Example 3.1.2 – Purification of a Composition of 26.52% GG purity

[0581] The crude material was obtained according to Example 2, and further purified (by the methods disclosed in US 6,350,453 or in the present disclosure) to have 26.52% GG purity as the start material of this example (390 g). Fourteen fractions were collected over the course of 710 minutes of run time. Measurements were taken approximately every 15 minutes. Vacuum was maintained at approximately 0.3-0.4 Torr throughout the entire process. The pot had achieved 50% GG purity during Fraction 7, and Fractions 1112-14 were all above 70% GG purity with Fractions 13 and 14 in particular reaching above 90% GG purity. It is unexpected to obtain end product of over 90% GG purity and an over 63% purity increase from the start material to end product. Table 2. Fraction collection and conditions in Example 3.1.2 POT HEAD VAC Example 3.1.3 – PurAttorney Docket No: 148232.001602

[0582] The crude material was obtained according to Example 2, and further purified (by the methods disclosed in US 6,350,453 or in the present disclosure) to have 52.70% GG purity as the start material of this example (389 g). The fractional distillation was successful in bringing the purity to above ~50% within ~500 min of run time. It is unexpected to obtain end product of over 80% GG purity and an over 27% purity increase from the start material to end product. Table 3. Fraction collection and conditions in Example 3.1.3 POT

[0583] Measur mp neared 140°C, GG begag p . p d on until approximately 200g of fractions were obtained. Example 3.1.4 – Purification of a Composition of 73.02% GG purity

[0584] The crude material was obtained according to Example 2, and further purified (by the methods disclosed in US 6,350,453 or in the present disclosure) to have 73.02% GG purity as the start material of this example (390.6g). Nine fractions were collected over the course of 445 minutes of run time. Measurements were taken approximately every 15 minutes. Vacuum was maintained at approximately 0.3-0.4 Torr throughout the entire process. Fractions 6 through 7 achieved over 80% GG purity and Fraction 8 and 9 achieved over 97% GG purity. It is unexpected to obtain end product of over 97% GG purity and an over 24% purity increase from the start material to end product.Attorney Docket No: 148232.001602 Table 4. Fraction collection and conditions in Example 3.1.4 % Example 3.1.5 – Pur

[0585] The crude material was obtained according to Example 2, and further purified (by the methods disclosed in the present disclosure) to have 94.70% GG purity as the start material of this example (400g). Nine fractions were collected over the course of 641 minutes of run time. Measurements were taken approximately every 15 minutes. Vacuum was maintained at approximately 0.2-0.4 Torr throughout the entire process. Fractions 6 through 7 combined achieved about 90% GG purity and Fraction 8 and 9 combined achieved about 98% GG purity. It is unexpected to obtain end product of over 98% GG purity and a 4% purity increase from the start material (with an exceedingly high GG purity of about 95%) to end product. Table 5. Fraction collection and conditions in Example 3.1.5 POT HEAD VAC FRACTION TEMP TEMP %GG % % % %Attorney Docket No: 148232.001602 % % % % %

[0586] Fractional distillation allows for obtaining the desired GG component in a lower distillation temperature. In the crude material, trans- to cis-GG ratio is 98:2. In all Examples described above, the GG in the end product consists essentially of trans-GG. In a fraction of the highest trans- to cis-GG ratio, trans- to cis-GG ratio is at least 99.9:0.1. Cis-GG is thermodynamically more stable in high temperature evidenced by the trans-to-cis isomerization of GG in high temperature. Thus, it is unexpected to achieve separation of trans- and cis-GG and attain the final composition consisting essentially of trans-GG.

[0587] The yields of trans-GG in each of the Examples are shown in Table 5A. The yield of the fraction(s) of above 70% trans-GG purity is based on the percentage of the total trans-GG amount in each of the fractions of at least 70% trans-GG purity over the total amount of GG in the start material. The yield of the fraction(s) of other purity level is calculated in the same way. “Total Recovery” means the percentage of the total trans-GG amount in all collected fractions over the total amount of trans-GG in the start material. The yields of 70% trans-GG purity are above 60%. The yields of 90% trans-GG purity (i.e., the composition consisting essentially of trans-GG) are above 35%. Table 5A. Yields of trans-GG Example Fraction(s) of Fraction(s) of Fraction(s) of Total Recovery above 70% Above 80% Above 90% (trans-GG) chemicalsynthesis and fermentation biosynthesis. Fractional distillation can process starting material onAttorney Docket No: 148232.001602 the scale of grams to hundreds of kilograms and the process can be finished in hours, while chemical synthesis and fermentation biosynthesis may take days to complete. Drawbacks to chemical synthesis are the extensive synthesis steps and purification procedures to obtain high yield and purity of product. Upon chemical synthesis, purification by (commonly) chromatography involves solvent recovery in large amounts, the procedure of which is complicated with low yield and not suitable for industrial application. Purification by distillation is considered extremely difficult because of the high boiling points of GG and T3 and the possibility of trans-to-cis isomerization of GG at high temperatures. Drawbacks to fermentation biosynthesis are the large amount of unwanted biomass being produced and the yield is at best low. Invariably, all GG and T3 products contain genetically modified materials rather than nature-derived nutrients. Furthermore, solvent usage and subsequent recovery are required for biomass extraction, which would lead to product loss. Fractional distillation does not have these drawbacks. It does not require any synthesis or purification by chromatography involving solvent recovery. Nor does it involve unwanted biomass or genetically modified materials. The T3 or GG purity can be improved from 30% to 80%, more preferably 20% to 90%, and most preferably 10% to high than 99.5 % or even approaching the absolute 100% purity through one or multiple passes of fractional distillation. Remarkably, fractional distillation can improve product yield and purity, not only to GG or T3, but also to trans-GG or delta-T3 specifically. Delta- and gamma-T3 have very similar molecular weights. Trans- and cis-GG have the same molecular weight. Based on the close boiling points and close molecular structures of delta- and gamma-T3 and of trans- and cis-GG, one skilled in the art would not expect improved purity of trans-GG or delta-T3 (shown below). Example 3.2 Purification of GG by Liquid-Solid Extraction (LSE) in a Container

[0589] This example sets forth a purification method of GG by utilizing liquid-solid extraction (LSE) in a container. The procedure of purification was performed in the following steps: 1. 10 g crude material were added to an absorbent and 100 mL hexane to form a mixture in an Erlenmeyer flask; 2. The mixture was stirred at 120 rpm for 60 min; 3. The mixture was filtered by rinsing the solid phase with hexane. The solid phase bounded with GG (as demonstrated by a yellow color) was transferred to a new flask for step 4; 4. 100 mL grain alcohol (95% v / v ethanol) was added to the flask from step 3;Attorney Docket No: 148232.001602 5. The mixture was stirred at 120 rpm for 60 min; 6. The mixture was filtered and the liquid fraction (yellow) was collected; 7. A rotary evaporator was used to remove ethanol and water from the liquid fraction; 8. The concentration of GG was analyzed in the sample acquired from step 7 using gas chromatography.

[0590] In step 1 above, various start materials of different purities of GG were used for purification, including GG40 (40% GG purity), GG48 (48% GG purity), GG75 (75% GG purity), and GG38 (38% GG purity). The “%” refers to weight percentage if not otherwise noted. In each experiment, only one type of GG was added for purification. The absorbent used in step 1 was either aluminum oxide or silica gel. Three types of aluminum oxide were used, including neutral, basic, and acidic aluminum oxide. In each experiment, only one type of aluminum oxide was used. The type of GG and absorbent used in each experiment and their weight ratios are listed in the tables below. The purity and yield data were measured in these tables.

[0591] The gas chromatography protocol for GG analysis used at step 4 and step 9 is described.50-100 mg of the sample comprising GG was mixed with 1 mL squalene as internal standard (50 mg / mL) and diluted with hexane. The sample was analyzed with Agilent 7820A 73*694) RPGKE 5NRGQV*- ALIRJK ' / , J U .0, \J U ,+.0 \J(+ =FC GKHCAQLO QCJMCO?QROC T?P PCQ ?Q 280°C. Helium was used as the carrier gas. The column oven temperature was started at 200°C, increased to 340°C at 10°C / min, and was held at 340°C for 6.5 min. FID detector was used at 340°C, H2flow was at 40mL / min, and air flow was at 400mL / min. Concentration of GG was quantified using relative response factor. RRF calculations determine the purity of the GG sample using a GC-FID and standards as described above. Table 6. GG analysis using GC-FID (with squalene) Retention Time (min) Peak Area%Attorney Docket No: 148232.001602Table 7. GG analysis using GC-FID (without squalene) Retention Time

[0592] The purity and yield data for GG40 purified by the above procedure is presented in Table 8. The neutral, basic, and acidic aluminum oxides were used respectively. Table 8. The purity and yield data for GG40 Absorbent GG:Absorbent GG purity GG yield (w / w) (w%) de (neutral, basic, and w / w) GG to aluminumoxide, all three types produced similar final GG purity. GG had lower yield when purified by acidic aluminum oxide. When less aluminum oxide is used (1:3), the same final GG purity was achieved, while the yield was lower. Therefore, neutral and basic aluminum oxide are theAttorney Docket No: 148232.001602 preferred absorbents due to their higher yields. The ratio between GG and aluminum oxide does not seem to affect the final GG purity.

[0594] The purity and yield data for GG48 purified by the above procedure is presented in Table 9. Table 9. The purity and yield data for GG48 Absorbent GG:Absorbent GG purity GG yield, basic, and acidic), similar findings to GG40 were made for GG48. As for silica gel, the final GG purity was lower and the GG yield was slightly higher compared to aluminum oxide.

[0596] The purity and yield data for GG75 purified by the above procedure is presented in Table 10. Table 10. The purity and yield data for GG75 Absorbent GG:Absorbent GG purity GG yield (w%) (w / w)Attorney Docket No: 148232.001602

[0597] Surprisingly, the purification method using neutral aluminum oxide yielded high purity GG, and the method improves the GG purity from 75% to 92-96%. With a 1:6 (w / w) ratio of GG to aluminum oxide, GG has a high yield at 68%. This result is unexpected because previous trials involving silica and activated charcoal did not produce the same yield, although in theory were expected to have elicited similar results due to their absorbency. The unexpected result is that aluminum oxide works to achieve GG purity above 95% while other methods do not.

[0598] The purity and yield data for GG38 purified by the above procedure is presented in Table 11. Table 11. The purity and yield data for GG38 Absorbent GG:Absorbent GG purity at GG purity at GG yield at (w / w) ste 4 ste 9 ste 9 (w%), and the recovery in the ethanol fraction was 70% 78.9%. In the production using molecular distillation (Tan, B. and Foley, J., Tocotrienols and Geranylgeraniol from Bixa Orellana byproducts, U.S. Pat. No.6350453B1, 2002), on the other hand, in order to get 75% product, the final recovery was shown to be as low as 30%.Attorney Docket No: 148232.001602

[0600] In the LSE, a column may not be needed. LSE in a container can lead to fast equilibrium and efficient conversion to a high purity product. This setup is surprisingly simple. The evaporation increases efficiency for solvent recovery. The solids and liquids can be reused repeatedly. The LSE process can be scaled infinitely because alumina is a “slurry” mixture to ensure a uniform mixture. Example 3.3 Purification of GG via Liquid-Solid Extraction (LSE) by Column Chromatography

[0601] The procedure used to purify GG with silicaperformed as follows: 1. 10 g GG75 was loaded to 40 g Redisep Rf Gold high performance column; 2. The sample was eluted with mobile phase A (hexane) until the blue fraction was completely eluted out and the collection became colorless; 3. The sample was then eluted with mobile phase B (hexane: ethyl acetate, 3:1). When the collection became yellow, fractions were collected at 10 mL intervals until the collection became colorless again; 4. The residue was eluted in the column with mobile phase C (ethyl acetate); 5. Nitrogen flush or rotary evaporator was used to evaporate solvent; 6. GC was used to analyze the concentrations of the fractions.

[0602] The results from this procedure were that >95% GG purity was obtained at a recovery of 40%. Example 4. Purification of T3

[0603] The vitamin E isomers can be separated using countercurrent chromatography in a co- current mode. The difficulties include long separation times (longer than 7 hours) and a large volume and variety of solvent usage to improve the complexity of separation. The following example shows increased purity of T3 and specifically delta-T3 in a quick and simple way that does not involve adding solvent. The example also shows an increased ratio of delta- to gamma- T3 in the product relative to the starting material. Example 4.1 Purification of T3 by Fractional Distillation Example 4.1.1 - Purification of a T3 Composition

[0604] The fractional distillation setup is described in Example 3.1. The crude material is obtained according to Example 2. The T3 purity in the crude (391 g) is about 15%. The GG purity in the crude is 26.73%. Example 4.1.2 - Purification of a Composition of 70% T3 purityAttorney Docket No: 148232.001602

[0605] The crude described in Example 4.1.1 was further purified to have a T3 purity of 70% (63% delta-T3 and 7% gamma-T3 in the total start material). The fractional distillation setup described in Example 3.1 was used. The T3 purity increased from Fraction 7 to 11 as shown in Table 12. There was an unexpected increase in Fraction 9 where the delta-T3 purity increased significantly. The molecular masses for delta-T3 and gamma-T3 were GC / MS identified. Table 12. The fractions and the corresponding delta-T3 purity (T3%) in the fractions Fraction Delta-T3 Purity (w%) *D delta-T3 over thecombined peak areas of all peaks in the GC / MS.

[0606] The isomeric percentage of delta-T3 was assessed based on the percentage of the peak area of delta-T3 over the combined peak areas of delta-T3 and gamma-T3 (Table 13). The delta- T3 and gamma-T3 have their individual peaks in GC / MS. Unexpectedly, delta-T3 enrichment (increase of purity) was attained in all Fractions 7-11, especially Fractions 10 and 11.

[0607] Fractional distillation allows for lower distillation temperature to obtain the T3 component of desired purity in the fractions. T3 purity was increased by about 19% from Feed to Fraction 11. Delta-T3 purity was increased by about 25% from Feed to Fraction 10 or 11. It is unexpected to achieve separation of delta- and gamma-T3 and obtain a product of specific high purity delta-T3. Table 13. The fractions shown with delta-T3 percentage Fraction Isomeric percentage Area Counts as %Attorney Docket No: 148232.001602Example 4.1.3 - Purification of a Composition of 83.25% T3 purity

[0608] The crude described in Example 4.1.1 was further purified to have a T3 purity of 83.25% as the start material. The start material presents a red color.

[0609] The fractional distillation setup described in Example 3.1 was adjusted to have a 250 mL round-bottom, two-necked flask that contains the feed material and a vacuum sealed, silvered Vigreux column was attached to the center neck approximating 10 theoretical plates. The remaining of the setup did not change.

[0610] The sample of approximately 150g of feed material was slowly brought up in temperature until equilibrium was achieved in the column resulting in reflux of the more volatile compounds (referred to as the “light” fraction). This portion brought the head temperature from 23°C to 50°C in roughly 100 minutes. Then full heating was applied to quickly distill the “light” fraction until a temperature range of 200°C to 220°C was reached at the head. This took roughly 80 to 90 minutes. Fraction 1 was distilled between 200°C to 220°C and Fraction 2 was distilled in a range of 220°C to 250°C. The distillation process ran for a total of 300 minutes as at that time an adequate amount of sample was acquired for each fraction. The average vacuum reading throughout the whole process was 0.3 Torr.

[0611] The two fractions presented a light-yellow color, which when exposed to oxygen, slowly turned to amber. Table 13A. T3, delta- and gamma-T3 purity during fractional distillation Weight T3 Purity Delta-T3 Gamma- Ratio Delta- (g) (w%) Purity T3 Purity T3 to 3Attorney Docket No: 148232.001602pu y was c ease y a ou o ee o ac o . elta-T3 purity was increased by about 20% from Feed to Fraction 2.

[0613] Unexpectedly, delta-T3 enrichment (increase of purity) was attained of an already high purity (83.25% T3) starting material. The ratio of delta-T3 to gamma-T3 increased from 87:13 in the feed material to up to 95:5 in Fraction 1. Typically, a ratio of 90 to 10 for delta- to gamma-T3 may be found in feed materials from annatto seed and a ratio of 10 to 90 for delta- to gamma-T3 may be found in feed materials from palm oil. This method, when being applied to tocotrienol mixtures of compositions typically found in annatto and palm, can yield products comprising delta- to gamma-tocotrienol at a ratio ranging from less than 10:90 to above 90:10. An unexpected increase in delta- to gamma-T3 ratio indicates improvements in separation of T3 isomers. Previously it was thought that due to the close molecular weights, structures, and boiling points of delta- to gamma-T3, they were deemed inseparable through distillation. As confirmed by HPLC and MS, Fraction 1 was more delta-T3 rich than the feed material, and Fraction 2 saw a slight increase in the ratio as gamma-T3 was distilled at higher temperatures (230°C to 250°C), contrary to what may be expected. The delta- to gamma-T3 ratio could be improved from any starting tocotrienol compositions to preferably 80 to 20, more preferably 90 QL -,) ?KB JLPQ MOCDCO?@IV 22+2 QL X,+- @V JRIQGMIC M?PPCP @V DO?AQGLK?I BGPQGII?QGLK+Attorney Docket No: 148232.001602

[0614] Fraction 1 yielded the essentially pure delta-T3 in the delta- and gamma-T3 mixture (delta-T3 accounts for 95% of the delta-and gamma-T3 mixture). Fraction 2 yielded the highest = / MROGQV 'Y 22+ / &(+

[0615] Total T3 has a 85% recovery (15% loss), delta-T3 has a 90% recovery (10% loss), and gamma-T3 has a 54% recovery (46% loss). The loss of gamma-T3 is 4 to 5-fold higher than delta-T3. The fractional distillation method preferentially separates or removes gamma-T3 from delta-T3.

[0616] Fractions 1 and 2 have very light color and did not exhibit deep coloration of the starting feed. The distillation setup, including its temperature and time parameters, relatively short column (~10 theoretical plates) with a fixed vacuum (0.3Torr), has a high recovery of delta-T3 with low loss and minimal oxidative degradation. Example 4.2 Purification of T3 by Liquid-Solid Extraction in a Container Example 4.2.1 Purification of T3 by Liquid Solid Extraction (start material: aluminum oxide is 1:4 (w / w))

[0617] This example sets forth a purification method of T3 by Liquid-Solid Extraction (LSE). The procedure of purification is described in the following steps: 1. 10 g crude material DeltaGold® (63% delta-T3 and 7% gamma-T3), 40g neutral aluminum oxide, and 100 mL hexane were added to an Erlenmeyer flask; 2. The mixture was stirred at 120 rpm for 60 min; 3. The mixture was filtered by rinsing the solid phase with hexane. The solid phase bounded with T3 was transferred to a new flask for step 4; 4. 100 mL grain alcohol (95% ethanol) was added to the flask from step 3; 5. The mixture was stirred at 120 rpm for 60 min; 6. The mixture was filtered and the liquid fraction was collected;. 7. A rotary evaporator was used to remove ethanol and water from the liquid fraction; 8. The concentration of T3 was analyzed in the sample acquired from step 7 using gas chromatography.

[0618] The gas chromatography protocol for T3 analysis used at step 4 and step 9 is described. 50-100 mg of T3 sample was mixed with 1 mL squalene internal standard (50 mg / mL) and diluted with hexane. The sample was analyzed with Agilent 7820A GC-FID, using Equity-1 ALIRJK ' / , J U .0, \J U ,+.0 \J(+ =FC GKHCAQLO QCJMCO?QROC T?P PCQ ?Q .1,W3+ 8CIGRJ T?PAttorney Docket No: 148232.001602 used as the carrier gas. The column oven temperature started at 200°C, increased to 340°C at 10C / min, and was held at 340°C for 6.5 min. FID detector was used at 340°C, H2flow was at 40mL / min, and air flow was at 400mL / min. Concentrations of T3 were quantified using relative response factor. RRF calculations determine the purity of a T3 sample using a GC-FID and standards as described above. Delta-T3 and gamma-T3 were separated on the gas chromatography with different retention times, as shown in Figure 1. Delta-T3 and gamma-T3 have retention times at 12.612 min and 13.271 min, respectively. Table 14. T3 analysis using GC-FID (with squalene)Attorney Docket No: 148232.001602a for T3, including delta-T3 and gamma-T3, purified by the above procedure is presented in Table 16. Table 16. The purity and yield data for T3 Absorbent Sample:Absorbent DT3 purity GT3 purity DT3 yield GT3 yieldDT3 stands for delta-T3. GT3 stands for gamma-T3.

[0620] Surprisingly, the end product has pure T3. The total T3 purity (including delta-T3 and gamma-T3) amount to 104.34% at step 9. As for results above 100%, there is a general idea of about ±3 to 5% for instrumental error and RRF errors (namely when the GG or T3 peak area exceeds the internal standard peak area on the GC-FID). The total T3 yield (including delta-T3 and gamma-T3) is 56.64% (reflecting the ethanol fraction recovering 56.64% of T3 from the original sample). Table 17. The purity of T3, including delta-T3 and gamma-T3 delta-T3% gamma-T3% Total T3% Hexane Phase (4.4g) 32.84% 6.75% 39.59% luminum oxide yields high purityof delta-T3 specifically, and the purity of delta-T3 was significantly enhanced from 63% in the original sample to 97.27%. The purity of gamma-T3 remained the same. Taken together, delta- T3 and gamma-T3, the total T3 purity went from 70% in the original sample to about 100%. TheAttorney Docket No: 148232.001602 unexpected feature of this data is that delta-T3 increased from 63% to 97% while gamma-T3 did not increase at all, remaining at 7%. Example 4.2.2 Purification of T3 by Liquid Solid Extraction (start material: aluminum oxide is 1:10 (w / w))

[0622] A ratio of T3 and aluminum oxide of 1:10 was used. The mixture stirred for 1 hour at 40°C. Hexane was used then alcohol. The steps are as described in Example 4.2.1. In the first trial sample, a start material of 51.23% T3 purity (delta-T3 = 47.4%, gamma-T3 = 3.83%) was purified to a product of 71.92% T3 purity (delta-T3 = 66.58%, gamma-T3 = 5.34%) for a recovery of 42%. In the second trial, the T3 purity increase from ~70% to 86.32% with a recovery of 54%. Table 18. T3 purification process recovery Start Material T3 Purity Product T3 Purity Recovery

[0623] The procedure used to purify delta-tocotrienol (T3) with silica column is as follows: 1. 10 g Start Material of 90% T3 purity (purified from a composition of 70% T3 purity using aluminum oxide) was loaded to a column packed with 50 g aluminum oxide; 2. The sample was eluted with mobile phase A (hexane) until the light green fraction was completely eluted out and the collection became colorless; 3. The sample was eluted with mobile phase B (hexane : ethyl acetate, 5:1). When the collection became brown, fractions were collected at 10 mL intervals until the collection became colorless again; 4. The residue was eluted in the column with mobile phase C (ethyl acetate) leading to a dark brown color; 5. Nitrogen flush or rotary evaporator was used to evaporate solvent;Attorney Docket No: 148232.001602 6. GC was used to analyze the concentrations of the fractions.

[0624] 98% purity of delta-T3 was obtained at a recovery of 20%.

[0625] The fractional distillation and liquid-solid extraction (in a container or in column chromatography) methods all show unexpected results to obtain high purity of delta-T3 specifically. Both LSE separation (delta-T3 to gamma-T3 ratio = 93:7) and fractional distillation separation (delta-T3 to gamma-T3 ratio = 95:5) improved delta-T3 relative amount from the delta-T3 to gamma-T3 ratio of typical starting material (90:10). This is shown in Tables 14-16 and 13A, respectively.

[0626] The fractional distillation and liquid-solid extraction methods as described above can be combined in any of the combinations thereof. The product from one method can be subsequently provided as the start material of a different method or a same method. The combination allows for producing end product of specific purity and of a particular component or isomer. These methods obtain high purity GG, or T3, or any one of the GG or T3 isomers with simple procedures, reduced amount of product loss. These methods can capture the desired isomeric components and are applicable for commercial applications. Example 5. Scale-Up Studies of Fractional Distillation of GG, T3, and any of GG or T3 isomers

[0627] 0.8kg start material is be used. The start material is the crude or purified crude as described in Example 2. By using the same column and distillation head as described above in the fractional distillation set-up, similar end purity is achieved. By increasing the column length, the target purity increases, resulting in further purification.

[0628] 1kg to 200 kg start material is used. Similar end purity is achieved. By increasing the column length, the target purity increases, resulting in further purification. The start material is the crude or purified crude as described in Example 2.

[0629] Automation, part optimization (such as replacing fine glass tubing with metal), varying parameters (such as fraction take-off, pressure, heat application, agitation, etc.) allow for concise production of specific purity of the product. References 1. Wang, J., et al., Engineering Saccharomyces cerevisiae YPH499 for Overproduction of Geranylgeraniol. J Agric Food Chem, 2023.71(25): p. 9804-9814.Attorney Docket No: 148232.001602 Verdaguer, I.B., et al., The Biomedical Importance of the Missing Pathway for Farnesol and Geranylgeraniol Salvage. Molecules, 2022.27(24). Wang, J., et al., Enhancing Geranylgeraniol Production by Metabolic Engineering and Utilization of Isoprenol as a Substrate in Saccharomyces cerevisiae. J Agric Food Chem, 2021. 69(15): p.4480-4489. Pearce, B.C., et al., Hypocholesterolemic activity of synthetic and natural tocotrienols. J Med Chem, 1992. 35(20): p.3595-606. Attioua, B., Weniger, B., & Chabert, P. (2007). Antiplasmodial Activity of Constituents Isolated from Croton lobatus. In Pharmaceutical Biology (Vol.45, Issue 4, pp.263–266). Informa UK Limited. https: / / doi.org / 10.1080 / 13880200701214607. Coates, R. M., Ley, D. A., & Cavender, P. L. (1978). Synthesis and carbon-13 nuclear magnetic resonance spectra of all-trans-geranylgeraniol and its nor analogs. In The Journal of Organic Chemistry (Vol.43, Issue 26, pp.4915–4922). American Chemical Society (ACS). https: / / doi.org / 10.1021 / jo00420a003. Motta, L. B., Furlan, C. M., Santos, D. Y. A. C., Salatino, M. L. F., Duarte-Almeida, J. M., Negri, G., Carvalho, J. E. de, Ruiz, A. L. T. G., Cordeiro, I., & Salatino, A. (2011). Constituents and antiproliferative activity of extracts from leaves of Croton macrobothrys. In Revista Brasileira de Farmacognosia (Vol.21, Issue 6, pp.972–977). Springer Science and Business Media LLC. https: / / doi.org / 10.1590 / s0102- 695x2011005000174. Tanaka, Y., Sato, H., Kageyu, A., & Tomita, T. (1985). Separation of geranylgeraniol isomers by high-performance liquid chromatography and identification by 13C nuclear magnetic resonance spectroscopy. In Journal of Chromatography A (Vol.347, pp.275– 283). Elsevier BV. https: / / doi.org / 10.1016 / s0021-9673(01)95493-7. Szewczyk, K., Daniluk, P., & Górnicka, M. (2022). Assessment of Tocotrienols Intake in Adults—A Pilot Study. In IECN 2022. IECN 2022. MDPI. https: / / doi.org / 10.3390 / iecn2022-12397. Ruzicka, L., & Firmenich, G. (1939). Zur Kenntnis der Diterpene. (37. Mitteilung). Synthese des aliphatischen Diterpenalkohols Geranyl-geraniol. In Helvetica Chimica Acta (Vol.22, Issue 1, pp.392–396). Wiley. https: / / doi.org / 10.1002 / hlca.19390220150 Tang, F., Chen, Z. (2005). Synthesis of geranyl geraniol. CN1218918C. Liu, L., Chen, J., et al. (2023). Method for synthesizing delta-tocotrienol from saccharomyces cerevisiae through metabolic engineering modification. CN116411013A.Attorney Docket No: 148232.001602 13. Meng, Y., Gou, Y., et al. (2023). Recombinant yarrowia lipolytica for high yield of tocotrienol, construction method and application thereof. CN113736677B. 14. Wright et al. (1993). Tocotrienols in the treatment of hypercholesterolemia, hyperlipidemia and thromboembolic disorders. US5217992A. 15. Mori et al. (1997). Process for producing geranylgeraniol. US5663461. 16. Hu, L., Zhou, Y., Wang, J., & Yang, Z. (2023). Countercurrent chromatography PCM?O?QGLK LD SGQ?JGK 5 GPLJCOP GK ? AL]AROOCKQ JLBC+ :LROK?I LD <CM?O?QGLK <AGCKAC) 46(21). https: / / doi.org / 10.1002 / jssc.202300285. 17. Vetter, Walter, et al. “The use of countercurrent chromatography in the separation of nonpolar lipid compounds.” Journal of Chromatography A, vol.1501, June 2017, pp.51– 60. https: / / doi.org / 10.1016 / j.chroma.2017.04.035. * * *

[0630] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0631] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

Attorney Docket No: 148232.001602 What Is Claimed Is:

1. A method of preparing high purity geranylgeraniol, said method comprising: a) providing a composition comprising low purity geranylgeraniol; b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising the low purity geranylgeraniol in step (a).

2. The method of claim 1, wherein step c) comprises: obtaining one or more fractions comprising high purity geranylgeraniol; or obtaining the composition comprising high purity geranylgeraniol in the residue after one or more fractions are vaporized.

3. The method of claim 1 or claim 2, wherein step c) comprises obtaining one or more fractions comprising high purity geranylgeraniol.

4. The method of any one of claims 1-3, wherein the fraction is collected at about 80°C to about 220°C.

5. The method of any one of claims 1-4, wherein the fraction is collected at about 130°C to about 180°C.

6. The method of any one of claims 1-5, where the fraction is collected at about 155°C to about 160°C.

7. The method of any one of claims 1-6, wherein the fraction is collected at lower than about 0.9 torr.

8. The method of any one of claims 1-7, wherein the fraction is collected at lower than about 0.3 Torr.

9. The method of any one of claims 1-8, wherein the fraction is collected at lower than about 0.1 Torr or about 0.1 to about 0.3 Torr.

10. The method of any one of claims 1-6, wherein the fraction is collected at vacuum.

11. The method of any one of claims 1-5, wherein the fraction is collected at about 130°C to about 180°C and about 0.1 Torr.

12. The method of any one of claims 1-6, wherein the fraction is collected at about 155°C to about 160°C and about 0.25 Torr.Attorney Docket No: 148232.001602 13. The method of any one of claims 1-12, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 70%.

14. The method of any one of claims 1-13, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 50%.

15. The method of any one of claims 1-13, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 40%.

16. The method of any one of claims 1-14, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is less than about 20%.

17. The method of any one of claims 1-12, the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol is about 12%, about 27%, about 53%, or about 73%.

18. The method of any one of claims 1-17, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 4% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

19. The method of any one of claims 1-18, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is about 4% to about 20%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

20. The method of any one of claims 1-19, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is about 4% to about 80% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

21. The method of any one of claims 1-20, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is about 30% to about 70% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

22. The method of any one of claims 1-21, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 40%.Attorney Docket No: 148232.001602 23. The method of any one of claims 1-22, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 70%, at least about 80%, at least about 90%, or at least 95%.

24. The method of any one of claims 1-23, wherein the composition in step (a) comprises both trans-geranylgeraniol and cis-geranylgeraniol.

25. The method of any one of claims 1-24, wherein the high purity geranylgeraniol obtained in step c) consists essentially of trans-geranylgeraniol.

26. The method of any one of claims 1-25, wherein said method prepares high purity trans- geranylgeraniol and the method comprises: a) providing a composition comprising low purity trans-geranylgeraniol, wherein the composition comprises both trans-geranylgeraniol and cis-geranylgeraniol, b) distilling the composition in a fractional distillation system under subatmospheric pressure, and c) obtaining a composition comprising high purity trans-geranylgeraniol with increased purity of trans-geranylgeraniol as compared to the composition comprising the low purity trans-geranylgeraniol in step (a), wherein the obtained composition consists essentially of trans-geranylgeraniol.

27. The method of any one of claims 1-26, wherein the purity of trans-geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) is at least about 70% and / or wherein the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in the last step is at least about 98:

2.

28. The method of any one of claims 1-27, wherein the yield of geranylgeraniol is at least about 30% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol obtained in step c) over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a).

29. The method of any one of claims 1-28, wherein the purity of geranylgeraniol is measured by gas chromatography based on the ratio of the peak area of geranylgeraniol over the total area of all peaks.

30. A method of preparing high purity geranylgeraniol, said method comprising: a) providing a composition comprising low purity geranylgeraniol;Attorney Docket No: 148232.001602 b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase; c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with geranylgeraniol; d) mixing the absorbent bonded with geranylgeraniol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising geranylgeraniol; and f) concentrating the filtrate to obtain a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising low purity geranylgeraniol in step a).

31. The method of claim 30, wherein step b) further comprises stirring the first mixture for at least about 5 minutes.

32. The method of any one of claims 30-31, wherein step b) further comprises stirring the first mixture for at least about 1 hour.

33. The method of any one of claims 30-32, wherein step c) further comprises rinsing the first mixture with the non-polar solvent at filtration.

34. The method of any one of claims 30-33, wherein step d) further comprises stirring the second mixture for at least about 5 minutes.

35. The method of any one of claims 30-34, wherein step d) further comprises stirring the second mixture for at least about 1 hour.

36. The method of any one of claims 30-35, wherein step e) further comprises rinsing the second mixture with the polar solvent at filtration.

37. The method of any one of claims 30-36, wherein step f) further comprises using a rotary evaporator to remove the solvent.

38. The method of any one of claims 30-37, wherein the method further comprises repeating steps a)-f) to increase the purity of geranylgeraniol.

39. A method of preparing a composition comprising high purity geranylgeraniol, said method comprising: a) loading a composition comprising low purity geranylgeraniol and other components onto a column packed with an absorbent; b) separating geranylgeraniol from other components by column chromatography; andAttorney Docket No: 148232.001602 c) obtaining a composition comprising high purity geranylgeraniol with increased purity of geranylgeraniol as compared to the composition comprising low purity geranylgeraniol in step a).

40. The method of claim 39, wherein step b) further comprises: i. eluting the column with a non-polar solvent and then a polar solvent; ii. eluting the column with a non-polar solvent and then a mixture of non-polar and polar solvents; or iii. eluting the column with a gradient mobile phase that is a mixture of non-polar and polar solvents with an increased ratio of the polar solvent to the non-polar solvent over time.

41. The method of claim 40, wherein step b) further comprises using a rotary evaporator to remove the solvent.

42. The method of any one of claims 39-41, wherein the method further comprises repeating steps a)-c) to increase the purity of geranylgeraniol.

43. The method of any one of claims 30-42, wherein the non-polar solvent is a C3 to C12 alkane, a C3 to C12 alkene, a C3 to C12 alkyne, a C6 to C12 arene, or any of the combinations thereof.

44. The method of any one of claims 30-43, wherein the non-polar solvent is a C3 to C12 alkane.

45. The method of claim 44, wherein the C3to C12alkane is pentane, hexane, heptane, or any of the combinations thereof.

46. The method of claim 39, wherein the C3to C12alkane is hexane.

47. The method of any one of claims 30-43, wherein the non-polar solvent is a C3to C12alkene.

48. The method of claim 47, wherein the C3to C12alkene is limonene.

49. The method of any one of claims 30-43, wherein the non-polar solvent is a C3to C12arene.

50. The method of claim 49, wherein the C3to C12arene is benzene, toluene, xylene, or any of the combinations thereof.

51. The method of claim 40, wherein the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane and ethyl acetate, optionally at a ratio of about 3:1 to about 6:1 in (ii).Attorney Docket No: 148232.001602 52. The method of claim 40, wherein the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane, water, and ethanol.

53. The method of any one of claims 30-52, wherein the absorbent comprises alumina, aluminum oxide, silica, silicon dioxide (SiO2), or a combination thereof.

54. The method of any one of claims 30-53, wherein the absorbent comprises aluminum oxide.

55. The method of claim 54, wherein the aluminum oxide is acidic, basic, or neutral.

56. The method of claim 55, wherein the aluminum oxide is basic.

57. The method of any one of claims 30-53, wherein the absorbent comprises SiO2.

58. The method of claim 57, wherein the absorbent is silica gel or silica.

59. The method of any one of claims 30-58, wherein the polar solvent comprises a C1 to C10 alkyl alcohol, water, acetic acid, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, hexamethyl phosphoric triamide (HMPT), or any of the combinations thereof.

60. The method of claim 59, wherein the C1 to C10 alkyl alcohol is methanol, ethanol, or propanol.

61. The method of claim 59, wherein the polar solvent comprises ethyl acetate.

62. The method of claim 59, wherein the polar solvent comprises a mixture of ethanol and water.

63. The method of claim 62, wherein the polar solvent comprises a mixture of ethanol and water, and ethanol is at least 35% by volume over the total volume of ethanol and water.

64. The method of claim 63, the polar solvent comprises a mixture of ethanol and water, and ethanol is about 35% to about 95% by volume over the total volume of ethanol and water.

65. The method of any one of claims 30-64, wherein the weight ratio of geranylgeraniol to the absorbent is about 1:1 to about 1:

100.

66. The method of any one of claims 30-64, wherein the weight ratio of geranylgeraniol to the absorbent is about 1:1 to about 1:

10.

67. The method of any one of claims 30-64, wherein the weight ratio of geranylgeraniol to the absorbent is about 1:1, 1:3, 1:4, or 1:

6.

68. The method of any one of claims 30-67, wherein the weight ratio of geranylgeraniol to the absorbent is about 1:6.Attorney Docket No: 148232.001602 69. The method of any one of claims 30-68, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 70%.

70. The method of any one of claims 30-69, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 50%.

71. The method of any one of claims 30-69, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 40%.

72. The method of any one of claims 30-70, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is less than about 20%.

73. The method of any one of claims 30-68, wherein the purity of geranylgeraniol in the composition comprising low purity geranylgeraniol in step a) is about 38%, about 40%, or about 48%, or about 75%.

74. The method of any one of claims 30-73, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 4% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

75. The method of any one of claims 30-74, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 7% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

76. The method of any one of claims 30-75, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is about 4% to about 20%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

77. The method of any one of claims 30-76, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is about 10% to about 50% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

78. The method of any one of claims 30-77, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is about 20% to about 40% greater than the purity of the geranylgeraniol in the composition comprising low purity geranylgeraniol.

79. The method of any one of claims 30-78, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 40%.

80. The method of any one of claims 30-78, wherein the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 70%.Attorney Docket No: 148232.001602 81. The method of any one of claims 30-80, the purity of geranylgeraniol in the composition comprising high purity geranylgeraniol is at least about 80%, at least 90%, or at least 95%.

82. The method of any one of claims 30-82, wherein the composition in step (a) comprises both trans-geranylgeraniol and cis-geranylgeraniol.

83. The method of any one of claims 30-82, wherein the geranylgeraniol in the obtained composition in the last step consists essentially of trans-geranylgeraniol.

84. The method of any one of claims 30-83, wherein the weight ratio of trans-geranylgeraniol to cis-geranylgeraniol in the obtained composition in the last step is at least about 98:

2.

85. The method of any one of claims 30-84, wherein the yield of geranylgeraniol is at least about 30% by weight, wherein the yield is calculated based on the percentage of the amount of geranylgeraniol in the composition comprising high purity geranylgeraniol over the amount of geranylgeraniol in the composition comprising low purity geranylgeraniol.

86. The method of any one of claims 30-85, wherein the purity of geranylgeraniol is measured by gas chromatography based on the ratio of the peak area of geranylgeraniol over the total area of all peaks.

87. The method of any one of claims 1-86, wherein the composition comprising low purity geranylgeraniol in step a) is obtained from chemical synthesis, fermentation biosynthesis, or extraction of natural sources.

88. The method of claim 87, wherein the composition comprising low purity geranylgeraniol in step a) is obtained from extraction of natural sources.

89. The method of any one of claims 1-86, wherein the composition comprising low purity geranylgeraniol in step a) is obtained from annatto extracts.

90. The method of any one of claims 1-86, wherein the composition comprising low purity geranylgeraniol in step a) is obtained from extracts of linseed oil, Cedrela toona wood, or palm oil.

91. A composition comprising high purity geranylgeraniol prepared by the method of any one of claims 1-90.

92. The composition of claim 91, wherein the composition further comprises limonene and / or tocotrienol.

93. A composition comprising geranylgeraniol of at least 40% purity.

94. The composition of claim 93, comprising geranylgeraniol of at least 70% purity.Attorney Docket No: 148232.001602 95. The composition of claim 93, comprising geranylgeraniol of at least 80% purity.

96. The composition of claim 93, comprising geranylgeraniol of at least 90% purity.

97. The composition of any one of claims 93-97, wherein the geranylgeraniol consists essentially of trans-geranylgeraniol.

98. The composition of any one of claims 93-97, wherein the weight ratio of trans- geranylgeraniol to cis-geranylgeraniol is at least about 98:

2.

99. The composition of any one of claims 93-98, wherein the purity of geranylgeraniol is measured by gas chromatography based on the ratio of the peak area of geranylgeraniol over the total area of all peaks.

100. The composition of any one of claims 93-99, wherein the composition is obtained from chemical synthesis, fermentation biosynthesis, or extraction of natural sources.

101. The composition of any one of claims 93-100, wherein the composition further comprises less than about 1% of tocotrienols in the total weight of the composition.

102. The composition of any one of claims 93-101, wherein the composition is obtained from annatto extracts.

103. The composition of any one of claims 93-102, wherein the composition is obtained from extracts of linseed oil, Cedrela toona wood, or palm oil.

104. A method of preparing high purity tocotrienol, said method comprising: a) providing a composition comprising low purity tocotrienol; b) distilling the composition in a fractional distillation system under subatmospheric pressure; and c) obtaining a composition comprising high purity tocotrienol with increased purity of tocotrienol as compared to the composition comprising the low purity tocotrienol in step a).

105. The method of claim 104, wherein the composition comprising low purity tocotrienol in step a) comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof.

106. The method of any one of claims 104-105, wherein the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol, gamma-tocotrienol, or a combination thereof.Attorney Docket No: 148232.001602 107. The method of any one of claims 104-106, wherein the method prepares high purity delta-tocotrienol, high purity gamma-tocotrienol, or a combination thereof.

108. The method of any one of claims 104-107, wherein: the method prepares high purity delta-tocotrienol; the composition comprising low purity tocotrienol in step a) is a composition comprising low purity delta-tocotrienol; and the composition comprising high purity tocotrienol in step c) is a composition comprising high purity delta-tocotrienol with increased purity of delta-tocotrienol as compared to the composition comprising the low purity delta-tocotrienol in step a).

109. The method of any one of claims 104-108, wherein the high purity tocotrienol in the composition in step c) consists essentially of delta-tocotrienol.

110. The method of any one of claims 104-109, wherein the high purity tocotrienol in the composition in step c) comprises a weight ratio of gamma-tocotrienol to delta-tocotrienol up to about 1:

9.

111. The method of any one of claims 104-109, wherein the obtained composition in step c) is free of alpha-tocopherol, or the obtained composition in step c) has substantially less alpha- tocopherol as compared to the amount of alpha-tocopherol in the composition in step a).

112. The method of any one of claims 104-111, wherein step c) comprises obtaining one or more fractions comprising high purity tocotrienol, or obtaining the composition comprising high purity tocotrienol in the residue after one or more fractions are vaporized.

113. The method of any one of claims 104-111, wherein step c) comprises obtaining one or more fractions comprising high purity tocotrienol.

114. The method of any one of claims 104-113, wherein the fraction is collected at about 200°C to about 280°C.

115. The method of any one of claims 104-114, wherein the fraction is collected at about 200°C to about 250°C.

116. The method of any one of claims 104-115, wherein the fraction is collected at lower than about 0.9 torr.

117. The method of any one of claims 104-116, wherein the fraction is collected at lower than about 0.3 Torr.Attorney Docket No: 148232.001602 118. The method of any one of claims 104-118, wherein the fraction is collected at lower than 0.1 Torr or about 0.1 to about 0.3 Torr.

119. The method of any one of claims 104-118, wherein the fraction is collected at vacuum.

120. The method of any one of claims 104-119, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 70% purity.

121. The method of any one of claims 104-119, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 50% purity.

122. The method of any one of claims 104-119, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 40% purity.

123. The method of any one of claims 104-119, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 20% purity.

124. The method of any one of claims 104-123, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 10% to about 20%, about 20 to about 50%, or about 50% to about 70%.

125. The method of any one of claims 104-124, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 4% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

126. The method of any one of claims 104-125, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 4% to about 20%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

127. The method of any one of claims 104-126, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 4% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

128. The method of any one of claims 104-127, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 10% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

129. The method of any one of claims 104-128, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 40%.

130. The method of any one of claims 104-128, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 70%.Attorney Docket No: 148232.001602 131. The method of any one of claims 104-130, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is about 70% to about 90%.

132. The method of any one of claims 104-130, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 80%.

133. The method of any one of claims 104-130, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 90%.

134. The method of any one of claims 104-130, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol in step c) is at least about 95%.

135. The method of any one of claims 104-134, wherein tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% to about 90% of delta- tocotrienol by weight.

136. The method of any one of claims 104-135, wherein tocotrienol in the composition comprising low purity tocotrienol in step c) comprises about 10% or about 90% of delta- tocotrienol by weight.

137. The method of any one of claims 104-136, wherein tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% to about 90% of gamma- tocotrienol by weight.

138. The method of any one of claims 104-137, wherein tocotrienol in the composition comprising low purity tocotrienol in step c) comprises a weight ratio of gamma-tocotrienol to delta-tocotrienol at about 1:99 to about 1:9 or about 5:95 to about 1:

9.

139. The method of any one of claims 104-138, wherein the tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

140. The method of any one of claims 104-139, wherein the tocotrienol in the composition comprising high purity tocotrienol in step c) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

141. The method of any one of claims 104-140, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:9 to about 9:

1.

142. The method of any one of claims 104-141, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:9.Attorney Docket No: 148232.001602 143. The method of any one of claims 104-142, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is about 1:9 to about 9:

1.

144. The method of any one of claims 104-143, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol in step c) is up to about 1:9, about 5:95, or about 1:

99.

145. The method of any one of claims 104-144, wherein the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 63% purity.

146. The method of any one of claims 104-145, wherein the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 45% purity.

147. The method of any one of claims 104-146, wherein the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 18% purity.

148. The method of any one of claims 104-147, wherein the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 63% purity.

149. The method of any one of claims 104-148, wherein the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 90% purity.

150. The method of any one of claims 104-148, wherein the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of at least about 90% purity.

151. The method of any one of claims 104-148, wherein the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of about 63% to about 81% purity.

152. The method of any one of claims 104-151, wherein the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of about 7% to about 10% purity.

153. The method of any one of claims 104-152, wherein the yield of tocotrienol is at least 30% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in step c) over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

154. A method of preparing a composition comprising high purity tocotrienol, said method comprising: a) providing a composition comprising low purity tocotrienol; b) mixing the composition of step a) with an absorbent and a non-polar solvent to form a first mixture comprising a solid phase;Attorney Docket No: 148232.001602 c) filtering the first mixture to obtain the solid phase comprising the absorbent bonded with tocotrienol; d) contacting the absorbent bonded with tocotrienol of step c) with a polar solvent to form a second mixture; e) filtering the second mixture to obtain the filtrate comprising tocotrienol; and f) concentrating the filtrate to obtain the composition comprising high purity tocotrienol with increased purity as compared to the composition comprising the low purity tocotrienol in step a).

155. The method of claim 154, wherein step b) further comprises stirring the first mixture for at least about 5 minutes or at least about 1 hour.

156. The method of any one of claims 154-155, wherein each of the steps is performed in a container.

157. The method of any one of claims 154-156, wherein step c) further comprises rinsing the first mixture with the non-polar solvent at filtration.

158. The method of any one of claims 154-157, wherein step d) further comprises stirring the second mixture for at least about 5 minutes.

159. The method of any one of claims 154-158, wherein step d) further comprises stirring the second mixture for at least about 1 hour.

160. The method of any one of claims 154-159, wherein step e) further comprises rinsing the second mixture with the polar solvent at filtration.

161. The method of any one of claims 154-160, wherein step f) further comprises using a rotary evaporator to remove the solvent.

162. The method of any one of claims 154-161, wherein the method further comprises repeating steps a)-f) to increase the purity of tocotrienol.

163. A method of preparing a composition comprising high purity tocotrienol, said method comprising: a) loading a composition comprising low purity tocotrienol and other components onto a column packed with an absorbent; b) separating tocotrienol from other components by column chromatography; andAttorney Docket No: 148232.001602 c) obtaining a composition comprising high purity tocotrienol with increased purity of tocotrienol as compared to the composition comprising the low purity tocotrienol in step a).

164. The method of claim 163, wherein step b) further comprises: i. eluting the column with a non-polar solvent and then a polar solvent; ii. eluting the column with a non-polar solvent and then a mixture of non-polar and polar solvents; or iii. eluting the column with a gradient mobile phase that is a mixture of non-polar and polar solvents with an increased ratio of the polar solvent to the non-polar solvent over time.

165. The method of claim 164, wherein step b) further comprises using a rotary evaporator to remove the solvent.

166. The method of any one of claims 163-165, wherein the method further comprises repeating steps a)-c) to increase the purity of tocotrienol or delta-tocotrienol.

167. The method of any one of claims 154-166, wherein the composition in step a) comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol, beta- tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof.

168. The method of any one of claims 154-167, wherein the composition in step a) comprises delta-tocotrienol, gamma-tocotrienol, or a combination thereof.

169. The method of any one of claims 154-168, wherein the method prepares high purity delta-tocotrienol, high purity gamma-tocotrienol, or a combination thereof.

170. The method of any one of claims 154-169, wherein: the method prepares high purity delta-tocotrienol; the composition comprising low purity tocotrienol in step a) is a composition comprising low purity delta-tocotrienol; and the composition comprising high purity tocotrienol is a composition comprising high purity delta-tocotrienol with increased purity of delta-tocotrienol as compared to the composition comprising the low purity delta-tocotrienol in step a).

171. The method of any one of claims 154-170, wherein high purity tocotrienol consists essentially of delta-tocotrienol.Attorney Docket No: 148232.001602 172. The method of any one of claims 154-170, wherein high purity tocotrienol comprises a weight ratio of gamma-tocotrienol to delta-tocotrienol of up to about 1:

9.

173. The method of any one of claims 154-172, wherein the obtained composition in the last step is free of alpha-tocopherol, or the composition obtained in the last step has substantially less alpha-tocopherol as compared to the amount of alpha-tocopherol in the composition in step a).

174. The method of any one of claims 154-173, wherein the method prepares high purity delta- tocotrienol and the method comprises: providing a composition comprising low purity delta-tocotrienol, wherein the composition comprises alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha- tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, or any of the combinations thereof; and obtaining the composition comprising high purity delta-tocotrienol with increased delta- tocotrienol purity as compared to the composition comprising the low purity delta- tocotrienol in step a), wherein the obtained composition consists essentially of delta- tocotrienol.

175. The method of any one of claims 154-174, wherein the non-polar solvent is a C3 to C12 alkane, a C3 to C12 alkene, a C3 to C12 alkyne, a C6 to C12 arene, or any of the combinations thereof.

176. The method of any one of claims 154-175, wherein the non-polar solvent is a C3to C12alkane, optionally pentane, hexane, heptane, or any of the combinations thereof.

177. The method of claim 176, wherein the C3to C12alkane is hexane.

178. The method of any one of claims 154-177, wherein the non-polar solvent is a C3to C12alkene, optionally limonene.

179. The method of any one of claims 154-178, wherein the non-polar solvent is a C3to C12arene.

180. The method of claim 179, wherein the C3 to C12 arene is benzene, toluene, xylene, or any of the combinations thereof.

181. The method of any one of claims 154-180, wherein the absorbent comprises alumina, aluminum oxide, silica, silicon dioxide (SiO2), or a combination thereof.

182. The method of any one of claims 154-181, wherein the absorbent comprises aluminum oxide.Attorney Docket No: 148232.001602 183. The method of claim 182, wherein the aluminum oxide is acidic, basic, or neutral.

184. The method of claim 183, wherein the aluminum oxide is basic.

185. The method of any one of claims 154-184, wherein the absorbent comprises SiO2.

186. The method of claim 185, wherein the absorbent is silica gel or silica.

187. The method of any one of claims 154-186, wherein the polar solvent comprises a C1to C10 alkyl alcohol, water, acetic acid, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, hexamethyl phosphoric triamide (HMPT), or any of combinations thereof.

188. The method of claim 187, wherein the C1 to C10 alkyl alcohol is methanol, ethanol, or propanol.

189. The method of claim 187, wherein the polar solvent comprises ethyl acetate.

190. The method of claim 187, wherein the polar solvent comprises a mixture of ethanol and water.

191. The method of claim 164, wherein the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane and ethyl acetate.

192. The method of claim 164, wherein the mixture of non-polar and polar solvents in (ii) or (iii) comprises hexane, water, and ethanol.

193. The method of claim 190, wherein the polar solvent comprises a mixture of ethanol and water, and ethanol is at least 35% by volume over the total volume of ethanol and water.

194. The method of claim 193, the polar solvent comprises a mixture of ethanol and water, and ethanol is about 35% to about 95% by volume over the total volume of ethanol and water.

195. The method of claim 164, wherein the mixture of non-polar and polar solvents comprises hexane and ethyl acetate at a ratio of about 0.5:1 to about 3:1 by volume.

196. The method of any one of claims 154-195, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 70% purity.

197. The method of any one of claims 154-195, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 50% purity.

198. The method of any one of claims 154-195, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 40% purity.

199. The method of any one of claims 154-195, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is less than about 20% purity.Attorney Docket No: 148232.001602 200. The method of any one of claims 154-199, wherein the purity of tocotrienol in the composition comprising low purity tocotrienol in step a) is about 10% to about 20%, about 20 to about 50%, or about 50% to about 70%.

201. The method of any one of claims 154-200, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol is at least about 4% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

202. The method of any one of claims 154-201, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol is about 4% to about 20%, about 20% to about 40%, about 40% to about 60%, or about 60% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

203. The method of any one of claims 154-202, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol is about 4% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

204. The method of any one of claims 154-203, wherein the purity of tocotrienol in the composition comprising high purity tocotrienol is about 30% to about 80% greater than the purity of the tocotrienol in the composition comprising low purity tocotrienol in step a).

205. The method of any one of claims 154-204, wherein the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 40%.

206. The method of any one of claims 154-204, wherein the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 70%.

207. The method of any one of claims 154-206, wherein the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is about 70% to about 90%.

208. The method of any one of claims 154-206, wherein the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 80%.

209. The method of any one of claims 154-206, wherein the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 90%.

210. The method of any one of claims 154-206, wherein the purity of the high purity tocotrienol in the composition comprising high purity tocotrienol is at least about 95%.

211. The method of any one of claims 154-210, wherein tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% to 90% delta-tocotrienol by weight.Attorney Docket No: 148232.001602 212. The method of any one of claims 154-211, wherein tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% or about 90% delta-tocotrienol by weight.

213. The method of any one of claims 154-212, wherein tocotrienol in the composition comprising low purity tocotrienol in step a) comprises a weight ratio of gamma-tocotrienol to delta-tocotrienol at about 1:99 to about 1:9 or about 5:95 to about 1:

9.

214. The method of any one of claims 154-213, wherein tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% or about 90% gamma- tocotrienol by weight.

215. The method of any one of claims 154-214, wherein the tocotrienol in the composition comprising low purity tocotrienol in step a) comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

216. The method of any one of claims 154-215, wherein the tocotrienol in the composition comprising high purity tocotrienol comprises about 10% gamma-tocotrienol and about 90% delta-tocotrienol by weight.

217. The method of any one of claims 154-216, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:9 to about 9:

1.

218. The method of any one of claims 154-217, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising low purity tocotrienol in step a) is about 1:

9.

219. The method of any one of claims 154-218, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is about 1:9 to about 9:

1.

220. The method of any one of claims 154-219, wherein the weight ratio of gamma-tocotrienol to delta-tocotrienol in the composition comprising high purity tocotrienol is up to about 1:9, about 5:95, or about 1:

99.

221. The method of any one of claims 154-220, wherein the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 63% purity.

222. The method of any one of claims 154-221, wherein the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 45% purity.Attorney Docket No: 148232.001602 223. The method of any one of claims 154-222, wherein the composition comprising low purity tocotrienol in step a) comprises delta-tocotrienol of less than about 18% purity.

224. The method of any one of claims 154-223, wherein the composition comprising high purity tocotrienol comprises delta-tocotrienol of at least about 63% purity.

225. The method of any one of claims 154-223, wherein the composition comprising high purity tocotrienol in step c) comprises delta-tocotrienol of at least about 90% purity.

226. The method of any one of claims 154-223, wherein the composition comprising high purity tocotrienol in step c) comprises gamma-tocotrienol of at least about 90% purity.

227. The method of any one of claims 154-224, wherein the composition comprising high purity tocotrienol comprises delta-tocotrienol of about 63% to about 81% purity.

228. The method of any one of claims 154-227, wherein the composition comprising high purity tocotrienol comprises gamma-tocotrienol of about 7% to about 10% purity.

229. The method of any one of claims 154-228, wherein the yield of tocotrienol is at least 30% by weight, wherein the yield is calculated based on the percentage of the amount of tocotrienol in the composition comprising high purity tocotrienol obtained in the last step over the amount of tocotrienol in the composition comprising low purity tocotrienol in step a).

230. The methods of any one of claims 154-229, wherein the weight ratio of tocotrienol to the absorbent is about 1:1 to about 1:

100.

231. The methods of any one of claims 154-229, wherein the weight ratio of tocotrienol to the absorbent is about 1:1 to about 1:

10.

232. The methods of claim 230, wherein the weight ratio of tocotrienol to aluminum oxide or silica gel is about 1:1, 1:3, 1:4, or 1:

6.

233. The methods of claim 232, wherein the weight ratio of tocotrienol to aluminum oxide or silica gel is about 1:

4.

234. The method of any one of claims 104-233, wherein the purity of tocotrienol is measured by gas chromatography based on the ratio of the peak area of tocotrienol over the total area of all peaks.

235. The method of any one of claims 104-234, wherein the composition comprising low purity tocotrienol in step a) is obtained from extracts of Bixa orellana seed components.

236. The method of any one of claims 104-235, wherein the composition comprising low purity tocotrienol is obtained from extracts of vegetable oil.Attorney Docket No: 148232.001602 237. The method of claim 236, wherein the vegetable oil is rice bran, soybean, sesame, or palm oil.

238. A composition comprising high purity tocotrienol prepared by the method of any one of claims 104-237.

239. The composition of claim 238, wherein the composition further comprises limonene and / or geranylgeraniol.

240. A composition comprising high purity geranylgeraniol prepared by the method of any one of claims 1-90 and high purity tocotrienol prepared by the method of any one of claims any one of claims 104-237.

241. The composition of claim 240, wherein high purity geranylgeraniol consists essentially of trans-geranylgeraniol and high purity tocotrienol consists essentially of delta-tocotrienol.

242. A composition comprising tocotrienol of at least about 40% purity.

243. The composition of claim 242, comprising tocotrienol of at least about 70% purity.

244. The composition of claim 242, comprising tocotrienol of at least about 80% purity.

245. The composition of claim 242, comprising tocotrienol of at least about 90% purity.

246. The composition of claim 242, comprising tocotrienol of at least about 95% purity.

247. The composition of any one of claims 242-246, wherein the tocotrienol comprises delta- tocotrienol, gamma-tocotrienol, or a combination thereof.

248. The composition of any one of claims 242-247, wherein the tocotrienol comprises delta- tocotrienol and gamma-tocotrienol at a ratio of at least about 9:

1.

249. The composition of any one of claims 242-247, wherein the tocotrienol comprises at least about 95% or about 99% delta-tocotrienol.

250. The composition of any one of claims 242-247, wherein the tocotrienol comprises delta- tocotrienol and gamma-tocotrienol at a ratio of at least about 95:5 or about 99:

1.

251. The composition of any one of claims 242-251, wherein the tocotrienol consists essentially of delta-tocotrienol.

252. The composition of any one of claims 242-247, wherein the tocotrienol consists essentially of gamma-tocotrienol.

253. The composition of any one of claims 242-252, wherein the purity of geranylgeraniol is measured by gas chromatography based on the ratio of the peak area of geranylgeraniol over the total area of all peaks.Attorney Docket No: 148232.001602 254. The composition of any one of claims 242-253, wherein the composition is obtained from the byproduct solution of Bixa orellana seed components.

255. The composition of any one of claims 242-254, wherein the byproduct solution of Bixa orellana seed components comprises natural annatto extracts.

256. The composition of any one of claims 242-255, wherein the composition is obtained from annatto extracts.

257. The composition of any one of claims 242-256, wherein the composition is obtained from extracts of linseed oil, Cedrela toona wood, or palm oil.

258. A composition comprising at least about 90% of geranylgeraniol and less than about 1% of tocotrienol.

259. The composition of claim 258, wherein the geranylgeraniol consists essentially of trans- geranylgeraniol.

260. A method, the method comprising: i. causing an antioxidant, anti-inflammatory, hypolipidemic, or neuroprotective effect; ii. reducing atherogenic apolipoprotein B, lipoprotein(a) (Lpa), triglyceride (TG), and / or low-density lipoprotein (LDL) plasma levels; iii. suppressing cholesterol level; iv. inducing apoptosis of breast cancer cells or prostate cancer cells; v. protecting normal cells in radiation oncology; vi. preventing or treating pre-diabetes, Type 2 diabetes, or a metabolic syndrome; vii. preventing or treating ovarian cancer, pancreatic cancer, or colon cancer; viii. preventing or treating a Non-Alcoholic Fatty Liver Disease (NAFLD); ix. preventing or treating genetic, epilepsy, or neurologic disorders; x. preventing or treating brain trauma or strokes; or xi. preventing or treating inflammation-associated diseases, cardiovascular disease, or cancer, in a subject in need of, comprising administering to the subject in need of the composition comprising high purity tocotrienol of any one of claims 238-257 or a composition comprising high purity tocotrienol prepared according to the method of any one of claims 104-237.

261. A method, the method comprising: i. promoting the maintenance and growth of skeletal muscle proteins;Attorney Docket No: 148232.001602 ii. preventing or treating Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ); iii. preventing or treating Statin-Associated Muscle Symptoms (SAMS), sarcopenia, preventing loss of muscle, or maintaining muscle mass; iv. promoting or increasing muscle force production and / or energy production; v. promoting or increasing the biosynthesis of CoQ10, MK-4, and / or testosterone; vi. promoting or increasing bone mineralization or density; vii. increasing vitamin K-dependent proteins (VKDP), osteocalcin, Matrix Gla Protein (MGP); viii. reversing depressive symptoms and improving cognitive memory; ix. preventing or treating calcified atherosclerosis, kidney stone, biliary stone, gallstone, osteopenia, or osteoporosis; x. promoting or increasing the conversion of white adipose tissue (WAT) to brown tissue (BAT); xi. maintaining and regulating body temperature and blood sugar; or xii. boosting immunity and reducing pain, in a subject in need of, comprising administering to the subject in need of the composition comprising high purity geranylgeraniol of any one of claims 91-103 and 258-259 or a composition comprising high purity geranylgeraniol prepared according to the method of any one of claims 1-90.

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