WO2023128750A1 - Composition auto-émulsionnable - Google Patents

Composition auto-émulsionnable Download PDF

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Publication number
WO2023128750A1
WO2023128750A1 PCT/MY2022/050086 MY2022050086W WO2023128750A1 WO 2023128750 A1 WO2023128750 A1 WO 2023128750A1 MY 2022050086 W MY2022050086 W MY 2022050086W WO 2023128750 A1 WO2023128750 A1 WO 2023128750A1
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WIPO (PCT)
Prior art keywords
composition
oil
range
weight
palm
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PCT/MY2022/050086
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English (en)
Inventor
Tommy Julianto Bustami Effendi
Teh Huey FANG
Theresa Lee Mei NG
Nurhazirah MOHD IHSAN
Zalina HAMID
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Sime Darby Plantation Intellectual Property Sdn Bhd
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Publication of WO2023128750A1 publication Critical patent/WO2023128750A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention relates generally to a self-emulsifying composition. More particularly, the present invention relates to a palm-based vitamin E self-emulsifying composition.
  • European Patent Application EP3223795A1 entitled ‘Formulation for Effective Tocotrienol Delivery’ describes a self-emulsifying drug delivery formulation for improved delivery of Tocotrienols, said formulation comprising a fat-soluble compound selected from Tocotrienols and the derivatives thereof, at least one emulsifier selected from the group consisting of nonionic surfactants and an oil carrier selected from the group consisting of glycerides.
  • the formulation contains two emulsifiers selected from the group consisting of nonionic surfactants.
  • the emulsifiers are selected from a group consisting of sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters and are sorbitan monolaurate (Span 20) and polyoxyethylene sorbitan 20 monooleate (Polysorbate 80).
  • the amount of emulsifiers is about 15% to about 45%, by weight of the formulation.
  • SEDDS Self-emulsifying drug delivery systems
  • SEDDS formulation development, characterization, and applications
  • SEDDS self-emulsifying drug delivery systems
  • these systems rapidly disperse in gastrointestinal fluids, yielding micro- or nanoemulsions containing the solubilized drug. Owing to its minuscule globule size, the micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect.
  • SEDDS Self-emulsifying drug delivery systems
  • SEDDS Self-emulsifying drug delivery systems
  • SEDDS can be orally administered in soft or hard gelatin capsules and form fine relatively stable oil-in-water (o/w) emulsions upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids.
  • the efficiency of oral absorption of the drug compound from the SEDDS depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, the polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification ability. Thus, only very specific pharmaceutical excipient combinations will lead to efficient self-emulsifying systems. Although many studies have been carried out, there are few drug products on the pharmaceutical market formulated as SEDDS confirming the difficulty of formulating hydrophobic drug compounds into such formulations.
  • United States Patent Application US6596306B1 entitled “Drug Delivery System: Formulation for Fat-Soluble Drugs” describes a novel formulation for fat-soluble drugs which self-emulsify in the presence of an aqueous medium with little agitation. More specifically, the invention is concerned with the formulation of a new dosage form for fat-soluble drugs in the form of a soft-gelatin capsule which forms emulsion instantly when the contents are released and mixed with gastrointestinal fluid.
  • the formulation comprises a suitable mixture of a drug with an appropriate oil and an appropriate surfactant system.
  • a self-emulsifying drug delivery composition for use with oral administration of fat-soluble drugs said composition consisting essentially of a fat-soluble drug selected from the group consisting of Tocotrienols, tocopherols, vitamins A, D or K, and -carotene, an oil selected from the group consisting of palm olein and soybean oil and a surfactant system comprised of a first component consisting of caprylocaproyl macrogolglycerides and a second component consisting of polyoxyethylene 20 sorbitan monooleate, wherein the weight ratio of said first component to said second component is between 9/1 and 7/3 wherein said composition enhances the absorption of the said fat-soluble drug and the weight ratio of the fat-soluble drug and oil to the surfactant system is about 5/ 1.
  • a fat-soluble drug selected from the group consisting of Tocotrienols, tocopherols, vitamins A, D or K, and -carotene
  • an oil selected from the group consisting of palm olein and soybean
  • United States Patent Application US10493055B2 describes a self-emulsifying drug delivery formulation for improved delivery of tocotrienols, said formulation comprising a fat-soluble compound selected from tocotrienols and derivatives thereof, wherein the amount of the fatsoluble compound is about 10% to about 50%, by weight of the formulation; two emulsifiers each selected from the group consisting of nonionic surfactants, wherein the emulsifiers are sorbitan monolaurate and polyoxyethylene sorbitan 20 monooleate (Polysorbate 80), wherein the amount of emulsifiers is about 15% to about 45%, by weight of the formulation, and wherein the weight ratio of said sorbitan monolaurate to Polysorbate 80 is about 1:1 to about 1:20 and an oil carrier selected from the group consisting of glycerides, wherein the amount of oil carrier is about 6% to about 56%, by weight of the formulation.
  • a fat-soluble compound selected from tocotrienols and derivatives thereof, where
  • the weight ratio of said sorbitan monolaurate to Polysorbate 80 is about 1:2 to about 1:8.
  • the fat-soluble compound is tocotrienol.
  • the oil carrier comprises glycerol trioleate (GTO) oil.
  • the glycerol trioleate (GTO) oil includes the main triglycerides (TG) of triolein (OOO, C18:1).
  • the oil carrier comprises the amount of triolein (OOO, C18 : 1) about 55% to about 99% by weight of said GTO oil.
  • the oil carrier comprises the amount of triolein (OOO, Ci8:i) about 65% to about 85% by weight of said GTO oil.
  • the fatty acid selected from the group consists of oleic acid, palmitic acid, stearic acid and mixtures thereof.
  • the formulation is made into powder form, tablet or filled into a gelatin capsule. This prior art document does not describe or disclose the composition of the present invention.
  • the present invention relates generally to a self-emulsifying composition. More particularly, the present invention relates to a palm-based vitamin E self-emulsifying composition.
  • the present invention provides a self-emulsifying composition, the composition comprising at least one active ingredient in a range of between 15% to 40% by weight of the composition, at least one oil carrier in a range of between 14% to 55% by weight of the composition and at least one emulsifier in a range of between 25% to 55%.
  • the present invention also provides a use of a palm-based vitamin E self-emulsifying composition, comprising at least one active ingredient in a range of between 15% to 40% by weight of the composition, at least one oil carrier in a range of between 14% to 55% by weight of the composition and at least one emulsifier in a range of between 25% to 55% by weight of the composition.
  • the present invention further provides a method of producing a self-emulsifying composition comprising mixing together at least one active ingredient in a range of between 15% to 40% by weight of the composition to an at least one oil carrier in a range of between 14% to 55% by weight of the composition and an at least one emulsifier in a range of between 25% to 55% to form an oil-in-water emulsion.
  • FIG. 1 shows that the self-emulsification area or region for the Tocotrienols-rich fraction (TRF) is only a small range as indicated by the smaller triangle as contained within the bigger triangle on the left side.
  • the TRF is unable to emulsify, not able to retain good particle size and good physical stability of the composition at areas beyond the smaller triangle.
  • Figure 2 shows the screening of the composition of the present invention was conducted using a ternary phase diagram as a tool to screen possible components and concentrations that can be formulated to produce a self-emulsifying composition.
  • the components of the composition are divided by three phases in the ternary diagram - active ingredient, oil carrier and emulsifiers.
  • Multilayer ternary diagrams were also created according to the number and ratio of components in the oil carrier phase and emulsifier mixtures.
  • Figure 3 shows the measurement of particle size of the emulsion droplets formed by the selfemulsifying composition of the present invention using a particle size analyzer, Mastersizer MS3000 (Malvern Panalytical) for an average of 20 batches of composition which indicates that the average particle size of the emulsion is of a maximum nonm.
  • Figure 4 shows the average particle size of the emulsion based on stability studies conducted on the self-emulsifying composition of the present invention. Stability of the composition of the present invention were also studied whereby the prepared samples were stored at 25°C (Room Temperature) and 4O°C. Particle size analysis were carried out at intervals of 2 weeks - i-month, 3-months and 6-months to determine the stability of the self-emulsifying composition.
  • Palm oil is a rich source of edible oil and is the most efficient oil-bearing crop. Its fatty acid components are suitable for human needs and it is also a rich source of vitamin E. Palm oil contains a balanced proportion of saturated and unsaturated fatty acids. The saturated fatty acids are made up to 44% palmitic acid and 5% stearic acid, the unsaturated fatty acids consist of 40% monounsaturated oleic acid. Palm oil has high content of Vitamin-E tocotrienols, a potent antioxidant which helps fight free radicals, slow down ageing and others.
  • Tocotrienols are a group of chemicals that are part of the vitamin E family. Research has uncovered numerous benefits associated with Tocotrienols. Both Tocotrienols and tocopherols make up the vitamin E family and exist in four forms namely alpha, beta, delta, and gamma. Most vitamin E supplements are higher in tocopherols than Tocotrienols. Tocotrienols may help fight free radical damage to the gastrointestinal system, as Vitamin E is an oxidant which helps to neutralize free radicals as free radicals can cause health issues and many diseases.
  • Vitamin E is found in abundance in vegetable oils with tocopherols as the main constituent. In the past, tocopherols have been vastly studied but still lacking in clinical data where Tocotrienols are concerned. Palm oil contains about 70% Tocotrienols of the vitamin E content; making it one of the richest source of natural Tocotrienols. Gamma and delta Tocotrienols are isomers of Vitamin E with established potency in pre-clinical anti-cancer research.
  • Vitamin E is a fat-soluble vitamin widely used in pharmaceutical, supplement, food, and cosmetic preparations that must be encapsulated before it can be dispersed into aqueousbased products.
  • bile salt made in the liver from cholesterol and stored in the gall bladder
  • chylomicron acts as a natural emulsifier to produce small droplets of lipid (chylomicron) to allow absorption through the small intestines before being released into the bloodstream in the body.
  • Absorption of Vitamin E via oral intake varies from body to body as the absorption of Vitamin E depends on the presence of bile salt which helps in the absorption of fats to the body.
  • absorption of Vitamin E is increased by the presence of bile salt.
  • Those who are not able to produce enough bile salt due to medical reasons such as removal of gall bladders and others are not able to absorb fat-soluble vitamins and fatty acids.
  • Absorption of Vitamin E is also dependent on a person’s diet on a daily basis. Therefore, these reasons make Vitamin E less flexible when taken as dietary or health supplements although it is known to fight the oxidation of the body from free radicals.
  • Vitamin E is in the form of droplets as an emulsion to enhance absorption of the Vitamin E to the body when the supplements are taken orally. This way could be done via a capsule, using either soft or hard gelatin capsules.
  • a delivery system or approach which allows Vitamin E to be self-emulsified in the watery condition of a stomach after being taken orally is required for the most optimal absorption of Vitamin E to the body, without being affected by meals taken on a daily basis or the amount of bile salt made in the liver. This also provides a more flexible means of consuming Vitamin E dietary supplements for overall health and vitality.
  • SEDDS Self-emulsifying drug delivery system
  • Oral intake is the most convenient to take dietary supplements due to flexibility, ease of doing so, cost effectiveness and others.
  • the major challenge with this is the dietary supplements’ poor bioavailability.
  • Oral bioavailability depends on factors such as water solubility, metabolism, dissolution rate and others. Poor water-soluble drugs usually require a high dosage in order to reach the required concentrations for absorption into the bloodstream. However, more than 40% of drugs developed are insoluble in water and has slow absorption, hence leading to inadequate and variable bioavailability. Solubility is the most important to achieve desired concentration in the bloodstream and therefore, bio-availability remains one of the most challenging aspects of the drug development process especially, for an oral-drug delivery system. [Source: Drug Solubility: Importance and Enhancement Techniques, Volume 2012 ⁇ Article ID 195727
  • Vitamin E is best encapsulated in the form of an emulsion for optimal absorption into the bloodstream of the body.
  • Vitamin E is a fat or lipid-soluble vitamin and is hydrophobic in nature.
  • Vitamin E is absorbed into dietary oils and fats, then solubilized by bile acids as synthesized from cholesterol in the liver, absorbed into the epithelial cells of the small intestines in the body, combined with chylomicron (small fat globule of protein and fats) and finally transported into the blood.
  • Orally administered drugs must pass through the intestinal wall and then the portal circulation to the liver; both are common sites of first-pass metabolism (metabolism that occurs before a drug reaches systemic circulation). Thus, many drugs may be metabolized before adequate plasma concentrations are reached.
  • Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs. Insufficient time for absorption in the gastrointestinal (GI) tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane, time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low.
  • MSD MANUAL, Professional Version
  • Objectives of the present inventions are to provide the following:
  • a self-emulsifying composition which is able to self-emulsify on its own to form an oil-in- water emulsion on its own when comes in contact with an aqueous solution or watery conditions at the gastrointestinal tract;
  • a self-emulsifying composition which is able to form an oil-in-water emulsion with a particle size in the nanometer-range that provides a larger surface area for absorption into the bloodstream of the body;
  • a novel, enriched and improved combination of ingredients / components comprising of TRF, palm kernel olein, palm kernel oil, medium chain triglycerides (MCT) liquid, red palm oil, red palm olein, RBD (refined, bleached and deodorized) palm kernel oil, olive oil, coconut oil or in any combinations thereof whereby red palm oil is high in carotenes and other phyto nutrients and MCT liquid supports digestion, nutrition absorption and improves cognitive function together with Vitamin E which results in the palm-based vitamin E self-emulsifying composition of the present invention with many health benefits to the consumers;
  • MCT medium chain triglycerides
  • the palm-based vitamin E self-emulsifying composition can be taken at any time for the best / efficient absorption to the intestines of the body before being released into the bloodstream and not per current formulations in the market as Vitamin E supplements must only be taken after food and it also depends on the bile salt in the intestines for maximum absorption.
  • Bile salts naturally emulsifiers
  • Vitamin E capsules are best taken after food and preferably not in an empty stomach.
  • the present invention allows for the flexible intake of the Vitamin E supplements without being affected by meals taken on a daily basis or the amount of bile salt made in the liver for overall health and vitality;
  • TRF Tocotrienols-rich fraction
  • TRF Tocotrienols-rich fraction
  • the present invention provides a novel, enri ched and improved palm-based Vitamin E selfemulsifying composition which uses a combination of beneficial ingredients together with Vitamin E which has many known health benefits to the consumers.
  • the naturally occurring vitamin E family is known to consist of both tocopherols and Tocotrienols whereby Tocotrienols which are plentiful in palm oil has anticancer properties, able to reduce cholesterol levels, risk of cardiovascular disease and others.
  • MCT liquid provides beneficial protection for neurodegenerative disease, reduced appetite and weight loss, decreased cardiovascular disease and improved cognitive functions.
  • Red palm oil which acts as a source of pro Vitamin A carotenoids - has antioxidant properties, contains minor sterol contents such as ubiquinone to help boost immune systems and protect against heart disease.
  • a self-emulsifying composition per present invention in the market or prior arts, hence, these ingredients in combination are novel, unique and have multiple health benefits for use as a health and/ or dietaiy supplements.
  • the self-emulsifying composition of the present invention provides a much needed fl exibility for consumers to orally consume Vitamin E capsules at any time possible without worrying about optimal absorption to the bloodstream, hence able to enjoy the benefits of this composition to the fullest extent possible whenever and wherever.
  • the self-emulsifying composition of the present invention results in a delivery system of Vitamin E for optimal absorption into the bloodstream in the body as generally Vitamin E has low oral absorption and is highly dependent on various means to improve on its optimal absorption.
  • Vitamin E on its own without any unique formulation is a less-flexible health supplement due to its dependence on a person’s physiology condition which means that the absorption of Vitamin E if taken orally varies from person to person due to the presence of dietary fat in the body. It is generally preferred for Vitamin E to be in droplets form or for the Vitamin E to be encapsulated in edible emulsions fabricated using natural emulsifiers or surfactants.
  • the self-emulsifying composition of the present invention is able to self-emulsify on its own when comes in contact with an aqueous solution or watery conditions at the gastrointestinal tract to form an oil-in-water emulsion with particles size in the nano-range which provides a larger surface area for absorption to the bloodstream of the body.
  • the self-emulsifying composition of the present invention provides the flexibility of selecting the amount of TRF used in the composition based on the preference and needs of the user of the present invention.
  • the self-emulsifying composition of the present invention forms an emulsion with the particle size of not more than 15pm for TRF in a range of between 30% to 35% by weight of the composition and an emulsion with the particle size of less than 2oonm, preferably less than toonm for TRF in a range of between 22% to 29% by weight of the composition.
  • the composition is contained in soft gelatin capsules, hard gelatin capsulses, chewable gummies or plant-based capsules or others based on consumer preference, whereby the composition is administered orally.
  • the weight of the capsule can be selected based on the needs and preference of the user of the present invention - for example loomg, 2oomg, 3oomg, 5oomg capsules or others.
  • Tocotrienols and tocopherols are vitamin E isomers that are abundant in palm fruits.
  • the palm vitamin E could be extracted from palm oil, and the isomers usually available in the extract are a-tocotrienol, P-tocotrienol, 8-tocotrienol, y-tocotrienol, and a-tocopherol.
  • the absence of P ⁇ , 8-, and y- tocopherol in the extract may be due to the low level available that can be extracted from the palm oil.
  • the advantage of palm vitamin E is extracted from the palm fruit, which is categorized as a natural vitamin.
  • Palm kernel olein is the liquid fraction d erived from the fractionation of palm kernel oil. Palm kernel olein for this present invention has a composition of 48% lauric acid (C12), 16% myristic acid (C14) and 15% oleic acid (Ci8:i). There are many health benefits of palm kernel olein such as high in antioxidants, helps to dexotify the body, assist in slowing down aging, increases cholesterol as contained in the low-density lipoprotein and others.
  • MCT oil is a highly concentrated source of medium-chain triglycerides. It’s man-made via a process called fractionation. This involves extracting and isolating the MCTs from coconut or palm kernel oil. MCT oil generally contain either 100% caprylic acid (C8), 100% capric acid (C10), or a combination of the two.
  • MCT are a component of many foods including coconut oil, palm kernel oil, butter, milk, yogurt and cheese (Nagao and Yanagita, 2009), with coconut and palm oils representing the richest dietary source of MCT (Anonymous, 2002; Marten et al, 2006). Edible MCT oils are obtained through lipid fractionation from sources such as coconut, oil and milk (Nagao and Yanagita, 2009; Marten et al., 2006). Palm-based MCT as extracted from the oil palm fruit is used for the present invention. MCT used for this present invention consist of caprylic acid (C8) and capric acid (Cio). As an alternative, MCT from coconut oil can also be used for this present invention. Benefits of MCT are to improved cognitive function, increased energy level and improved mood, decreased risk of cardiovascular disease, protection from neurodegenerative disease, reduced appetite and weight loss.
  • Red palm oil is a rich source of phytonutrients such as tocotrienols, tocopherols, carotenoids, phytosterols, squalene, and coenzyme Qio, all of which exhibit nutritional properties and oxidative stability. Mutagenic, nutritional, and toxicological studies have shown that red palm oil contains highly bioavailable [3-carotene and vitamin A and is reasonably stable to heat without any adverse effects.
  • Red palm oil contains many phytonutrients. Red palm oil is extracted from the flesh / mesocarp of the oil palm fruit just like palm oil but with a different technology that maintains the presence of pro-vitamin A carotenoid, a vitamin precursor. Red palm oil contains mainly beta-carotene (apart from alpha-carotene), which yields the most vitamin A out of all the provitamin A carotenoids.
  • red palm oil The benefits of red palm oil are:
  • alpha-carotene has anti-carcinogenic properties and studies have shown that higher alphacarotene intake is associated with lower risk of cancer
  • beta carotene is known for boosting skin health by increasing the skin's defence against UV radiation.
  • lycopene can reduce heart disease factors by lowering LDL (low-density lipoprotein) cholesterol.
  • polyethylene glycol castor oil is a mixture of triricinoleate esters of ethoxylated glycerol with small amounts of polyethyleneglycol ricinoleate and the corresponding free glycols.
  • the number (n) associated with the name of the substance represents the average number of oxyethylene units in the compound.
  • emulsifiers from group comprising non-ionic hydrophilic surfactants Polyethoxylated sorbitan esters are also further used for this present invention such as to aid in the oil in water emulsion such as polysorbate 80.
  • Polysorbate 80 is the abbreviation of “polyoxyethylene (20) sorbitan monooleate”, is a nonionic surfactant and emulsifier commonly used in food and cosmetics mainly due to its ability to mix water-based and oil -based ingredients well. [Source: https://foodadditives.net/emulsifiers/polysorbate-8o/]
  • the present invention provides a self-emulsifying composition, the composition comprising:
  • the composition is a palm-based vitamin E self-emulsifying composition.
  • composition is able to form an oil-in-water emulsion when comes in contact with an aqueous solution or watery conditions at the gastrointestinal tract.
  • the at least one active ingredient is a Tocotrienols-rich fraction (TRF).
  • TRF is obtained from palm fatty acid distillate (PFAD), palm oil, palm oil fractions or any combinations thereof.
  • the TRF comprises of Tocotrienols and tocopherols in a ratio range of between 70%: 30% to 80%: 20%.
  • the Tocotrienols amount in the TRF is in a range of between 30% to 50%.
  • the Tocotrienols amount in the composition is in a range of between 8% to 20% by weight of the composition.
  • Tocotrienols and tocopherols amount in the composition is in a range of between io% to 25% by weight of the composition.
  • the at least one oil carrier is a palm kernel olein, palm kernel oil, medium-chain triglycerides (MCT) liquid, red palm olein, red palm oil, refined, bleached deodorised (RBD) palm kernel oil, coconut oil, olive oil or in any combinations thereof.
  • MCT medium-chain triglycerides
  • RBD bleached deodorised
  • polyoxyethylene sorbitan monooleate preferably polysorbate 80
  • Particle size (or droplet size) for this present invention refers to the size of particles or droplets of the oil-in-water emulsion which is formed by the self-emulsifying composition when in contact with an aqueous solution or watery conditions in the stomach for this present invention, is measured using the particle analyser equipment Mastersizer 3000 by Malvern using a wet dispersion technique.
  • the focus here is on an advanced mode of delivery system in the form of nanoemulsions to improve bioavailability of the composition hence targeting particle size of less than 200nm, preferably less than loonm.
  • the self-emulsifying composition of the present invention provides a flexibility of selecting the amount of TRF used in the composition based on the preference and needs of the user of the present invention.
  • the self-emulsifying composition of the present invention forms an emulsion with particle size of not more than 15 pm for Tocotrienols-rich fraction (TRF) in a range of between 30% to 35% by weight of the composition and an emulsion with particle size of less than 2oonm, preferably less than toonm for Tocotrienols-rich fraction (TRF) in a range of between 22% to 29% by weight of the composition.
  • TRF Tocotrienols-rich fraction
  • the composition comprises:
  • the TRF in a range of between 15% to 40% by weight of the composition
  • the palm kernel olein is in a range of between 5% to 30% by weight of the composition
  • the red palm oil is in a range of between 1% to 30% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 1% to 35% by weight of the composition.
  • the particle size of the emulsion formed by the self-emulsifying composition of this present invention is in a range of 50nm to 15pm.
  • the composition comprises:
  • the TRF in a range of between 22% to 35% by weight of the composition
  • the palm kernel olein is in a range of between 15% to 26% by weight of the composition
  • the red palm oil is in a range of between 5 to 20% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 16% to 26% by weight of the composition.
  • the particle size of the emulsion formed by the self-emulsifying composition of this present invention is in a range of sonm to 15pm. In more pref erred modes of the present invention:-
  • the composition comprises:
  • the TRF in a range of between 30% to 35% by weight of the composition
  • the palm kernel olein is in a range of between 16% to 20% by weight of the composition
  • the red palm oil is in a range of between 6% to 10% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 20% to 25% by weight of the composition.
  • the particle size of the emulsion formed by the self-emulsifying composition of this present invention is less than 15 pm.
  • Oil component of the composition comprises the at least one active ingredient and the at least oil carrier. Ratio of the at least one active ingredient to the at least one carrier is 1.2: 1. Ratio of the oil component to the at least one emulsifier is 3:2.
  • the composition comprises:
  • the palm kernel olein is in a range of between 20% to 25% by weight of the composition
  • the red palm oil is in a range of between 14% to 18% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 17% to 23% by weight of the composition.
  • the particle size of the emulsion formed by the self-emulsifying composition of this present invention is less than 2oonm, preferably less than toonm.
  • Oil component of the composition comprises the at least one active ingredient and the at least oil carrier. Ratio of the at least one active ingredient to the at least one carrier is in a range of between i: 1.3 to 1: 1.9, preferably 1: 1.6. Ratio of the oil component to the at least one emulsifier is approximately 2:1.
  • the composition comprises:
  • the TRF in a range of between 15% to 40% by weight of the composition
  • the palm kernel olein or palm kernel oil or coconut oil in a range of between 5% to 30% by weight of the composition
  • red palm oil or red palm olein or RBD palm kernel oil or olive oil is in a range of between 1% to 30% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 1% to 35% by weight of the composition.
  • the composition comprises:
  • the TRF in a range of between 22% to 35% by weight of the composition
  • the palm kernel olein or palm kernel oil or coconut oil is in a range of between 15% to 26% by weight of the composition
  • the MCT liquid or palm kernel oil or palm kernel olein or coconut oil in a range of between 0.5% to 4% by weight of the composition
  • red palm oil or red palm olein or RBD palm kernel oil or olive oil is in a range of between 5 to 20% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 16% to 26% by weight of the composition.
  • the composition comprises:
  • the TRF in a range of between 30% to 35% by weight of the composition
  • the palm kernel olein or palm kernel oil or coconut oil is in a range of between 16% to 20% by weight of the composition
  • the MCT liquid or palm kernel oil or palm kernel olein or coconut oil in a range of between 1% to 3% by weight of the composition
  • red palm oil or red palm olein or RBD palm kernel oil or olive oil is in a range of between 6% to 10% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 20% to 25% by weight of the composition.
  • the composition comprises:
  • the palm kernel olein or palm kernel oil or coconut oil in a range of between 20% to 25% by weight of the composition
  • the MCT liquid or palm kernel oil or palm kernel olein or coconut oil in a range of between 1% to 3% by weight of the composition
  • red palm oil or red palm olein or RBD palm kernel oil or olive oil in a range of between 14% to 18% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 17% to 23% by weight of the composition.
  • Palm kernel olein can be substituted with palm kernel or coconut oil.
  • MCT liquid can be substituted with palm kernel oil, palm kernel olein or coconut oil.
  • Red palm oil can be substituted with red palm olein, palm kernel olein, palm kernel oil, RBD (refined, bleached and deodorised) palm kernel oil or olive oil.
  • MCTs have medium length fatty acids, 6 to 12 carbon atoms which makes it unique and this allows for efficient digestion and absorption into the blood system without additional enzymes as compared to other sources of fat such as olive oil, nuts and fish which consists of long-chain triglycerides.
  • MCTs are generally obtained from refining crude palm oil or coconut oil.
  • Coconut oil and palm kernel oil consists of up to 55% of MCT.
  • Olive oil can be used as an alternative due to the relatively similar fatty acid composition to red palm oil.
  • Red palm oil has about 70% unsaturated fatty acids and 30% saturated fat and olive oil has more than 70% unsaturated fatty acid and 20% saturated fat.
  • Palm kernel olein can be replaced with palm kernel oil and coconut oil due to its similar chemical composition.
  • TRF is preferably not more than 40% and not less than 15% as it will disrupt the selfemulsifying properties based on the screening and analysis using the ternary phase diagram technique.
  • Palm kernel olein is preferably not more than 30% and not less than 5% in order to achieve the self-emulsifying properties for the required hydrophilic-lipophilic balance of the selfemulsifying composition of the present invention.
  • Palm kernel olein or palm kernel oil or coconut oil is preferably not more than 30% and not less than 5% in order to achieve the self-emulsifying properties for the required hydrophilic- lipophilic balance of the self-emulsifying composition of the present invention.
  • MCT liquid is preferably not more than 7% and not less than 0.3% in order to achieve the selfemulsifying properties for the required hydrophilic-lipophilic balance of the self-emulsifying composition of the present invention.
  • MCT liquid or palm kernel oil or palm kernel olein or coconut oil is preferably not more than 7% and not less than 0.3% in order to achieve the self-emulsifying properties for the required hydrophilic-lipophilic balance of the self-emulsifying composition of the present invention.
  • Red palm oil is preferably not more than 30% and not less than 1 % in order to achieve the self-emulsifying properties for the required hydrophilic-lipophilic balance of the selfemulsifying composition of the present invention.
  • Red palm oil or red palm olein or RBD palm kernel oil or olive oil or palm kernel olein or palm kernel oil is preferably not more than 30% and not less than 1 % in order to achieve the selfemulsifying properties for the required hydrophilic-lipophilic balance of the self-emulsifying composition of the present invention.
  • Polyoxyethylene sorbitan monooleate are preferably not more than 35% and not less than 1% in order to achieve the self-emulsifying properties for the required hydrophilic-lipophilic balance of the self-emulsifying composition of the present invention.
  • the composition is contained in soft gelatin capsules, hard gelatin capsules, chewable gummies or plant-based capsules or others based on consumer preference, whereby the composition is administered orally.
  • the composition self-emulsifies into an emulsion when comes in contact with an aqueous solution or watery conditions in the stomach, when the capsule ruptures in the presence of a sufficien t amoun t of water in the stomach.
  • the emulsion formed has a particle size of less than 15pm for TRF in a range of between 30% to 35% by weight of the composition and particle size of less than 2oonm (preferably less than loonm) for TRF in a range of between 22% to 29% by weight of the composition.
  • the wei ght of the capsule can be selected based on the needs and preference of the user of the present invention - for example loomg, 2oomg, 3oomg, soomg capsules or others.
  • the present invention also provides the use of a palm-based vitamin E self-emulsifying composition as health and dietary supplements comprising at least one active ingredient in a range of between 15% to 40% by weight of the composition, at least one oil carrier in a range of between 14% to 55% by weight of the composition and at least one emulsifier in a range of between 25% to 55% by weight of the composition.
  • the present invention also provides the use of a palm-based vitamin E self-emulsifying composition as health and dietary supplements further comprising:
  • a TRF in a range of between 22% to 29% by weight of the composition
  • a palm kernel olein in a range of between 20% to 25% by weight of the composition
  • an MCT liquid in a range of between 1% to 3% by weight of the composition
  • a red palm oil is in a range of between 14% to 18% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 17% to 23% by weight of the composition.
  • the particle size of emulsion formed by this composition is less than 2oonm, preferably less than loonm; and/or
  • a TRF’ in a range of between 15% to 40% by weight of the composition
  • a palm kernel olein or palm kernel oil or coconut oil in a range of between 5% to 30% by weight of the composition
  • an MCT liquid or palm kernel oil or palm kernel olein or coconut oil in a range of between 0.3% to 7% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 1% to 35% by weight of the composition
  • a TRF in a range of between 30% to 35% by weight of the composition
  • a palm kernel olein or palm kernel oil or coconut oil in a range of between 16% to 20% by weight of the composition
  • an MCT liquid or palm kernel oil or palm kernel olein or coconut oil in a range of between 1% to 3% by weight of the composition
  • polyoxyethylene sorbitan monooleate in a range of between 20% to 25% by weight of the composition.
  • the particle size of emulsion formed by this composition is less than 2oonm, preferably less than loonm.
  • the present invention further provides a method of producing a palm-based vitamin E selfemulsifying composition, the method comprising mixing together at least one active ingredient in a range of between 15% to 40% by weight of the composition to an at least one oil carrier in a range of between 14% to 55% by weight of the composition and an at least one emulsifier in a range of between 25% to 55% to form an oil-in-water emulsion.
  • the method further comprising:
  • the particle size of emulsion formed by the composition is less than 200nm, preferably less than toonm; and/or
  • the particle size of emulsion formed by the composition is less than 15 pm; and/or
  • the particle size of emulsion formed by the composition is less than 200nm, preferably less than loonm.
  • Emulsifiers polyoxyethylene sorbitan monooleate, polyethylene-glycol (PEG) 20 castor oil, lecithin, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil
  • TRF miscibility of the TRF was tested with the carrier oils and surfactants to obtain a homogenous composition. It was found that the TRF was miscible with each oil carrier component of the composition but immiscible with some emulsifiers tested with.
  • Polyoxyethylene sorbitan monooleate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, palm kernel oil and MCT liquid were used in the screening of the self-emulsifying composition of the present invention.
  • the screening was done using the ternary phase diagram technique (per Figure 1) which showed possible phases and their equilibrium according to the composition of the mixture of all components as tested for the proposed self-emulsifying composition.
  • Optimisation of the selected self-emulsifying compositions were further conducted by adjusting the existing components in the composition and by adding new components to the composition.
  • the objectives for optimisation here are to obtain high-loading capacity for the TRF, fine droplets and fast emulsification rate.
  • the optimisation of the selected self-emulsifying compositions were based on the TRF amount in a range of between 15% to 40% (by weight of the composition).
  • a self-emulsifying composition with a TRF loading capacity of 50% was able to be reached, however, the droplet or particle size of the emulsion as formed by the self-emulsifying composition is in the micrometer size range.
  • Self-emulsifying compositions with TRF loading capacity in a range of between 40% to 50% (by weight of the composition) has shown a poor capability to produce particle size of the composition below 1 micrometer (nanometer range).
  • Self-emulsifying compositions with TRF loading capacity in a range of between 30% to 40% has shown the capability to produce particle size of the emulsion to be below 1 pm (nm range), however some inconsistencies can still be noticed using different batches of TRF.
  • Self-emulsifying compositions with TRF loading capacity in a range of 15% to 40% has shown good emulsification properties and particle size (or droplet size) of the composition below 1 micrometer (nanometer range).
  • Particle size (or droplet size) for this present invention refers to the size of particles or droplets of the oil-in-water emulsion which is formed by the self-emulsifying composition when in contact with an aqueous solution or watery conditions in the stomach for this present invention, is calculated using the equipment Mastersizer 3000 by Malvern using a wet dispersion technique.
  • “Good emulsification properties” for this present invention means the mixing of all components of the composition to create a homogenous oil-in-water emulsion that is stable.
  • Figure 1 shows that there is only a small range for the self-emulsification area for the TRF (indicated by the smaller triangle as contained in the bigger triangle on the left-side).
  • the TRF is unable to emulsify, not able to retain good particle size and good physical stability of the formulation at the area beyond the triangle.
  • the screening was conducted using a ternary phase diagram as a tool to screen possible components and concentrations that can be formulated to produce a self-emulsifying composition.
  • the components of the composition are divided by three phases in the ternary diagram - active ingredient, oil carrier and emulsifiers.
  • Multilayer ternary diagrams were also created according to the number and ratio of components in the oil carrier phase and emulsifier mixtures.
  • Some self-emulsifying compositions were prepared and evaluated on their self-emulsifying properties by considering the lipophilic and hydrophilic balance. The results for each line series of the individual component ratio for each phase of the composition according to each layer of the ternary diagram was used to predict final compositions that can produce a good self-emulsifying composition per the present invention. All information obtained was then evaluated further in order to arrive at the final self-emulsifying composition.
  • the self-emulsifying composition of the present invention comprises:-
  • the TRF is in a range of between 15% to 40% by weight of the composition, preferably in a range of between 22% to 35%;
  • the palm kernel olein is in a range of between 5% to 30% by weight of the composition, preferably in a range of between 15% to 26% or (b) the palm kernel olein or palm kernel oil or coconut oil is in a range of between 5% to 30% by weight of the composition, preferably in a range of between 15% to 26%;
  • the MCT liquid is in a range of between 0.3% to 7% by weight of the composition, preferably in a range of between 0.5% to 4% or (b) the MCT liquid or palm kernel olein or palm kernel oil or coconut oil is in a range of between 0.3% to 7% by weight of the composition, preferably in a range of between 0.5% to 4%;
  • red palm oil is in a range of between 1% to 30% by weight of the composition, preferably in a range of between 5% to 20% or
  • red palm oil or red palm olein or RBD palm kernel oil or palm kernel oil or palm kernel olein or olive oil is in a range of between 1% to 30% by weight of the composition, preferably in a range of between 5% to 20%;
  • polyoxyethylene sorbitan monooleate is in a range of between 1% to 35% by weight of the composition, preferably in a range of bet ween 16 % to 26%.
  • the stability of the composition of the present invention was also studied whereby the prepared samples were stored at_4°C, 25°C (Room Temperature) and 4O°C. Particle size analysis were carried out at intervals of 2 weeks, 1-month, 3-months and 6-months to determine the stability of the self-emulsifying composition.
  • the final self-emulsifying composition of the present invention has shown good physicochemical characteristics that the composition is miscible and able to self-emulsify to produce an emulsion upon contact with water under gentle agitation.
  • the exact quantity (%) for each component of the composition varies between different batches of TRF, hence, the proposed ranges as provided above in order to derive at a self-emulsifying composition with the highest loading capacity of the TRF in the composition, small particle size (droplet size) of the emulsion, fast rate of emulsification, high gastrointestinal absorption (i.e. high bioavailability), minimum ingredients and easy to source ingredients used in the selfemulsifying composition of the present invention.
  • the novel and unique components of the composition of the present invention are not found in any prior arts and/ or other Vitamin E products to-date. All components used produces a unique composition with tremendous health potential & benefits, high bioavailability for effective absorption into the bloodstream of the body and flexible oral intake without being affected by food intake or physiological circumstances of a consumer.
  • the closest prior arts / products are Tocotrienols capsules by Davos Life E3 and Tocovid.
  • the composition of the present invention varies greatly from the formulation of these products. Apart from that, the particle size of the emulsions by these competitors are more than 2oonm and not in the nanometer-range.
  • the selfemulsifying composition of the present invention provides a flexibility of selecting the amount of TRF used in the composition based on the preference and needs of the user of the present invention.
  • the self-emulsifying composition of the present invention forms an emulsion with particle size of not more than 15pm for Tocotrienols-rich fraction (TRF) in a range of between 30% to 35% by weight of the composition and an emulsion with particle size of less than 2oonm, preferably less than loonm for Tocotrienols-rich fraction (TRF) in a range of between 22% to 29% by weight of the composition.
  • TRF Tocotrienols-rich fraction

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Abstract

La présente invention concerne une composition auto-émulsionnable, la composition comprenant au moins un principe actif dans une plage comprise entre 15 % et 40 % en poids de la composition, au moins un véhicule huileux dans une plage comprise entre 14 % et 55 % en poids de la composition et au moins un émulsifiant dans une plage comprise entre 25 % et 55 %.
PCT/MY2022/050086 2021-12-27 2022-09-15 Composition auto-émulsionnable WO2023128750A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6596306B1 (en) 2000-07-07 2003-07-22 David Ho Sue San Ho Drug delivery system:formulation for fat-soluble drugs
US20160166535A1 (en) * 2013-07-22 2016-06-16 Ohio State Innovation Foundation Methods for Reducing the Occurrence of Hot Flashes
EP3223795A1 (fr) 2014-11-25 2017-10-04 Kl-Kepong Oleomas Sdn Bhd Formulation permettant une administration efficace du tocotriénol
WO2018194444A1 (fr) * 2017-04-21 2018-10-25 Kl-Kepong Oleomas Sdn Bhd Composition pour la régulation de l'appétit et sa méthode
WO2021246861A1 (fr) * 2020-06-04 2021-12-09 Hovid Berhad Composition pour la normalisation de la stéatose hépatique et son procédé de production

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6596306B1 (en) 2000-07-07 2003-07-22 David Ho Sue San Ho Drug delivery system:formulation for fat-soluble drugs
US20160166535A1 (en) * 2013-07-22 2016-06-16 Ohio State Innovation Foundation Methods for Reducing the Occurrence of Hot Flashes
EP3223795A1 (fr) 2014-11-25 2017-10-04 Kl-Kepong Oleomas Sdn Bhd Formulation permettant une administration efficace du tocotriénol
US10493055B2 (en) 2014-11-25 2019-12-03 Kl-Kepong Oleomas Sdn Bhd Formulation for effective tocotrienol delivery
EP3223795B1 (fr) * 2014-11-25 2021-09-01 KL-Kepong Oleomas Sdn Bhd Formulation permettant une administration efficace du tocotriénol
WO2018194444A1 (fr) * 2017-04-21 2018-10-25 Kl-Kepong Oleomas Sdn Bhd Composition pour la régulation de l'appétit et sa méthode
WO2021246861A1 (fr) * 2020-06-04 2021-12-09 Hovid Berhad Composition pour la normalisation de la stéatose hépatique et son procédé de production

Non-Patent Citations (1)

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Title
BIOMED PHARMACOTHER, vol. 58, no. 3, April 2004 (2004-04-01), pages 173 - 82

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