TW201325620A - Lecithin carrier vesicles and methods of making the same - Google Patents

Abstract

A hydrated lecithin carrier vesicle composition includes a lecithin-derived membrane-forming lipid vesicle in conditioned water for incorporation of an active ingredient to form a dispersed composition. A method of making the hydrated lecithin carrier vesicle includes using lecithin having not more than about 80% w/w phosphatidylcholine in the presence of conditioned water.

Description

Lecithin carrier vesicle and method for preparing same Reference related application

Priority is claimed on US Provisional Application No. 61/357,959, the entire disclosure of which is incorporated herein in

Field of invention

This application is directed to a lecithin carrier composition and a method of making a lecithin carrier composition.

Background of the invention

In order to store and utilize the active ingredient in an aqueous environment, it is necessary to be able to disperse and stabilize these compounds. A method generally used for dispersion includes emulsification in which droplets of the active ingredient are prepared by using a surfactant, or by grinding or shearing a desired compound into nanoparticle, and then dispersing the nanoparticle into a surfactant. Decentralized and stabilized. However, such surfactant emulsions are generally unstable and the surfactants may be toxic or have undesirable characteristics such as poor taste and/or a turbid appearance of the dispersion. These properties make these emulsions unsuitable for use in dispersing active ingredients for consumption.

Phospholipids and other film-forming lipids are widely used to coat active ingredients for delivery in aqueous environments. In particular, phospholipid bilayer vesicles are formed when the dried phospholipids are hydrated in an aqueous solution, thereby producing a concentric multiple phospholipid bilayer separated by an aqueous compartment, referred to as a multilamellar vesicle (MLV). Phospholipids can also be used to form monolayer vesicles (UV). These unilamellar vesicles can be separated into multi-layered vesicles into three types - small unilamellar vesicles (SUV) with an average diameter ranging from 20 to 100 nm; large unilamellar vesicles (LUV) with an average diameter ranging from 150 to 1,000 Nm; and multilamellar vesicles (MLV) with an average diameter ranging from 150 to 5,000 nm.

Phospholipid phosphocholine (PC) is a major component of commercially available phospholipid vesicles, usually with the addition of a suitable amount of charged lipids, such as phospholipid glycerol. Lecithin is a mixture of oils extracted from animals or plants and extracted with a hydrating solvent, which comprises acetone-insoluble phospholipids, the main components of which are phospholipid choline (PC), phospholipid oxime ethanol (PE) and phospholipids. Inositol alcohol (PI), combined with various amounts of other substances such as triglycerides, fatty acids, and carbohydrates.

A common source of lecithin phospholipid choline, which is used to prepare phospholipid bilayers (Keller, BC, 2001, Trends in Food Science Technology , 12, 25-31). Since the dispersing ability and stability of phospholipid vesicles have been shown to depend on the amount of phospholipid choline in the vesicles, a high PC content lipid mixture (i.e., greater than 80% PC) is used to form the phospholipid vesicle carrier. While attempts have been made to use a lower PC content to form dispersed vesicles for coating the curcumin compound, such attempts have not resulted in the dispersion of vesicles that coat the curcumin. Takahashi et al. J of Oleo Sci ., 2007, 56, 35-42; (attempting to make liposomes having low-PC content) and Takahashi et al. J. of Agr. and Food Chem ., 57, 9141-9146 ( Stating and proving that low-PC content liposomes did not work) All of which are incorporated herein by reference.

In many of the procedures, the phospholipid choline is separated from the lecithin by a de-oiling process using acetone followed by an extraction of ethyl ketone and a final lipid chromatography step to obtain a high level of phospholipid choline (ie, More than 80% of the total lipid content PC). To inhibit hydrolysis of phospholipid vesicles, ionic buffers are used to control and maintain the pH of the vesicle environment (Vernooij, E., et al., Journal of Controlled Release, 2002 , 79 , 299-303). However, the high PC content of lecithin is expensive to manufacture, and the manufacturing method requires certain organic solvents, making the composition unsuitable for human use. In this regard, there is a need for a phospholipid vesicle carrier that is capable of providing a dispersion of active ingredient stability using a minimum of components, and that does not require a toxic solvent or an expensive high PC content lipid mixture.

Summary of invention

In some embodiments of the invention, a composition comprises a stable homogeneous dispersion comprising a membrane having an membrane and an aqueous phase, the vesicle comprising a phospholipid choline content of about 80 w/w% or less Lecithin, and an active ingredient are incorporated into the film of the vesicle; and the stable homogeneous dispersion also includes conditioned water. In some embodiments, the conditioned water has less than 100 ppm hard ions and/or conductivity less than 20 microsiemens per centimeter. In some embodiments, the vesicle has a volume weighted mean diameter of about 120 nm or less. In other embodiments, the membrane of the vesicle is a phospholipid bilayer.

The stabilized homogeneous dispersion can be a clear dispersion. The stable homogeneous dispersion may also include stabilizers such as polysorbates or polyoxyethylene alkyl ethers.

In some embodiments, the stable homogeneous dispersion may also include an alcohol, and the alcohol may be a short chain aliphatic alcohol such as an isomer of methanol, ethanol, propanol or butanol.

In some embodiments, the active ingredient is a lipophilic compound, and the lipophilic compound can be at least one of the following: an olfactant, a natural flavor, an essential oil, a colorant, a vitamin, a vitamin salt. Class, pharmaceutically active vitamin metabolites, pharmaceutically active vitamin metabolite salts, phytochemicals, oil-soluble acids, oil-soluble alcohols, essential fatty acids, primrose oil, safflower oil, fish oil, marine life Lipids, cyclosporin A, propofol, liposoluble protease inhibitors, antiretroviral compounds, antibiotics, carotenoids, steroid hormones, flavonoids , proteins, enzymes, coenzymes, paints, inks and agrochemicals.

In other embodiments, a composition comprises a vesicle comprising lecithin having a phospholipid choline content of about 80 w/w% or less, and an active ingredient; and the composition also comprises conditioned water. In some embodiments, the membrane of the vesicle is a phospholipid bilayer. The composition also includes a stabilizer such as a polysorbate or a polyoxyethylene alkyl ether. In some embodiments, the composition can also include an alcohol.

In still other embodiments, a composition comprising a homogeneous mixture comprising lecithin having a phospholipid choline content of about 80 w/w% or less, an active ingredient, and an alcohol. The homogeneous mixture can also include conditioned water, which can be present in an amount of about 10% by weight or less relative to the lecithin. The homogeneous mixture may also include an oil. The alcohol of the homogeneous mixture may be present in an amount of about 50% by weight or less relative to the amount of the lecithin.

In still other embodiments, a method of producing a vesicle carrier composition comprises hydrating lecithin having a phospholipid choline content of 80 w/w% or less in adjusted water to form an egg having a membrane and an aqueous phase a phospholipid vesicle; and incorporating the active ingredient into the membrane of the lecithin vesicle to form a membrane-loaded lecithin vesicle.

Prior to incorporation of the active ingredient, the method of producing a vesicle carrier composition can further comprise treating the lecithin vesicles into a lecithin vesicle monolayer, and the treatment can include homogenization or high shear mixing. In some embodiments, the conditioned water can include an alcohol.

The method may further comprise adding a stabilizer to the lecithin prior to hydration, or adding a stabilizer to the lecithin vesicle before or after incorporation of the active ingredient. The method can further comprise treating the membrane-loaded lecithin vesicles after the active ingredient is incorporated into the membrane of the lecithin vesicles to reduce the size of the membrane-loaded lecithin vesicles, and the treatment can include Homogenization or high shear mixing.

In some embodiments, the method of producing a vesicle carrier composition further comprises drying the composition into a solid form and/or incorporating the composition into an emulsion or paste.

In still other embodiments, a method of producing a vesicle carrier composition having a membrane and an aqueous phase, comprising mixing lecithin, an active ingredient, and an alcohol having a phospholipid choline content of about 80 w/w% or less, Forming a homogeneous liquid mixture; and hydrating the homogeneous liquid mixture with the adjusted water to form a lecithin vesicle, wherein the active ingredient is incorporated into the membrane of the lecithin vesicle.

The method of producing a composition of a vesicle carrier may also include the step of providing oil and/or adjusted water with lecithin having an amount of phospholipid choline of about 80 w/w% or less, an active ingredient, and an alcohol. Heat during mixing while mixing. In some embodiments, up to about 10% by weight of the adjusted water relative to the lecithin can be provided. In some embodiments, an alcohol of about 50% by weight or less relative to the amount of the lecithin can be provided. In some embodiments, the method further comprises, after hydrating the homogeneous liquid mixture, treating the lecithin vesicles to form a lecithin vesicle monolayer, and in yet other specific examples, forming a homogeneous composition The method comprises mixing lecithin having an phospholipid choline content of 80 w/w% or less with an active ingredient and an alcohol, and providing an alcohol of about 50% by weight or less relative to the amount of the lecithin. The method may further comprise mixing the adjusted water with the lecithin having a phospholipid choline content of 80 w/w% or less and an active ingredient and an alcohol, and providing a lecithin relative to the lecithin The amount is up to about 10% by weight of the adjusted water.

In still other embodiments, a method of producing a vesicle carrier composition comprising hydrating lecithin having a phospholipid choline content of greater than about 80 w/w% in adjusted water to form a lecithin having a membrane and an aqueous phase a vesicle; and incorporating the active ingredient into the membrane of the lecithin vesicle to form a membrane-loaded lecithin vesicle. In some embodiments, the lecithin of the method can include phospholipid glycerol.

In some embodiments, the active ingredient of the method is selected from the group consisting of cyclosporin A, propofol, liposoluble protease inhibitors, antiretroviral compounds, Antibiotics, carotenoids, steroid hormones, flavonoids, enzymes and coenzymes.

In some embodiments, the method further comprises treating the lecithin vesicles prior to incorporation of the active ingredient into a lecithin vesicle monolayer, and the treatment can include homogenization and high shear mixing. .

In some embodiments, the method further comprises adding a stabilizer to the lecithin prior to hydration, or adding a stabilizer to the lecithin vesicle before or after incorporation of the active ingredient. The method may further comprise treating the membrane-loaded lecithin vesicles after the active ingredient is incorporated into the membrane of the lecithin vesicles to reduce the size of the membrane-loaded lecithin vesicles, and the treatment Homogenization or high shear mixing can be included.

In still other embodiments, a method of producing a vesicle carrier composition having a membrane and an aqueous phase comprises mixing lecithin having an phospholipid choline content of more than 80 w/w%, an active ingredient, and an alcohol to form a homogeneous a liquid mixture; and hydrating the homogeneous liquid mixture with the adjusted water to form a lecithin vesicle, wherein the active ingredient is incorporated into the membrane of the lecithin vesicle. In some embodiments, the lecithin of the method can include phospholipid glycerol.

In some embodiments, the active ingredient of the method is selected from the group consisting of cyclosporin A, propofol, liposoluble protease inhibitors, antiretroviral compounds, Antibiotics, carotenoids, steroid hormones, flavonoids, enzymes and coenzymes.

In some embodiments, the method further comprises mixing the oil and/or the adjusted water with the lecithin having an phospholipid choline content of more than 80 w/w%, an active ingredient, and an alcohol. heating. In some embodiments, up to about 10% by weight of the adjusted water relative to the lecithin can be provided. In some embodiments, an alcohol can be provided in an amount up to about 50% by weight or less relative to the lecithin.

In some embodiments, the method further comprises treating the lecithin vesicles after hydrating the homogeneous liquid mixture, forming the lecithin vesicle monolayer, and the treating can include homogenization or high shear mixing.

Simple illustration

Figure 1A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in hydrated water prepared in adjusted water and (left to right) 0, 10, 20, 30, 40 or 50% ethanol. Lecithin carrier vesicles.

Figure 1B is a graph depicting the turbidity of the fish oil composition shown in Figure 1A in accordance with a specific example of the present invention.

Fig. 1C is a graph showing particle size distribution data obtained from the fish oil composition shown in Fig. 1A according to a specific example of the present invention.

2A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in adjusted water and (left to right) 0, 10, 20, 30, 40 or 50% ethanol and polysorbate The hydrated lecithin carrier vesicles in the alcohol ester.

Figure 2B is a graph depicting the turbidity of the fish oil composition shown in Figure 2A in accordance with a specific example of the present invention.

Fig. 2C is a graph showing particle size distribution data obtained from the fish oil composition shown in Fig. 2A according to a specific example of the present invention.

Figure 3 is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and 30% ethanol (with or without polysorbate) .

Figure 4A is a photograph of the essential oil composition according to a specific example of the present invention at t = 0 and t = 12 months, wherein the essential oil is dispersed in a hydrated lecithin carrier formulated in adjusted water and polysorbate. In the vesicles.

Fig. 4B is a graph showing particle size distribution data obtained from the essential oil composition (t = 0) shown in Fig. 4A according to a specific example of the present invention.

Fig. 4C is a graph showing particle size distribution data obtained from the essential oil composition (t = 12 months) shown in Fig. 4A according to a specific example of the present invention.

Fig. 5A is a photograph of a krill oil composition according to a specific example of the present invention, wherein the krill oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and a stabilizer.

Fig. 5B is a graph showing particle size distribution data obtained from the krill oil composition shown in Fig. 5A according to a specific example of the present invention.

Figure 6A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and 30% isopropanol.

Figure 6B is a graph showing particle size distribution data obtained from fish oil compositions in 30% isopropanol shown in Figure 6A in accordance with a specific example of the present invention.

Figure 7A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and 5% isopropanol.

Fig. 7B is a graph showing particle size distribution data obtained from the fish oil composition in 5% isopropanol shown in Fig. 7A according to a specific example of the present invention.

Figure 8A is a hydrated lecithin-containing vesicle having (1) essential oil (carvacrol) and polysorbate; (2) essential oil; and (3) lecithin alone (without essential oil) according to a specific example of the present invention. A photo of the composition in the middle.

Fig. 8B is a graph showing particle size distribution data obtained from the composition ( 1 ) having essential oil and polysorbate in Fig. 8A of the specific example of the present invention.

Fig. 8C is a graph showing particle size distribution data obtained from the composition ( 2 ) having essential oil according to Fig. 8A of the specific example of the present invention.

Fig. 8D is a graph showing particle size distribution data obtained from the composition ( 3 ) having individual lecithin according to Fig. 8A of the specific example of the present invention.

Detailed description

In aspects of the invention, a hydrated lecithin carrier vesicle (HLCV) composition comprises lecithin having a phospholipid choline content of up to about 80 w/w% and adjusted water. The conditioned water hydrates the lecithin to form HLCV. In some embodiments, the HLCV can have at least one active ingredient dispersed therein. However, in some embodiments, the HLCV composition includes an alcohol that can help form the HLCV dispersion of the active ingredient and determine proper hydration in the conditioned water. In other embodiments, the HLCV composition further comprises one or more stabilizers. In some embodiments, the active ingredient is dissolved in the lecithin of a homogeneous liquid mixture in the presence or absence of an alcohol. Other aspects of the invention are directed to methods of making the HLCV composition and a homogeneous mixture.

In other embodiments of the invention, a hydrated lecithin carrier vesicle (HLCV) composition consists essentially of: a vesicle having a membrane and an aqueous phase, and conditioned water. In the specific examples, the term "consisting essentially of", in the meaning of the definition of the term below, means that lecithin particles that are not vesicles and lecithin-based particles (or nanoparticles) are generally absent. ) the composition. However, these specific examples include the same vesicles as the above and the specific examples described below, and can be produced by any of the methods described below. Moreover, these specific examples may further include any of the active ingredients and/or other components (e.g., stabilizers, alcohols, and/or oils) described below. Indeed, except for the general exclusion of non-vesicular lecithin-based materials (eg, non-vesicular lecithin particles and nanoparticles, and/or nanocrystals of active ingredients coated with non-vesicular lecithin) In addition to the composition, these specific examples have the same composition as the above and the specific examples described below (e.g., they may be prepared by using the same materials and methods, and may include the same active ingredients and other components, Such as alcohols, stabilizers, oils, etc.).

In accordance with this disclosure, the use of lecithin to disperse the active ingredient is beneficial to the compound to be absorbed and has utility in many other fields including, but not limited to, agriculture, horticulture, health foods, pharmaceuticals (for disease diagnosis). , treatment and mitigation), cosmetics and personal care products, fragrances and colorants, environmental care, inorganic and composite materials, paints and inks, catalysis, and other areas where low-cost natural dispersants are needed. For all of the specific examples of the invention, it is contemplated to optionally add other agents, including water soluble materials, to the hydrated lecithin carrier vesicle dispersion to increase its suitability for use in a given application, such as addition. A water soluble antioxidant, such as citric acid, to improve the shelf life of the nutritional product. The selection of a particular additive will be apparent to those skilled in the art.

Aspects of the present invention provide for the use of bulk food or industrial grade lecithin to cost-effectively dissolve water insoluble and partially water insoluble materials, and are widely used in consumer products, including foods, beverages, and nutritional supplements, among others. The efficiency of commercialization relies on the application of the cost of excluding raw materials using high PC lecithin (i.e., lecithin with more than 80 w/w% phospholipid choline).

The lecithins used herein are defined as a composite mixture obtained from an oil extracted by a hydrating solvent, as defined by the Joint World Health Orgαnizationl/United Nations Food Safety Agency Evaluation Committee for Food Additives (JECFA). (Food and Agriculture Organization of the United Nations, Food and Nutrition Paper 52, "Compendium of Food Additive Specifications" (FNP 52), Addendum 2 (1993), the entire disclosure of which is incorporated herein by reference. The composite mixture comprises acetone-insoluble phospholipids, including predominantly phospholipid choline, phospholipid oxime ethanolamine, and phospholipid osmolarity, as well as small amounts of triglycerides, fatty acids, and carbohydrates.

A vesicle as used herein is defined as a composition having a film-forming lipid component and an aqueous phase. In some embodiments, the film-forming lipid component is a phospholipid bilayer membrane. Moreover, the terms "vesicle" and "carrier" as used throughout this disclosure and in the scope of the patent application may be used interchangeably.

An active ingredient as used herein means any compound selected to be incorporated into a vesicle and capable of being incorporated into a vesicle. For example, in some embodiments, as discussed below, the active ingredient can be lipophilic, including many amphoteric compounds.

Lipophilic compounds have better solubility in fats, oils, lipids, and organic solvents such as ethanol, methanol, diethyl ether, acetone, chloroform, and benzene than in water. In such structures, the lipophilic compound contains a hydrophilic moiety such as a hydroxyl group in cortisol and a carboxylic acid group in the long chain fatty acid. In some embodiments, the lipophilic compound binds to the film-forming lipid component of the vesicle. In some embodiments, the lipophilic compound has a log P value ranging from about 0 to about 8, where a higher log P value corresponds to a higher lipophilicity. In some other embodiments, the lipophilic active ingredient has a log P value ranging from about 2 to about 7.

The terms "lipophilic compound" and "lipophilic active ingredient" as used herein are used interchangeably and mean that the solubility in organic solvents, fats and oils is higher than in water. The term "lipophilic" also encompasses a number of amphoteric compounds including compounds having both hydrophobic and hydrophilic regions. Indeed, the molecule may contain good aqueous (hydrophilic) motifs such as hydroxyl groups in cortisol and carboxylic acid groups in long chain fatty acids. This is true for many (biological) actives of the compositions and methods for aqueous dispersion formation provided by a number of specific examples of the invention. In these examples, the molecule can also be described as amphoteric. The methods and compositions of the present invention comprise entities that can be described as such and that are dispersible in the bilayer of the hydrated lecithin carrier; some specific examples are exemplified. In general, the amphiphile is disposed in two portions of the bilayer, and the hydrophilic portion thereof is bonded to the polar surface, and the lipophilic portion refers to the thiol chain of the phospholipid in the interior of the bilayer.

Dispersion as used herein means a dispersion in which the lecithin-based phase is generally uniformly distributed in a large amount of aqueous solution. In addition, if the dispersion used herein does not exhibit physical instability due to significant phase separation, such as vesicle aggregation and precipitation separation or cream formation (respectively, condensation sinks to the bottom of the mixture or rises to the surface of the mixture). ), or the incorporated lipophilic material is separated from the vesicles and forms a distinct agglomerate, which is stable. That is, in the dispersion of the HLCV in which the active ingredient is not stabilized, substantially no distribution of all the vesicles in the dispersion is agglomerated. For compositions comprising the stability of the active ingredient, in addition to the vesicle stability discussed above, the active ingredient is still properly associated with the vesicles. For example, if a lipophilic compound is incorporated into an HLCV dispersion, the hydrophobic region of the lipophilic compound binds (contacts) to the non-polar region of the phospholipid vesicle membrane. For a composition incorporating a lipophilic compound having a hydrophilic moiety in the HLCV dispersion, the hydrophilic region of the lipophilic compound binds to the polar region of the phospholipid vesicle membrane, and the hydrophobic region and the phospholipid sac The non-polar regions of the membrane are combined. Thus, a HLCV having a stability incorporated into an active ingredient also means that substantially all of the active ingredients in the composition are incorporated into or incorporated with the vesicle membrane. A vesicle carrier having an active ingredient on its membrane is also referred to as a "supported" carrier vesicle, in particular a phospholipid membrane incorporating the active ingredient into the vesicle, which is stabilized against agglomeration in a large amount of aqueous solution or degradation. Accordingly, the active ingredient incorporated into the phospholipid membrane environment and so dispersed in the aqueous medium is stable in other environments (eg, food, beverage, gastrointestinal tract or digestive tract).

The adjusted water used herein is defined as water having less than 100 ppm hard ions, and in some embodiments less than 60 ppm hard ions. Hard ions can cause water to harden, and the free hard-ion calcium and magnesium ions are generally found in water. Adjusted water means water with a reduced level of free hard ions, whether the water system is leveled without treatment (ie, "soft" water) or where treatment is required. The measurement of hardness is by EDTA titration, such as the method described in ASTM Method D1126 "Standard Test Method for Hardness in Water". The treatment to reduce the hardness may include a chelating method. Natural soft water (i.e., water having a hard ion having a hardness of less than about 100 ppm) is adapted to the adjusted water for the purposes of this disclosure. In some embodiments, the water is substantially free of buffer ions, while in other embodiments, the water has been purified by distillation, deionization, reverse osmosis or similar techniques such that the conductivity is less than 20 microsiemens per centimeter. Buffered ions are those that are resistant to pH changes, such as phosphates, citrates, acetates, and tris(hydroxymethyl)methylamine ions. In a specific example of the present invention, it is confirmed that the quality of water has an influence on the final dispersion and stability of lecithin vesicles. Vesicles with unstable vesicles and/or having a broad or skewed size distribution (even if they are stable) may result in turbid dispersion. Accordingly, although the addition or presence of a stabilizer is not necessary, the lack of a stabilizer, the possibility of whitening caused by HLCV depends inversely on the purity of water, that is, the purity of water increases, and the possibility of whitening decreases.

Hydrated lecithin carrier vesicles (HLCV)

A specific embodiment of the invention is directed to a hydrated lecithin carrier vesicle in which one or more active ingredients are incorporated. The HLCV is made using lecithin with a low PC content and adjusted water (CW).

Lecithin with low PC content

The lecithin used to make the HLCV has a low PC content. As used herein, lecithin having a low PC content means a lecithin ranging from non-deoiled lecithin to lecithin having a phospholipid choline content of about 80 w/w% or less. Indeed, in some embodiments, the lecithin has a PC content below, but does not include 80 w/w%. For example, the HLCV dispersion can be made from food grade materials that are known to be acceptable for consumption, including those listed by the U.S. Food and Drug Administration as Generally Regarded As Safe (GRAS). Accordingly, a specific example of the invention has a food grade lecithin having a phospholipid choline content of from about 20 to about 80 w/w%. In other embodiments, the lecithin has a phospholipid choline content of from about 20 to about 70 w/w%. In other embodiments, the lecithin has a phospholipid choline content of from about 20 to about 60 w/w%. In other embodiments, the lecithin has a phospholipid choline content of from about 20 to about 50 w/w%. In other embodiments, the lecithin has a phospholipid choline content of from about 20 to about 40 w/w%. In other embodiments, the lecithin has a phospholipid choline content of from about 20 to about 30 w/w%. In some embodiments, lecithin that has been deoiled is used, wherein the phospholipid choline content is from about 20 to about 25 w/w%.

Active ingredient

Non-limiting examples of lipophilic active ingredients include: olfactants, such as natural and synthetic flavors and essential oils (which will be described in more detail below); flavor compounds and taste modifiers, such as natural flavors and essential oils. , for example, from apples, oranges, and lemons (including combinations of such compounds with base oils); colorants, such as macropores, mainly porphyrins; vitamins such as vitamins A, D, E, and K, etc. Pharmaceutically active metabolites, salts and compounds such as vitamin D, vitamin E acetate and vitamin A palmitate; phytochemicals such as plant cortisol and essential oils such as beta-sitosterol, isoflavones, curcumin and Polyphenolic compounds; oil-soluble acids and alcohols such as chylolactic acid and essential fatty acids such as linoleic acid and linolenic acid, eicosapentaenoic acid (20:5 n-3) and docosahexaenoic acid ( 22:6 n-3) and its natural sources such as evening primrose oil, safflower oil and fish oil; drugs such as cyclosporine A, propofol, liposoluble protease inhibitors, stress resistance Record lipophilic members of viral drugs, antibiotics, and other drugs; carotenoids such as beta-carotene and lycopene; steroid hormones such as estrogen, estradiol, and cortisone; flavonoids, such as Resveratrol; proteins; enzymes; coenzymes and many other lipophilic bioactive compounds. However, it will be apparent to those skilled in the art that the compound is not limited to a particular type of lipophilic component of foods, beverages, pharmaceuticals, and nutritional supplements.

The essential oil used herein is a concentrated, hydrophobic liquid containing volatile aromatic compounds derived from plants. In addition to the characteristic aroma, essential oils are not necessarily groups with a common specific chemical property. They are well known for their use as fragrances and flavors, and offer a wide range of utility in traditional medicine (the traditional medicine defined by the World Health Organization refers to the theory, beliefs and experience inherent in different cultures). Knowledge, skills, and practices used to maintain health and prevent, diagnose, ameliorate, or treat physical and mental illness.

alcohol

In some embodiments, the HLCV composition comprises an alcohol. In some embodiments, an alcohol is added to the conditioned water for hydrating the lecithin to form the HLCV. In other embodiments, if the active ingredient is not readily soluble in the lecithin composition, the addition of the alcohol improves the solubility of the active ingredient in the homogeneous liquid mixture. According to a specific example of the invention, the alcohol is a short chain alcohol. Examples of short chain alcohols include isomers of methanol, ethanol, propanol, and isomers of butanol. The amount of alcohol required to promote dissolution of the active ingredient will depend on the type of alcohol and the particular active ingredient which may be determined experimentally by those skilled in the art.

In some embodiments, the alcohol provided to help dissolve the active ingredient in the lecithin ranges from about 5 to about 50% by weight relative to the combined weight of lecithin and the active ingredient. As described herein, in the lecithin and active ingredient compositions, the addition of the alcohol can be with or without heating, with or without the addition of oil.

In some embodiments, an alcohol is added to the conditioned water for hydrating lecithin. In some embodiments, the added alcohol is an aliphatic short chain alcohol (eg, methanol, ethanol, propanol or butanol). The amount of alcohol can vary and will depend on the nature of the active ingredient. For example, in the case of hydrated lecithin, a total amount of alcohol may be present in the HLCV composition of up to 40% v/v.

In some embodiments, the dispersion can be dried, for example, in the form of a powder, granule or cake, using standard commercial methods.

Stabilizer

In other aspects of the invention, the HLCV composition further comprises at least one stabilizer. Non-limiting examples of stabilizers include polysorbate (polyoxyethylene sorbitan monoester), polyoxyethylene alkyl ether (PAE), and the like. The addition of a stabilizer is optional and generally depends on the identity of the active ingredient to be dispersed in the HLCV. In some applications, the addition of polysorbate or PAE increases stability. Thus, those skilled in the art can experimentally determine that polysorbate or PAE is not required.

The term polysorbate as used herein includes the class of emulsifiers which are oily liquids derived from sorbitan (derivatives of sorbitol) derived from fatty acid monoesterified polyoxyethyl groups. Molecules of the PAE type are suitable for applications that do not involve absorption of HLCV. It will be apparent to those skilled in the art that suitable PAEs may be substituted for polysorbates in methods and compositions comprising and/or using polysorbates, as described herein, in connection with absorption.

The polysorbate-containing HLCV of the present invention has no appreciable bitter taste and is physiologically stable in water, many juices and other beverages, pasteurized, and physically stable upon storage, as evidenced by the maintenance of clarity. The following polysorbate esters can be used as non-limiting examples: polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) Monopalmitate and monostearate. In some embodiments, polyoxyethylene (20) sorbitan monooleate (i.e., polysorbate 80) or polyoxyethylene (20) sorbitan monolaurate is used. The effective amount of polysorbate can be determined using known methods. In some embodiments, for example, the polysorbate is used in a ratio of polysorbate to lecithin having a molar ratio of between about 1:3 and about 1:20. In other embodiments, the polysorbate is used in a molar ratio between about 1:5 and 1:10. In other embodiments, the polysorbate is used in a molar ratio between about 1:7 and 1:9. For the purpose of determining the molar ratio, the molecular weight of the lecithin is assumed to be 800.

Method for preparing HLCV

A specific example of the invention is directed to a method of preparing a hydrated lecithin carrier vesicle (HLCV). In some embodiments, the preparation of HLCV having at least one active ingredient supported therein does not use any organic solvent, alcohol or other similar material. However, in some embodiments, an alcohol may be used to aid in the manufacture of the HLCV, although other/additional organic solvents are not required or used. In some aspects of the invention, a method of forming an HLCV composition includes hydrating in treated water and treating lecithin having a low PC content, followed by addition of at least one active ingredient. In other aspects of the invention, the active ingredient can be combined with a low PC content of lecithin and an alcohol, and a minimum amount of water to form a homogeneous liquid phase (without vesicle formation), followed by hydration and treatment to form Dispersed vesicles. In other aspects, a method of forming an HLCV composition having an active ingredient dispersed therein comprises using a high PC content lecithin (i.e., greater than 80 w/w% phospholipid choline) in the conditioned water.

Lecithin hydration

In some embodiments, lecithin having a low phospholipid choline content produces hydration upon exposure to conditioned water to form a hydrated lecithin carrier vesicle dispersed in CW. In aspects of the invention, the lecithin is hydrated with sufficient conditioned water to effect the processing steps (e.g., homogenization, ultrasonication, microfluidization, high shear mixing, etc.). Indeed, prior to the drying or further compounding step, the HLCV dispersion contains an adjusted amount of water at least as much as lecithin (i.e., a ratio of CW to lecithin of at least 1:1). In some embodiments, for example, the ratio (weight) of one part lecithin can be hydrated with lecithin using 3 parts of water. In other embodiments, lecithin hydration can be carried out using a ratio of 4 parts of water to 1 part of lecithin, or a ratio of 5 parts of water to 1 part of lecithin. In other embodiments, the ratio (weight) of more than 5 parts of water to one part of lecithin can be hydrated with lecithin. In these specific examples, the relative amounts of CW and lecithin are relative to lecithin alone.

In other embodiments, the lecithin is hydrated in the presence of at least one active ingredient. In these specific examples, the weight ratio of lecithin to active ingredient is at least 1:1, and typically can be as high as about 5:1. However, there is no particular upper limit to this ratio other than the constraining claims of commercial or experimental processes that are apparent to those skilled in the art. In these specific examples, the ratio of adjusted water provided ranges from about 3:1 to about 5:1 for the ratio of CW to the sum of lecithin and the active ingredients. It is necessary to provide a ratio of active ingredient to lecithin of up to about 1:1. For example, when the total weight of lecithin and active ingredient is 200 to 250 mg (lecithin + active ingredient), the amount of CW may be 1 ml (1000 mg). It will be apparent to those skilled in the art that the amount of adjusted water relative to lecithin or lecithin and the active ingredient will generally only be subject to any further manufacturing or manufacturing steps required for the final application of the composition. The concentration of the HLCV composition and the active ingredient is limited.

Load of active ingredients in HLCV

In some embodiments, the HLCV composition (ie, lecithin is hydrated and then treated) is prepared as dispersed vesicles prior to the addition of at least one active ingredient. When the active ingredient is a liquid (eg, at a temperature up to the boiling point of the adjusted water or the temperature of the adjusted water and the boiling point of the alcohol mixture, in liquid form), the HLCV is formed prior to loading the active ingredient. The method is most effective so that the active ingredient is readily soluble in the hydrated lecithin vesicle composition. These methods of adding the active ingredient after treatment (i.e., preformed vesicles) are particularly suitable for components such as essential oils, lipophilic aromatic compounds, and mixtures of aromatic compounds having a lipophilic component. This method is most effective for HLCV that has been processed (eg, via homogenization or high shear mixing) to form UV prior to loading. Accordingly, if the active ingredient can be incorporated into the hydrated lecithin composition, the active ingredient can be added to the "preformed" lecithin vesicles. As noted above, the solubility of the active ingredient may require the addition of alcohol, heat, or any combination of these. It will be apparent to those skilled in the art that the active ingredient having a low solubility, even if added in a small amount, is incorporated into the vesicle composition at a slow rate and for a prolonged period of time. It is also known to those skilled in the art that the degree of incorporation of the dispersed HLCV depends on both the rate at which the active dissolves in water and the time. An active ingredient having a log Kow (ie, an octanol:water interfacial distribution coefficient) of less than about 4.5 without the aid of alcohol or heat is unlikely to be incorporated in a reasonable amount of time. However, the incorporation of active ingredients with a log Kow of 4.5 or greater is faster. The solubility of the active ingredient, including the increased solubility by heat and/or alcohol, can be determined experimentally by those skilled in the art.

A stabilizer can be added to the lecithin before or after treatment. In some embodiments, the stabilizer is added to the HLCV composition after treatment. In other embodiments, the mixture of lecithin and stabilizer is hydrated in the conditioned water prior to treatment.

After the active ingredient is added to the HLCV, the mixture is treated with high shear mixing or homogenization to form a HLCV dispersed composition having the active ingredient incorporated therein.

transparency

A further aspect of the invention is the size distribution of the lecithin carrier dispersion operably such that the dispersion is substantially optically clear (i.e., transparent). For the purposes of the present invention, the average diameter of the dispersion particles and the structure in the micrometer range (<1,000 nm) are defined as volume-weighted average diameters, typically having a single model size distribution. The volume-weighted average diameter of the vesicles can be determined by any known technique. For example, the volume-weighted average diameter can be measured by an electron microscope or a dynamic light scattering instrument. When determining the average vesicle size, the size of the vesicles can be reduced using standard methods well known in the art including, but not limited to, ultrasound, microfluidization, and high pressure homogenization.

In some embodiments, the lecithin carrier vesicles having the active ingredient therein are prepared by the process of the invention and are still clear (or transparent) in the dispersion. Clearness means being transparent rather than translucent. This transparency can be achieved by producing a dispersion in which the particles have an average diameter of about 120 nm or less, preferably less than 100 nm and more preferably less than 80 nm. In addition, the distribution of sizes includes a few larger diameter particles that cause turbidity, which may show whitening. For the purpose of describing the invention, the presence of such larger particles can be quantified by the degree of turbidity or blurring, hereinafter referred to as turbidity. Transparent dispersions are such low turbid dispersions. The quantification of this turbidity can be carried out using, for example, a turbidimeter. The turbidity of the dispersion can be expressed relative to a standard of known turbidity. Light-scattering microscopic particles, even those having a diameter much smaller than the wavelength of light, cause turbidity, a complex function of many variables, including both particle size and wavelength. In general, the presence of larger particles, such as those that cause turbidity (whitening, turbidity, blurring), is revealed by scattering at longer wavelengths. This scattering of light causes significant turbidity (i.e., lack of clarity) of the aqueous dispersion. The relative turbidity is based on the relative absorbance measured at 800, 860 and/or 900 nm using a conventional UV/visible spectrometer. The turbidity caused by the unstable dispersion can therefore be easily quantified by the spectrophotometric method within the desired range.

While it is desirable that the HLCV composition with or without dispersion of the active ingredient be transparent or nearly transparent, transparency is not a requirement of any of the specific examples of the invention. For example, if the composition is to be added to a food product and its clarity is typically not correlated in the solution, it is not necessary to reduce the size of the vesicle. However, if the composition is to be added to a clear or translucent beverage, the turbidity or haze needs to be adjusted to meet consumer expectations.

Homogeneous liquid mixture

In some embodiments, the active ingredient is added to the lecithin prior to hydration. In these specific examples, the active ingredient can be dissolved in a lecithin-based mixture at room temperature, which can also include alcohols and can also include minimal amounts of adjusted water and/or oil. In some embodiments, the weight of lecithin in the homogeneous liquid mixture is greater than any other single component of the homogeneous liquid mixture. That is, although lecithin may not be larger than all other combined components, it is provided in excess of any other single component. In this way, lecithin can be used as a solvent for a homogeneous liquid mixture. Some active ingredients are more soluble when heated. Thus, in some embodiments, the active ingredient is mixed with lecithin and may include an alcohol, a minimum amount of alcohol, an oil, and may be mixed at elevated temperatures. For example, the heating temperature is selected from the range of from about 60 ° C to about 80 ° C. The desired temperature will be determined by those skilled in the art in considering the nature of the active ingredient and the composition of the composition. For example, the heating temperature should not exceed the boiling point of the composition, which is determined by the various components of the composition. As understood by those skilled in the art, the heating temperature should not exceed the boiling point of the component having the lowest boiling point in the composition. For example, if an alcohol is present in the lecithin composition, the highest desired heating temperature should not exceed the boiling point of the alcohol (which is typically the lowest boiling component). In some embodiments, lecithin and at least one active ingredient are first dissolved in a homogeneous liquid mixture prior to formation of the vesicle.

By way of example, the plant phytol has a melting temperature above 100 ° C (eg, β-sitosterol has a T _mp of 130 to 140 ° C), so after the vesicle formation, the plant phytol can not be effectively incorporated into the HLCV composition In. Accordingly, in some embodiments of the invention, the composition having at least one active ingredient dispersed therein is prepared by first dissolving the active ingredient with lecithin to form a single phase homogeneous liquid mixture. In some embodiments, the addition of an alcohol aids in dissolving the active ingredient in the lecithin. In some embodiments, up to about 50% alcohol (relative to the weight of lecithin) is added to the lecithin and active ingredient mixture. As discussed, in some embodiments, a minimum amount of adjusted water can be added to aid in the solubility of the active ingredient in the lecithin-alcohol mixture. For example, no more than 10% by weight (w/w) of adjusted water may be added relative to the weight of the lecithin. It will be apparent to those skilled in the art that excess water will prevent the formation of a single phase. To further promote the formation of a homogeneous liquid mixture with lecithin, the active ingredient can be first dissolved in the oil (with heating if desired).

In some embodiments, to aid in dissolution in lecithin to form a homogeneous liquid mixture, the active ingredient can be first dissolved in the oil. For example, the active ingredient can be first dissolved in a non-polar, hydrophobic carrier material such as a natural oil, and then mixed with the HLCV composition. The dissolution of the active ingredient in the oil may also be combined with heating and/or addition of an alcohol. Examples of the oil include triglyceride seed oil extracted from plants such as soybean, corn, olive, sunflower, canola, and olive. Oils also include animal oils such as fish or krill and essential oils. Essential oils include, but are not limited to, the following oils: Citronella, clove leaf, eucalyptus, grapefruit, lemon, lime, wild mint/mint, orange, oregano, peppermint, spearmint (spearmint), star anise, orange, tea tree, thyme and holly, this specific example includes the use of primary chemical components of such oils, such as thymol, carvacrol, limonene, menthol, carvone, methyl water Salicylic acid, cineole, citranal, pine oil, and terpinen-4-ol.

The homogeneous liquid mixture is then mixed in CW for hydration to form vesicles. In some embodiments, short chain alcohols are added to the CW, i.e., if the amount of short chain alcohol previously present in the lecithin-containing mixture is insufficient. A sufficient amount of short chain alcohol is in the final lecithin hydration solution to provide an alcohol concentration of no less than at least about 5 v/v% and no more than 40 v/v%. In some embodiments, the concentration of alcohol in the final lecithin hydration solution is from about 20% v/v to about 30% v/v. The lecithin hydration is carried out at a temperature at which the homogeneous liquid mixture with lecithin is maintained in a liquid state.

After the HLCV is formed by hydration, the HLCV is treated by homogenization and high shear mixing to form a dispersion of the HLCV composition having the active ingredient.

HLCV with high PC content

In an aspect of the invention, the method of producing the HLCV composition uses a high lecithin having a high PC content (i.e., lecithin having a phospholipid choline content of more than 80% w/w). In this method, one of the methods described herein is used to dissolve the active ingredient in a low PC content lecithin, followed by a high PC content of lecithin (or, optionally, substantially pure phospholipid choline). Mix with an active ingredient. The method and intermediate composition for the addition of the active ingredient after hydration and treatment as described herein, or by forming a homogeneous liquid mixture prior to the hydration treatment, can also be applied to the preparation of HLCV using high PC content lecithin. This HLCV is suitable for pharmaceutical applications. Indeed, in these specific examples, the lecithin has a high PC content and thus it can be accepted for pharmaceutical use. For example, in these specific examples, the HCLV has a PC of 90 w/w% or more in terms of inhalation or injection of the product.

In order to achieve the desired function of the formulation in vivo, other purified phospholipids may be added as needed. In some embodiments, a pharmaceutically acceptable propofol formulation for parenteral use can be homogenized by hydrating a mixture of phospholipid choline and phospholipid glycerol in adjusted water followed by a high pressure homogenizer. Then, it is prepared by culturing with propofol.

Optionally, a pharmaceutically acceptable tranquilizer, such as a polysorbate, can be added during or after hydration. The organic solvent-free treatment method for lecithin disclosed herein can also be applied to the pharmaceutically acceptable phospholipid choline. An alternative method based on a homogeneous liquid mixture of lecithin and other ingredients may be used together with the pharmaceutically active ingredient which is soluble in the phospholipid choline-alcohol mixture, and a small amount is required in comparison with the low PC content lecithin. The adjusted water (up to 10% w/w relative to the phospholipid) produces a homogeneous liquid mixture. As described herein, the active ingredient is first dissolved in a pharmaceutically acceptable oil such as a fatty acid triglyceride (wherein the fatty acid may be the same or mixed) (heating if necessary).

Further processing, purification

After forming the HLCV, the composition can be further processed as needed. For example, to reduce the size of the vesicles, the dispersion can be subjected to high shear mixing or high pressure homogenization. If feasible, the presence of alcohol reduces the energy required to reduce the size compared to the corresponding downsizing treatment on the same component lacking alcohol. Lower energy processing has commercial benefits, resulting in lower processing energy costs and the ability to use a wider range of processing equipment. For example, in the presence of an alcohol, a given energy input can achieve a greater degree of size reduction; in some cases, this enables an HLCV that produces an optically clear appearance that may not be possible in the absence of alcohol. achieve.

The HLCV compositions disclosed herein can be dried into a solid form, such as a powder, flake or cake, by any standard industrial drying method, such as spraying or freeze drying, and optionally or subsequently incorporated into a paste or emulsion. Additional further processing steps can include adjusting the pH of the composition, adding a preservative or antimicrobial agent, or adding a fragrance to enhance the taste of the composition.

application

The HLCV dispersion according to a specific example of the present invention is substantially free of dispersion-free active ingredients (i.e., once dispersed in the HLCV composition, the active ingredient remains substantially dispersed and does not precipitate from the dispersion to any degree of severity. come out). In some embodiments, the lecithin vesicle composition of the present invention is different from the nanoemulsion and is different from the dispersion of non-bilayer solid nanoparticle stabilized with a surfactant such as lecithin.

The composition, intermediate solution and production method of the present invention use relatively inexpensive food grade lecithin, especially lecithin having a PC content of less than about 80% by weight, and provide water-based water-insoluble materials. Dispersion.

Although not limited to any application, HLCV in accordance with certain embodiments of the present invention can be used to make substantially clear aqueous dispersions of fat-soluble active ingredients which can be used in beverages or nutritional supplements because the dispersion is in water , fruit juice and other beverages are diluted, pasteurized and physically stable during storage. The fat soluble component can include an antioxidant (eg, vitamin E). The dispersion can be concentrated and dried to a powder which is then rehydrated as required for the desired application. The compositions and methods of the present invention also disclose the use of food grade materials, such as those that have been tested by the U.S. Food and Drug Administration for safety and reliability.

The HLCV compositions of the present invention can be processed using conventional equipment that is widely used in the food and beverage industry. The hydrated lecithin carrier vesicles are relatively inexpensive. In addition, the load of the food/beverage/nutrition supplement component into the carrier can be increased to a level that is cost-effective when used in related consumer products and other products.

The HLCV dispersion of the present invention actually acts as a true solution and can be, or can be used to prepare, a product for oral or other consumer access to the oral cavity. A particular advantage of some of the compositions of the present invention is that they provide an aqueous dispersion that is optically clear substantially when used in the final product, and when stored, added to some juices and other beverages, exposed to high temperatures, This clarity is maintained during Sterling sterilization. In some embodiments, the lecithin-based matrix also provides higher chemical stability of the water insoluble material, such as oxidation resistance, and inhibits unwanted odors and tastes of such materials as well as poor mouthfeel. Certain lipids are themselves a choice of foods or nutritional supplements, such as phospholipid choline, especially lipids derived from marine organisms, such as krill. It is clear that these lipids can be used arbitrarily in the HLCV, intermediates and methods of preparation described herein.

The following examples are for illustrative purposes only and do not limit the scope and content of this application.

example

Example 1-1 , HLCV dispersion of fish oil (omega-3 formula).

20 g of fish oil (EPAX 1050), 30 g of lecithin (Cargill Lecigran), 0.5 g of vitamin E and 4 ml of ethanol were combined in a bottle. The mixture was mixed by heating to 65 ° C for about 60 minutes until the solution was homogeneous in appearance. This mixture was added to 250 ml of pure water which had been heated to 65 ° C and mixed for 5 minutes. A 50 ml sample of this hydrated fish oil lecithin dispersion was combined with a suitable volume of ethanol to produce a dispersion containing about 0, 10, 20, 30, 40, and 50% (v/v) ethanol. For the purpose of determining the amount of ethanol to be added, a small amount of existing volume (from the homogeneous lecithin phase) can be ignored. The dispersions in this sequence were homogenized (Niro Soavi NSI00 IL homogenizer) at an inlet temperature of about 600 bar and 65 °C. The dispersion was then diluted in adjusted water to approximately 3 mg/ml fish oil. Figure 1A shows a photograph of such dispersions. The turbidity measured for these dispersions at 800 and 900 nm is shown in Figure 1B . Particle size distribution measurements were performed at room temperature using a Microtrac (USA) 'Nanotrac 150' dynamic light scattering instrument operating at 780 nm solid state laser and a controlled reference method (Doppler shift) for reflected light intensity Obtained by fluctuations. The volume-weighted average diameter of the vesicles of this composition is shown in Figure 1C . As shown, the volume weighted distribution is plotted along with a 95% pass diameter (where 95% of the vesicles are smaller than this diameter). The volume-weighted average diameter is in the case of a minimum amount of 30% ethanol (about 28 nm).

Example 1-2 , in addition to the addition of 1.0 g of polysorbate 80, the HLCV was fabricated as in Example 1-1. -3 dispersion. A photograph of each of the polysorbate-containing omega-3 formulations at 0, 10, 20, 30, 40, and 50% ethanol is shown in Figure 2A . The turbidity and particle size distribution data of these formulations from dynamic light scattering are shown in Figures 2B and 2C , respectively. As shown, the smallest volume-weighted average diameter of the polysorbate at 30% ethanol is about 35 nm. Figure 3 shows a photograph of this omega-3 formulation with no polysorbate at 30% ethanol.

Example 2 , HLCV dispersion of essential oil

10 g of lecithin (Lecigran, Cargill or Ultralec, ADM) was mixed and hydrated in 100 ml of distilled water, then homogenized at room temperature, and subjected to 6 times through a Niro Soavi NS 1001 L homogenizer at about 400 bar to form HLCV. Polysorbate 80 was added in a weight ratio of 5:1 lecithin:polysorbate to be mixed. The dispersion was then diluted to 200 ml using distilled water. Essential oils were added: thymol (0.7 g), cineole (1.0 g), methyl salicylic acid (0.65 g), and menthol (0.46 g), and then mixed to produce a substantially transparent aqueous dispersion of these essential oils. The resulting dispersion was filtered through a 0.2 micron filter. The clear dispersion is diluted and then sweetener is added to produce an ethanol free essential oil mouthwash. A photograph of a sample of two essential oil dispersions is shown in Figure 4A , one freshly prepared (t = 0) and one stored at room temperature for 12 months (t = 12 months). The results of the Nanotrac particle size distribution analysis of these samples are presented in Figures 4B and 4C . In each case, the volume weighted mean diameter was determined to be 37 (+/1) nm. In comparison, Figure 4 shows the cumulative amount (the S-shaped curve is added to the distribution bar graph); and the size data of the two samples is basically indistinguishable.

Example 3, HLCV dispersion of lemon essential oil

5 g of lecithin (Lecigran, Cargill or Ultralec, ADM) was mixed and hydrated in 100 ml of distilled water, followed by homogenization 4 times through a Niro Soavi NS 1001 L homogenizer at about 400 bar and an inlet temperature of 65 °C. Polysorbate 80 was added in a weight ratio of 5:1 lecithin:polysorbate to be mixed. The lemon essential oil is added in a weight ratio of 5:1 lecithin: lemon essential oil to produce an HLCV dispersion of lemon essential oil. The resulting substantially transparent solution can be filtered through a 0.2 micron filter.

Example 4 : HLCV dispersion of lemon essential oil in beverages

6 g of lecithin (Lecigran, Cargill or Ultralec, ADM) was mixed and hydrated in 100 ml of distilled water, followed by homogenization 4 times through a Niro Soavi NS 1001 L homogenizer at about 400 bar and an inlet temperature of 65 °C. 1.2 g of polysorbate 80 was added in a weight ratio of 5:1 lecithin:polysorbate, and lemon essential oil was added and mixed at a weight ratio of 5:1 lecithin:lemon oil. After mixing, the dispersion was again treated 4 times through the same homogenizer under the same conditions. The resulting substantially transparent dispersion was filtered through a 0.2 micron filter. The transparent dispersion was added to a solution of sucrose and citric acid to prepare a lemon-flavored beverage.

Example 5, HLCV Dispersion of Plant Cortisol

10 g of lecithin (Lecigran, Cargill or Ultralec, ADM) and 2 g of plant cortisol (Cardioaid, ADM or Corowise, Cargill) were dissolved in 11 ml of 90% ethanol at about 70 ° C to obtain lecithin: cortisol weight Than 5:1. Once all of the components had dissolved, the solution was added to distilled water and mixed, and then homogenized 6 times through an APV Rannie 7.30.VH homogenizer at an inlet temperature of 65 ° C and nearly 600 bar to produce plant cortisol HLCV.

Example 6 , HLCV in water drinks

The HLCV dispersion of Example 1-1 was combined with polysorbate 80 (weight ratio lecithin: polysorbate 5:1) at room temperature and with mixing. The dispersion is then diluted in a sports drink to produce a clear (low turbidity) water beverage containing fish oil.

Example 7 , lipids of marine life

20 g of krill oil (oil extracted from Euphasia superba ), 30 g of lecithin (Cargill Lecigran), 0.5 g of vitamin E, 1.0 g of polysorbate 80, and 4 ml of absolute alcohol were combined in a bottle. The mixture was allowed to mix for 60 minutes while heating to 65 ° C until the solution appeared homogeneous. This mixture was added to pure water which had been heated to 65 ° C and then mixed for 5 minutes. The dispersion was homogenized through a Niro Soavi NS 100 1L homogenizer at an inlet temperature of about 600 bar and 65 °C. The resulting dispersion is translucent and has the pink character of krill oil. Photographs of the krill oil HLCV composition and particle size data are shown in Figures 5A and 5B , respectively. The volume weighted mean diameter was determined to be 64 nm.

Example 8 , fish oil in ethanol, isopropanol and isobutanol

20 g of fish oil (EPAX 1050), 30 g of lecithin (Cargill Lecigran), 0.5 g of vitamin E, 1.0 g of polysorbate 80, and 4 ml of ethanol were combined in a bottle. In each case, the composition was allowed to mix for 60 minutes at 65 ° C until the solution appeared homogeneous and single phase. These mixtures were added to 250 ml of pure water which had been heated to 65 ° C and then mixed for 5 minutes. A 50 ml sample of the hydrated fish oil and lecithin dispersion is combined with additional pure water and alcohol to produce about 30% (v/v) ethanol, 30% (v/v) isopropanol or 5 in a total volume of 100 ml. % (v/v) hydrated dispersion of isobutanol. Each dispersion was homogenized 4 times through a Niro Soavi NS 100 1L homogenizer at an inlet temperature of about 600 bar and 65 °C. The dispersion was diluted in pure water to about 3 mg/ml fish oil. Photographs and particle size data of the isopropyl alcohol fish oil HLCV composition are shown in Fig. 6A and Fig . 6B , respectively. Photographs of the isobutanol fish oil HLCV composition and particle size data are shown in Figures 7A and 7B , respectively. Figure 3 shows the appearance of a 30% ethanol sample.

Example 9-1, Essential Oil: Carvacrol (no polysorbate)

10 g of lecithin (Cargill lecigran) was diluted in 200 ml of purified water heated to 65 °C. The dispersion was mixed and hydrated for 10 minutes, then homogenized 6 times through a Niro Soavi NS 100 1L homogenizer at about 550 bar and 65 ° C inlet temperature. To the dispersion was added 1 g of carvacrol, the solution was maintained at 65 ° C, and mixed for 1 hour, and then allowed to cool to room temperature under mixing to produce a carvacrol dispersion in HLCV.

Example 9-2, Essential Oil: Carvacrol (containing polysorbate)

The carvacrol was prepared as in Example 9-1 except that after homogenization, 1 g of polysorbate 80 was added and the dispersion was stirred for 10 minutes, followed by addition of 1 g of carvacrol and mixing at 65 ° C for 1 hour. The HLCV composition. The dispersion was then allowed to cool to room temperature with mixing to produce a carvacrol dispersion in HLCV.

Example 9-3, Essential Oil: Lecithin Control

The HLCV composition of Example 9-1 was prepared, but no carvacrol was added.

Figure 8A is a photograph of the HLCV composition of Examples 9-1(1), 9-2(2), 9-3(3). The appearance of the carvacrol sample (1) prepared with polysorbate 80 was similar to that of the lecithin control group (3). Although slightly less opaque, the appearance of the carnosol sample (2) without polysorbate 80 clearly shows that carvacrol can be completely dispersed in the HLCV without the need for sorbitol ester 80. Figures 8B , 8C, and 8D show particle size data from Examples 9-1 (1) , 9-2 (2) , and 9-3 (3) , respectively, and their volume-weighted mean diameters, respectively. They are 56 nm, 97 nm, and 37 nm. Figure 8C shows that when polysorbate is not used, a skewed distribution occurs and a small number of larger diameter particles appear - this corresponds exactly to the reduction in transparency and the larger average (volume) diameter seen in Figure 8A. . However, it is important to note that the sub-micron particle size measured by dynamic laser light scattering is suitable for displaying the average size, but only the similarity and difference of the average particle size distribution are characterized (ie, the bar graph shows Differences, but should not provide more information).

As the entire discussion, as well as examples and illustrations, HLCV with a low PC content is loaded with an active ingredient (and may also include alcohol and/or stabilizer) in the presence of conditioned water to form a dispersion composition. Photographs of Figures 1A, 2A, 3, 4A, 5A, 6A, 7A, and 8A show examples of the disclosure of active ingredients loaded in HLCV, 1C, 2C, 4B, 4C, 5B, 6B, 7B, 8B, 8C And the corresponding particle size data in the 8D map is supported.

Although the present invention has been illustrated by way of example specific examples, those skilled in the art will appreciate that various modifications can be made without departing from the scope of the inventions Modifications and changes.

Figure 1A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in hydrated water prepared in adjusted water and (left to right) 0, 10, 20, 30, 40 or 50% ethanol. Lecithin carrier vesicles.

Figure 1B is a graph depicting the turbidity of the fish oil composition shown in Figure 1A in accordance with a specific example of the present invention.

Fig. 1C is a graph showing particle size distribution data obtained from the fish oil composition shown in Fig. 1A according to a specific example of the present invention.

2A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in adjusted water and (left to right) 0, 10, 20, 30, 40 or 50% ethanol and polysorbate The hydrated lecithin carrier vesicles in the alcohol ester.

Figure 2B is a graph depicting the turbidity of the fish oil composition shown in Figure 2A in accordance with a specific example of the present invention.

Fig. 2C is a graph showing particle size distribution data obtained from the fish oil composition shown in Fig. 2A according to a specific example of the present invention.

Figure 3 is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and 30% ethanol (with or without polysorbate) .

Figure 4A is a photograph of the essential oil composition according to a specific example of the present invention at t = 0 and t = 12 months, wherein the essential oil is dispersed in a hydrated lecithin carrier formulated in adjusted water and polysorbate. In the vesicles.

Fig . 4B is a graph showing particle size distribution data obtained from the essential oil composition (t = 0) shown in Fig. 4A according to a specific example of the present invention.

Fig. 4C is a graph showing particle size distribution data obtained from the essential oil composition (t = 12 months) shown in Fig. 4A according to a specific example of the present invention.

Fig. 5A is a photograph of a krill oil composition according to a specific example of the present invention, wherein the krill oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and a stabilizer.

Fig. 5B is a graph showing particle size distribution data obtained from the krill oil composition shown in Fig. 5A according to a specific example of the present invention.

Figure 6A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and 30% isopropanol.

Figure 6B is a graph showing particle size distribution data obtained from fish oil compositions in 30% isopropanol shown in Figure 6A in accordance with a specific example of the present invention.

Figure 7A is a photograph of a fish oil composition according to a specific example of the present invention, wherein the fish oil is dispersed in a hydrated lecithin carrier vesicle formulated in adjusted water and 5% isopropanol.

Fig. 7B is a graph showing particle size distribution data obtained from the fish oil composition in 5% isopropanol shown in Fig. 7A according to a specific example of the present invention.

Figure 8A is a hydrated lecithin-containing vesicle having (1) essential oil (carvacrol) and polysorbate; (2) essential oil; and (3) lecithin alone (without essential oil) according to a specific example of the present invention. A photo of the composition in the middle.

Fig. 8B is a graph showing particle size distribution data obtained from the composition ( 1 ) having essential oil and polysorbate in Fig. 8A of the specific example of the present invention.

Fig. 8C is a graph showing particle size distribution data obtained from the composition ( 2 ) having essential oil according to Fig. 8A of the specific example of the present invention.

Fig. 8D is a graph showing particle size distribution data obtained from the composition ( 3 ) having individual lecithin according to Fig. 8A of the specific example of the present invention.

Claims (63)

A composition comprising a stable homogeneous dispersion comprising: a vesicle having a membrane and an aqueous phase, the vesicle comprising: lecithin having a phospholipid choline content of about 80 w/w% or less, and an activity The ingredients are incorporated into the membrane of the vesicle; and the conditioned water. The composition of claim 1, wherein the adjusted water has less than 100 ppm of hard ions. The composition of claim 1, wherein the adjusted water has a conductivity of less than 20 microsiemens per centimeter. The composition of claim 1, wherein the vesicle has a volume-weighted average diameter of about 120 nm or less. The composition of claim 1, wherein the membrane of the vesicle is a phospholipid bilayer. The composition of claim 1, wherein the composition is a transparent dispersion. The composition of claim 1 further comprises a stabilizer. The composition of claim 7, wherein the stabilizer is a polysorbate or a polyoxyethylene alkyl ether. The composition of claim 1 further comprises an alcohol. The composition of claim 9, wherein the alcohol has an aliphatic alcohol of 6 carbons or less. The composition of claim 10, wherein the alcohol is selected from the group consisting of aliphatic alcohols of the group consisting of: methanol, ethanol, an isomer of propanol, and an isomer of butanol. The composition of claim 1, wherein the active ingredient is a lipophilic compound. The composition of claim 12, wherein the lipophilic compound is at least one selected from the group consisting of: an olfactant, a natural flavor, an essential oil, a colorant, a vitamin, Vitamin salts, pharmaceutically active vitamin metabolites, pharmaceutically active vitamin metabolite salts, phytochemicals, oil-soluble acids, oil-soluble alcohols, essential fatty acids, primrose oil, safflower oil, fish oil, from Marine organisms, lipids, cyclosporin A, propofol, liposoluble protease inhibitors, antiretroviral compounds, antibiotics, carotenoids, steroid hormones, Flavonoids, proteins, enzymes, coenzymes, paints, inks, and agrochemicals. A composition comprising: a vesicle comprising: lecithin having a phospholipid choline content of about 80 w/w% or less, and an active ingredient; and adjusted water. The composition of claim 14, wherein the vesicle is a phospholipid bilayer. The composition of claim 14 further comprises a stabilizer. The composition of claim 14, wherein the stabilizer is a polysorbate or a polyoxyethylene alkyl ether. The composition of claim 14 further comprises an alcohol. A composition comprising a homogeneous mixture having lecithin having a phospholipid choline content of about 80 w/w% or less; an active ingredient; and an alcohol. The composition of claim 19, further comprising adjusted water. The composition of claim 20, wherein the adjusted water is present in an amount of about 10% by weight or less relative to the lecithin. The composition of claim 19, further comprising an oil. The composition of claim 19, wherein the alcohol is present in an amount of about 50% by weight or less relative to the lecithin. A method of producing a composition of a vesicle carrier, comprising: hydrating lecithin having a phospholipid choline content of 80 w/w% or less in adjusted water to form lecithin vesicles having a membrane and an aqueous phase; The active ingredient is incorporated into the membrane of the lecithin vesicle to form a membrane-loaded lecithin vesicle. The method of claim 24, further comprising treating the lecithin vesicle to form a lecithin vesicle monolayer prior to incorporation of the active ingredient. The method of claim 25, wherein the treatment of the lecithin vesicles comprises homogenization or high shear mixing. The method of claim 24, wherein the incorporation of the active ingredient into the lecithin vesicle comprises heating. The method of claim 24, wherein the adjusted water further comprises an alcohol. The method of claim 24, further comprising adding a stabilizer to the lecithin prior to hydration, or adding stability to the lecithin vesicle before or after incorporation of the active ingredient The agent contains a stabilizer. The method of claim 24, further comprising treating the membrane-loaded lecithin vesicles after the active ingredient is incorporated into the membrane of the lecithin vesicle to reduce the membrane-loaded lecithin vesicles size. The method of claim 30, wherein the treatment of the lecithin vesicles comprises homogenization or high shear mixing. The method of claim 24, further comprising drying the composition into a solid form. The method of claim 24, further comprising incorporating the composition into an emulsion or paste. A method of producing a vesicle carrier composition having a film and an aqueous phase, the method comprising: mixing lecithin having an phospholipid choline content of about 80 w/w% or less, an active ingredient, and an alcohol to form a homogeneous liquid a mixture; and hydrating the homogeneous liquid mixture with the adjusted water to form a lecithin vesicle, wherein the active ingredient is incorporated into the membrane of the lecithin vesicle. The method of claim 34, further comprising heating during mixing of the lecithin having an amount of phospholipid choline of about 80 w/w% or less, an active ingredient, and an alcohol. The method of claim 34, further comprising mixing the oil with the lecithin having an amount of phospholipid choline of about 80 w/w% or less, an active ingredient, and an alcohol. The method of claim 34, further comprising mixing the adjusted water with the lecithin having an amount of phospholipid choline of about 80 w/w% or less, an active ingredient, and an alcohol. The method of claim 37, wherein the adjusted water is provided in an amount of up to about 10% by weight relative to the lecithin. The method of claim 34, further comprising treating the lecithin vesicles after hydrating the homogeneous liquid mixture to form a lecithin vesicle monolayer. The method of claim 39, wherein the treatment of the lecithin vesicles comprises homogenization or high shear mixing. The method of claim 34, wherein the alcohol is present in an amount of about 50% by weight or less relative to the lecithin. A method of forming a homogeneous composition comprising: mixing lecithin having an phospholipid choline content of 80 w/w% or less with an active ingredient and an alcohol. The method of claim 42, further comprising mixing the adjusted water with the lecithin having a phospholipid choline content of 80 w/w% or less and an active ingredient and an alcohol. The method of claim 43, wherein up to about 10% by weight of the adjusted water relative to the lecithin is provided. The method of claim 42, wherein the alcohol is present in an amount of about 50% by weight or less relative to the lecithin. A method of producing a composition of a vesicle carrier, comprising: hydrating lecithin having a phospholipid choline content of more than about 80 w/w% in adjusted water to form a lecithin vesicle having a membrane and an aqueous phase; and The active ingredient is incorporated into the membrane of the lecithin vesicle to form a membrane-loaded lecithin vesicle. The method of claim 46, wherein the lecithin further comprises phospholipid glycerol. The method of claim 46, wherein the active ingredient is selected from the group consisting of cyclosporin A, propofol, and liposoluble protease. Agents, antiretroviral compounds, antibiotics, carotenoids, steroid hormones, flavonoids, enzymes and coenzymes. The method of claim 46, further comprising treating the lecithin vesicle to form a lecithin vesicle monolayer prior to incorporation of the active ingredient. The method of claim 49, wherein the treatment of the lecithin vesicles comprises homogenization or high shear mixing. The method of claim 46, further comprising adding a stabilizer to the lecithin prior to hydration, or adding stability to the lecithin vesicle before or after incorporation of the active ingredient The agent contains a stabilizer. The method of claim 46, further comprising treating the membrane-loaded lecithin vesicles after the active ingredient is incorporated into the membrane of the lecithin vesicle to reduce the membrane-loaded lecithin vesicles size. The method of claim 52, wherein the treatment of the lecithin vesicles comprises homogenization or high shear mixing. A method of producing a vesicle carrier composition having a film and an aqueous phase, the method comprising: mixing lecithin having an phospholipid choline content of more than 80 w/w%, an active ingredient, and an alcohol to form a homogeneous liquid mixture; The homogeneous liquid mixture is hydrated with the adjusted water to form a lecithin vesicle, wherein the active ingredient is incorporated into the membrane of the lecithin vesicle. The method of claim 54, wherein the lecithin further comprises phospholipid glycerol. The method of claim 54, wherein the active ingredient is selected from the group consisting of cyclosporin A, propofol, and liposoluble protease. Agents, antiretroviral compounds, antibiotics, carotenoids, steroid hormones, flavonoids, enzymes and coenzymes. The method of claim 54, further comprising heating during the mixing of the lecithin having a phospholipid choline content of more than 80 w/w%, an active ingredient, and an alcohol. The method of claim 54, further comprising mixing the oil with the lecithin having an phospholipid choline content of more than 80 w/w%, an active ingredient, and an alcohol. The method of claim 54, further comprising mixing the adjusted water with the lecithin having an phospholipid choline content of more than 80 w/w%, an active ingredient, and an alcohol. The method of claim 54, wherein the adjusted water is provided in an amount of up to about 10% by weight relative to the lecithin. The method of claim 54, further comprising treating the lecithin vesicles after hydrating the homogeneous liquid mixture to form a lecithin vesicle monolayer. The method of claim 61, wherein the treatment of the lecithin vesicles comprises homogenization or high shear mixing. The method of claim 54, wherein the alcohol is present in an amount of about 50% by weight or less relative to the lecithin.