Liquid-filled capsule having a two-phase liquid fill

Abstract

The present disclosure relates to an active ingredient delivery system having a container having an internal compartment and a liquid fill composition comprising first and second liquid phases disposed within the internal compartment of the container, wherein the first and second liquid phases are incompatible with each other such that the first and second liquid phases are immiscible and separate into two distinct phases within the internal compartment.

Description

[Background technology]

[0001] The delivery of two or more active ingredients that are incompatible (immiscible) with each other in a single delivery device has been achieved using various techniques. These techniques include, for example, placing a tablet in a capsule, forming mini-tablets or microbeads of material and placing them in a capsule, placing one ingredient in a capsule and placing that capsule in a larger capsule, or forming lipid (oil) multiparticulates and placing them in a capsule. Each of these methods of delivering incompatible active ingredients has advantages and disadvantages. One of the main disadvantages is cost. Costs include the cost of making tablets, mini-tablets, microbeads, and additional capsule costs. Furthermore, configurations such as capsule-in-capsule or tablet-in-capsule may result in the need for larger outer capsules, which may be difficult for some users to swallow.

[0002] Other methods of placing incompatible ingredients together in a delivery form include forming emulsions of the incompatible ingredients in the aqueous and lipid (oil) phases. These emulsions can be water-in-oil or oil-in-water emulsions. Emulsifiers are present to allow the incorporation of two-phase systems into a single capsule, but the addition of additional ingredients such as emulsifiers consumes valuable space in an already limited amount of space for ingredients. The addition of emulsifiers can result in the need for larger capsules used to deliver the active ingredient. Furthermore, the cost of emulsifiers increases the cost of delivering the active ingredient to the user. Another disadvantage of using emulsifiers is that they result in a fill composition with an opaque, one-phase appearance that does not communicate to the user that multiple ingredients are being administered to the user.

[0003] The present disclosure provides a unique method for combining an aqueous phase and a lipid (oil) based phase, and an effective method for delivering active ingredients to the user, and in some cases a method for delivering more active ingredients to the user. The product of the present disclosure can also be visually appealing to the user. This is achieved through creating an aqueous phase containing one or more water-soluble active ingredients combined with a lipid (oil) based phase that incorporates a fat-soluble active. This provides a wide range of applications for creating new delivery technologies that are visually appealing and solve the problem of immiscibility between the two phases in one dosage form. In addition to being visually appealing, it also provides a reduction in manufacturing costs and allows for a reduction in capsule size to hold the active ingredients. Summary of the Invention

[0004] In general, the present disclosure relates to an active ingredient delivery system comprising a container having an internal compartment and a liquid fill composition comprising a first liquid phase and a second liquid phase disposed in the internal compartment of the container. The first liquid phase and the second liquid phase are incompatible with each other, so that the first liquid phase and the second liquid phase are immiscible and separated into two different phases in the internal compartment. An active ingredient is present in at least one of the first liquid phase and the second liquid phase. In a particular embodiment, both the first and second liquid phases contain an active ingredient.

[0005] In one aspect of the present disclosure, the liquid fill composition of the delivery system is essentially free of emulsifiers. Additionally, the liquid fill composition is not an emulsion.

[0006] In another embodiment of the present disclosure, the first liquid phase is a lipid (oil)-based phase and the second phase is an aqueous-based phase.

[0007] In one embodiment of the present disclosure, each of the first and second liquid phases contains at least one active ingredient.

[0008] In another embodiment of the present disclosure, the container is a capsule. In a typical embodiment, the capsule is a hard capsule. In a particular embodiment, the container is a molded body obtained from a film-forming composition comprising at least one polysaccharide or polysaccharide derivative. In a particular embodiment, the polysaccharide is a cellulose derivative or pullulan.

[0009] In yet another embodiment of the present disclosure, the specific embodiment of the cellulose derivative is alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, carboxyalkyl cellulose, carboxyalkyl alkyl cellulose, and cellulose ether. In a specific embodiment, the cellulose derivative is selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetyl phthalate (CAP), sodium carboxymethyl cellulose, methyl cellulose ether, hydroxyethyl cellulose ether, hydroxypropyl cellulose ether, hydroxyethyl methyl cellulose ether, hydroxyethyl ethyl cellulose ether, and hydroxypropyl methyl cellulose ether. Typically, the cellulose derivative is hydroxypropyl methyl cellulose (HPMC).

[0010] In another aspect of the present disclosure, one or both liquid phases of the liquid fill composition contain a colorant. In one particular aspect, the colorant, when present in the lipid phase, is present in an amount of about 0.01 to about 10%, based on the total weight of the liquid. It should be noted that in another embodiment, the active ingredient(s) may provide color to one or both phases.

[0011] In a further embodiment, the first phase is a lipid phase, which contains from about 0.1% to about 100% by weight, typically from about 0.5% to about 75% by weight, more typically from about 1% to about 20% by weight, and more specifically from about 3% to about 15% by weight, based on the total weight of the lipid (oil) phase, of the active ingredient. In another embodiment, the second phase is an aqueous phase, which contains from 1% to 75% by weight, more typically from 3% to 70% by weight, based on the total weight of the aqueous phase.

[0012] In another aspect of the present disclosure, a method is provided for forming a two-phase liquid capsule filling composition containing a lipid phase and an aqueous phase. The lipid phase and the aqueous phase are separate and distinct from each other. The filling composition is formed by a method comprising: 1) forming a lipid phase, optionally containing a fat-soluble active ingredient; 2) forming an aqueous phase, optionally containing a water-soluble active ingredient; 3) using a high shear rate mixer to mix the lipid phase with the aqueous phase to form a combined liquid phase; 4) placing the combined liquid phase in a container or capsule; and 5) allowing the lipid phase and the aqueous phase to separate in the container or capsule. At least one of the lipid phase and the aqueous phase contains an active ingredient.

[0013] In a further embodiment, the mixing is carried out in a high shear mixer with a mixing speed of between 100 RPM (revolutions per minute) and 15,000 RPM.

[0014] In yet another embodiment of the present disclosure, a delivery system is provided in which the container is coated or banded.

[0015] Other features and aspects of the disclosure are discussed in more detail below.

[0016] definition As used herein, the terms "about," "approximately," or "generally," when used to modify a value, indicate that the value can be increased or decreased by 10% and still remain within the disclosed embodiment.

[0017] As used herein, the phrase "essentially free" means that there is no component in the formulation, or less than 0.05% by weight of the component. This means that only trace amounts of the component may be present.

[0018] As used herein, the term "active ingredient" means an ingredient that has nutritional value.

[0019] The term "nutraceutical" refers to any compound added to a nutritional source (e.g., a food, beverage, or dietary supplement) that provides a health or medical benefit in addition to its basic nutritional value.

[0020] As used herein, the terms "delivering" or "administering" refer to any route for providing a composition, product, active ingredient, or nutritional supplement to a subject, as accepted as standard by the medical community. For example, the present disclosure contemplates delivery or administration routes including oral ingestion.

[0021] Other features and aspects of the disclosure are discussed in more detail below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] It should be understood by those skilled in the art that this discussion is merely a description of exemplary embodiments and is not intended to limit the broader aspects of the present disclosure.

[0023] In the present disclosure, the liquid-fill composition is placed in a container or capsule from which a user can ingest the liquid-fill composition. The choice of container or capsule container is limited to materials that are not soluble in water and lipids (oils). In one embodiment, the container or capsule is formed from a film-forming composition that includes at least one polysaccharide or polysaccharide derivative. The polysaccharide or its derivative can be cellulose, cellulose derivatives, starch, modified starch, pullulan, dextran, and the like, and mixtures of any of the foregoing.

[0024] Suitable cellulose derivatives are selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, carboxyalkyl cellulose, and carboxyalkyl alkyl cellulose, including, but not limited to, members selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetyl phthalate (CAP), sodium carboxymethyl cellulose, and mixtures of any of the foregoing. Particularly usable in the present disclosure is hydroxypropyl methyl cellulose (HPMC).

[0025] Additional cellulose derivatives include cellulose ethers. Suitable cellulose ethers are selected from the group consisting of alkyl and / or hydroxyalkyl substituted cellulose ethers having 1-4 carbon atoms in the alkyl chain, preferably methyl cellulose ether, hydroxyethyl cellulose ether, hydroxypropyl cellulose ether, hydroxyethyl methyl cellulose ether, hydroxyethyl ethyl cellulose ether, hydroxypropyl methyl cellulose ether, and the like, and mixtures of any of the foregoing. Particularly preferred is hydroxypropyl methyl cellulose ether.

[0026] In addition to starch, modified starches such as starch ethers and oxidized starches, carboxymethyl starches, hydroxyalkylated starches, and succinylated starches can be used, more specifically hydroxypropylated starch (HPS) or hydroxyethylated starch (HES), or a mixture thereof, can be used as film-forming materials in the film-forming composition to obtain the container according to the present invention. The modified starches disclosed in US Patent No. 6,635,275 B1 are suitable for the present invention. The desired modified starch is HPS.

[0027] In one particular embodiment, the container is a molded body obtained from a film-forming composition comprising at least one polysaccharide or polysaccharide derivative, or a mixture thereof, at about 90% to 99% by weight of the final container or capsule. One particular polysaccharide usable in the present disclosure is pullulan. Pullulan is a polysaccharide polymer composed of maltotriose units, also known as α-1,4-, α-1,6-glucan'. Three glucose units in maltotriose are connected by α-1,4 glycosidic bonds, whereas consecutive maltotriose units are connected to each other by α-1,6 glycosidic bonds. Pullulan containers or capsules usable in the present disclosure include those described in US 10,130,587, which have low monosaccharide, disaccharide, and oligosaccharide content.

[0028] In one exemplary embodiment according to the present invention, the container is a HPMC hard capsule. The capsule can be a two-piece hard capsule, which can be produced by dipping or injection molding. The capsule can be a one-compartment dosage form and a multi-compartment dosage form. Suitable methods for producing such two-piece capsules include those found in the art. For example, the two-piece capsule can be produced by dipping.

[0029] The container or capsule according to the present disclosure is a commercially available hard capsule intended for oral administration to humans or animals. Such hard capsules are generally manufactured from polymers by using a dip-molding process and equipment. In this process, a pin mold is immersed in an aqueous-based film-forming composition. The composition attached to the pin is then gelled to form a film. The film is then dried, the pin is peeled off, and cut to the desired length. Thus, a capsule cap and a body are obtained. Then, such two parts are coaxially and elastically joined to form a capsule shell. Usually, the cap and the body have a side wall, an open end, and a closed end. The length of each side wall of the parts is generally larger than the diameter of the capsule. The capsule cap and the body are elastically joined together to overlap their side walls and obtain a hard capsule shell. "Partially overlapping" also encompasses an embodiment in which the side walls of the cap and the body have substantially the same length, such that when the cap and the body are elastically joined, the side walls of the cap envelop the entire side walls of the body. Unless otherwise indicated, "capsule" refers to a filled capsule shell, while "shell" refers specifically to an empty capsule.

[0030] The film-forming composition for obtaining the container of the present invention may optionally contain a suitable gelling agent selected from known gelling agents, provided that such gelling agent improves the gelling ability of the capsule and does not interact with the matrix composition and / or the liquid fill containing the active agent(s).Examples of suitable gelling agents include alginic acid, sodium alginate, potassium alginate, calcium alginate, agar, carrageenan, carob gum, and gellan gum.The most preferred gelling agent is gellan gum.

[0031] The capsule may optionally be coated with a suitable coating agent, such as, for example, to provide enteric properties, a member selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, gelatin methacrylate, hypromellose phthalate, hydroxypropyl methylcellulose phthalate, hydroxyalkyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and mixtures thereof.

[0032] In a further embodiment of the present invention, the capsule may be additionally sealed using means known in the art, such as banding or liquid sealing techniques. Examples of suitable sealing techniques are those described in WO 01 / 08631. In one embodiment, the capsule is sealed using a hydrogen alcohol solution, for example as described in WO 01 / 08631 (hereby incorporated by reference).

[0033] Commercially available capsules such as DRCAPS® and VCAPS® Plus, LICAP® available from Lonza Consumer Health Inc. (offices located in Greenwood, South Carolina) are exemplary capsules that can be used to deliver the fill composition.

[0034] The container or capsule has an internal compartment that can hold a fill formulation containing an active ingredient. In one embodiment, the container or capsule is typically transparent or nearly transparent so that the liquid content is visible to the user. The container or capsule may have a color, but is generally completely transparent.

[0035] The liquid fill composition in the container or capsule has two phases: a water-based phase and a lipid (oil)-based phase. These two phases are separate, different, and incompatible (insoluble) with each other. The two phases and the fill formulation should be essentially free of emulsifiers or ingredients that may have emulsifying properties. The presence of emulsifiers or ingredients that have emulsifying properties will not result in a liquid fill composition with two different phases. This is because emulsifiers or ingredients that have emulsifying properties tend to reduce the surface tension between the water phase and the lipid (oil) phase. Depending on the components of the water phase and the lipid (oil) phase, this will result in a water-in-oil or oil-in-water emulsion.

[0036] The water phase or aqueous phase of the fill composition contains water and at least one water-soluble active ingredient. Other ingredients may be present in the water phase, provided that any additional ingredients do not have emulsifying properties. Examples of additional ingredients that may be present in the water phase or aqueous phase include glycerin, gum thickening systems, or any other system that may be used to thicken the water phase. Additionally, choline chloride may be used as a diluent for the water phase.

[0037] The lipid (oil) base may be an oil-based composition. The oil itself may be the active agent, or the oil may contain a lipid (oil) soluble active ingredient. The oil usable in the present disclosure may be a vegetable oil, an animal oil, a marine oil, or a mineral oil, and / or any other edible oil. In general, the oil should be acceptable in pharmaceuticals and / or foods.

[0038] In one embodiment, vegetable oil is used.Examples of vegetable oil include safflower oil, olive oil, soybean oil, linseed oil, rice germ oil, wheat germ oil, coconut oil, corn oil, cottonseed oil, palm oil, palm kernel oil, peanut oil, rapeseed oil, sesame oil, sunflower oil, almond oil, cashew oil, hazelnut oil, macadamia nut oil, mongongo oil, pecan oil, pine nut oil, pistachio oil, walnut oil, calabash seed oil, buffalo gourd oil, pumpkin seed oil, watermelon seed oil, blackcurrant seed oil, borage seed oil, evening primrose oil, amaranth oil, apricot oil, apple seed oil, These include argan oil, artichoke oil, avocado oil, babassu oil, ben oil, cape chestnut oil, carob oil, coffea palm oil, coriander oil, dica oil, camellia oil, grape seed oil, hemp oil, kapok seed oil, lalemantia oil, marula oil, meadowfoam seed oil, mustard oil, okra seed oil (hibiscus oil), papaya oil, perilla oil, poppy seed oil, prune kernel oil, quinoa oil, ramtil oil, camellia oil, thistle oil, tomato oil, saw palmetto oil, and / or borage oil.

[0039] Animal oils include oils derived from milk fat, which is the fat in milk, including milkfat, butterfat, and butter oil.

[0040] Marine oils include fish oil, krill oil, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) from marine sources.

[0041] Other pharma- ceutical or nutritionally acceptable oils, such as mineral oil and castor oil, may also be used.

[0042] The aqueous phase has water soluble active ingredients usable in the present disclosure, including, but not limited to, L-theanine, carnitine, vitamin C (ascorbic acid), vitamin B6, vitamin B12, alpha GPC (L-alpha glyceryl phosphorylcholine), melatonin, and elderberry.

[0043] Lipid (oil) soluble active ingredients that can be used in the present disclosure include, but are not limited to, vitamin E, algae oil, lavender oil, safflower oil, vitamin A, vitamin D, and vitamin K. In an alternative embodiment, the oil in the lipid (oil) phase itself may be the beneficial ingredient, and the lipid (oil) phase need not contain any additional active ingredients, such as additional lipid (oil) soluble active ingredients.

[0044] The active ingredient in the lipid (oil) phase can be up to 100% of the lipid (oil) phase. Generally, the lipid (oil) phase contains about 0.1% to about 100% by weight, typically about 0.5% to about 75% by weight, more typically about 1% to about 20% by weight, more specifically about 3% to about 15% by weight, based on the total weight of the lipid (oil) phase, depending on the active ingredient. The upper limit of the active ingredient in the lipid (oil) phase can be up to 100% by weight of the lipid (oil) term, for example up to 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% by weight, or any amount therebetween. The lower limit of the active ingredient in the lipid (oil) phase can be 0.1%, 0.5%, 1%, 3%, 5%, 7%, 10%, 15%, 20%, 30% or more by weight, and any amount between these defined lower limits.

[0045] The active ingredient in the aqueous phase may be present in an amount of up to 100% by weight, based on the total weight of the aqueous phase. Generally, the aqueous phase contains an active ingredient in the range of 0.1% to 80% by weight, based on the total weight of the aqueous phase, typically 1% to 75% by weight, based on the total weight of the aqueous phase, more typically 3% to 70% by weight, depending on the active ingredient. The upper limit of the active ingredient in the aqueous phase may be up to 80% by weight of the aqueous phase, for example up to 75%, 70%, 60%, 50%, 40%, 30%, or 20% by weight, or any amount therebetween. The lower limit of the active ingredient in the aqueous phase may be 0.1%, 0.5%, 1%, 3%, 5%, 7%, 10%, 15%, 20%, 30% or more by weight, and any amount between these defined lower limits.

[0046] Other ingredients may be present in each of the lipid (oil) and aqueous phases of the fill composition. Examples of other ingredients include, for example, antioxidants, colorants, preservatives, taste masking materials, surfactants that do not cause phase separation, viscosity modifiers, and mixtures thereof. Non-limiting examples of antioxidants include ascorbic acid and preservatives. Non-limiting examples of preservatives are BHA (butyl hydroxyanisole), BHT (butyl hydroxutoluene), and ascorbyl palmitate. Non-limiting examples of surfactants include polysorbates. Non-limiting examples of viscosity modifiers include silicon dioxide and HPMC. Other ingredients are necessary to maintain the oil and aqueous phases in the container or capsule to remain separated. Furthermore, additional ingredients desirably help the user of the capsule or container to distinguish the two phases present in the capsule or container. In addition, the liquid nature of both the lipid (oil) and aqueous phases must not contain ingredients of the fill and must not provide a detrimental effect on the hard capsule shell.

[0047] The fill composition can be added into the container or capsule as a single-phase formulation. To form a single-phase formulation, the lipid (oil) phase and the aqueous phase are subjected together to a high shear rate mixing process, which results in the formation of a single-phase formulation. Typical shear rates can be from 100 RPM (revolutions per minute) to 15,000 RPM, which ensures that the aqueous phase and the lipid (oil) phase are homogeneously mixed and can be added into the container or capsule. Also, the use of heat during mixing should be avoided, as heat can cause catalyst separation. Generally, high shear mixing should occur at or near room temperature of 25°C.

[0048] After being placed in the container, considering the incompatibility of the aqueous phase and the lipid (oil) phase, the two phases start to separate from each other to form very different phases in the container or capsule.Generally, the lipid (oil) phase is about 10% to about 90% by volume of the fill composition, and the aqueous phase is about 90% to about 10% by volume of the fill composition.The actual ratio may depend on the amount of active ingredient in each of the lipid (oil) phase and the aqueous phase, and the desired amount of active ingredient in the container or capsule.

[0049] The addition of colorants or tints to one or both of the lipid (oil) and aqueous phases provides an aesthetically pleasing concept, much like nostalgic lava lights, given the compatibility of the lipid (oil) and aqueous phases. When present, the colorants or tints may be present in an amount of about 0.01% to about 10%, based on the total weight of the liquid. In some embodiments, depending on the active ingredient, the active ingredient also serves to provide color to one or both of the lipid (oil) and aqueous phases.

[0050] Unless otherwise indicated, reference to compatibility of the liquid fill with the container or capsule means that after filling into the container or capsule shell, the liquid fill does not affect the physical stability of the capsule, i.e., the capsule remains intact and rigid without leakage, deformation, discoloration, and / or excessive softening or brittleness when observed over the indicated period of time. Physical stability or physically stable refers to at least the mechanical stability of the shell, more preferably both the mechanical and chemical stability of the shell. Mechanical stability can be evaluated, for example, based on the maintenance of the hardness of the shell and the lack of leakage. Chemical stability can be evaluated, for example, based on the maintenance of the appropriate dissolution profile of the encapsulated substance (for this latter aspect, reference can be made, for example, to the USP-32 substance monograph).

[0051] In one embodiment, the liquid fill does not affect the mechanical and chemical stability after filling into the hard capsule shell as defined above beyond an acceptable level. In one embodiment, the acceptable level is a commercially acceptable level. In one embodiment, the commercially acceptable level is a level recognized by those skilled in the art of hard capsules, preferably liquid-filled hard capsules, as a satisfactory level for commercializing carrier-filled hard capsules at acceptable manufacturing costs.

[0052] In one embodiment, a batch of preferably at least 50 hard capsule shells is filled with the liquid fill and when the filled capsules are subjected to mechanical robustness testing (e.g., tube testing) at a specified shell loss on drying (LOD), the liquid fill does not affect the physical stability (mechanical or chemical) of the hard capsule shell beyond an acceptable level if 0% of the capsules in the batch fail at a shell moisture content comprised between about 2% and about 6% LOD. Such "mechanical robustness testing" demonstrates changes in the mechanical properties of the capsule due to interactions between the fill and the shell and evaluates the potential tendency for brittleness or softening when filled and stored at various relative humidity conditions and temperatures.

[0053] Because the containers or capsule shells of the present disclosure are filled with a liquid form of the substance, it is contemplated that, if desired, the hard capsules may be sealed or banded in accordance with conventional techniques, either manually or via automated banding or sealing equipment.

[0054] Several solutions have been developed to reduce leakage through the gap between the body and the cap. For example, hard gelatin capsule banding with a gelatin banding solution is commonly used to prevent leakage of contents during storage. Another method to reduce leakage is to directly seal the cap and the body of the capsule to each other with a "sealing fluid". See, for example, U.S. Pat. No. 3,071,513, U.S. Pat. No. 2,924,920, FR 2,118,883, EP 0152517, U.S. Pat. No. 4,756,902, FR 2118883, EP 0152517, and U.S. Pat. No. 4,756,902. For methods of banding two-piece hard capsules and apparatus for banding, see, e.g., U.S. Pat. Nos. 8,181,425, 7,229,639, 7,094,425, 5,054,208, 4,940,499, 4,922,682, 4,761,932, and 4,734,149, all of which are incorporated herein by reference.

[0055] Nonetheless, certain embodiments of the present disclosure may be better understood in accordance with the following examples, which are intended to be non-limiting and exemplary in nature. EXAMPLES

[0056] Example 1 The liquid fill formulation is prepared by forming the aqueous phase and the lipid (oil) phase in separate formulation steps as shown below, using the components shown in Table 1 for the aqueous phase and the components shown in Table 2 for the oil phase. After the lipid (oil) phase and the aqueous phase are prepared, 100 parts by weight of the oil phase and 100 parts by weight of the aqueous phase are combined together using a high shear mixer at a shear rate of 3500 RPM to form a nearly uniform single-phase mixture of the aqueous phase and the oil phase. The single-phase mixture is then added into a transparent capsule. The two phases of water and lipid (oil) mixed together are left in the capsule for a period of time, and the two phases separate to form the aqueous phase and the lipid (oil) phase in the capsule. [Table 1] [Table 2]

[0057] Example 2 A liquid fill formulation is prepared by forming an aqueous phase and a lipid (oil) phase in separate formulation steps as shown below, using the components shown in Table 1 for the aqueous phase and the components shown in Table 2 for the oil phase. After the lipid (oil) phase and the aqueous phase are prepared, 100 parts by weight of the oil phase and 100 parts by weight of the aqueous phase are combined together using a high shear mixer at a shear rate of 3500 RPM to form a nearly uniform single-phase mixture of aqueous and oil phases. The single-phase mixture is then added into a transparent capsule and allowed to stand for a period of time to allow the phases to separate into an aqueous phase and a lipid (oil) phase. The resulting capsule has an aqueous phase and a liquid phase in the capsule. [Table 3] [Table 4]

[0058] Example 3 The liquid fill formulation is prepared by forming the aqueous phase and the lipid (oil) phase in separate formulation steps as shown below, using the components shown in Table 5 for the aqueous phase and the components shown in Table 6 for the oil phase. After the lipid (oil) phase and the aqueous phase are prepared, 100 parts by weight of the oil phase and 100 parts by weight of the aqueous phase are combined together using a high shear mixer at a shear rate of 3500 RPM to form a nearly uniform single-phase mixture of the aqueous phase and the oil phase. The single-phase mixture is then added into a transparent capsule and allowed to stand for a period of time to allow the phases to separate into the aqueous phase and the lipid (oil) phase. The resulting capsule has an aqueous phase and a liquid phase in the capsule. [Table 5] [Table 6]

[0059] These and other modifications and variations to the present invention may be implemented by those of ordinary skill in the art without departing from the spirit and scope of the present invention, which is particularly set forth in the appended claims. In addition, it should be understood that aspects of the various embodiments may be interchanged in whole or in part. Moreover, those skilled in the art will appreciate that the foregoing description is by way of example only, and is not intended to limit the invention as further set forth in such appended claims.

Claims

**Claim 1** An active ingredient delivery system comprising: a. A container having an internal compartment; b. A liquid-filled composition comprising a first liquid phase and a second liquid phase, wherein the first liquid phase and the second liquid phase are immiscible with each other due to their incompatibility, and the first liquid phase and the second liquid phase are immiscible; c. An active ingredient present in at least one of the first liquid phase and the second liquid phase. The active ingredient delivery system, wherein the liquid-filled composition is contained within the internal compartment of the container. **Claim 2** The delivery system according to claim 1, wherein the liquid-filled composition essentially does not contain an emulsifier. **Claim 3** The delivery system according to claim 1, wherein the first liquid phase is a lipid (oil)-based phase and the second phase is an aqueous-based phase. **Claim 4** The delivery system according to claim 3, wherein each of the first and second liquid phases contains at least one active ingredient. **Claim 5** The delivery system according to any one of claims 1 to 4, wherein the liquid-filled composition is not an emulsion. **Claim 6** The delivery system according to any one of claims 1 to 4, wherein the container is a capsule. **Claim 7** The delivery system according to claim 6, wherein the capsule is a hard capsule. **Claim 8** The delivery system according to claim 6, wherein the container is a shaped body obtained from a film-forming composition containing at least one polysaccharide or polysaccharide derivative. **Claim 9** The delivery system according to claim 8, wherein the polysaccharide is a cellulose derivative selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkylalkyl cellulose, carboxyalkyl cellulose, carboxyalkylalkyl cellulose, and cellulose ether. **Claim 10** The delivery system according to claim 9, wherein the cellulose derivative is selected from the group consisting of methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate phthalate (CAP), sodium carboxymethylcellulose, methylcellulose ether, hydroxyethylcellulose ether, hydroxypropylcellulose ether, hydroxyethylmethylcellulose ether, hydroxyethylethylcellulose ether, and hydroxypropylmethylcellulose ether.

11. The delivery system according to claim 10, wherein the cellulose derivative is selected from hydroxypropylmethylcellulose (HPMC).

12. The delivery system according to claim 8, wherein the polysaccharide is pullulan.

13. The delivery system according to claim 1, wherein one or both liquid phases of the liquid-filled composition contain a colorant.

14. The delivery system according to claim 13, wherein when the colorant is present in one or both of the liquid phases, it is present in an amount of about 0.01% to about 10% based on the total weight of each liquid phase.

15. The delivery system according to any one of claims 1 to 4, wherein the first phase is a lipid (oil) phase, and the lipid (oil) phase contains 0.1% to 100% by weight, typically 0.5% to 75% by weight, and more typically 1% to 20% by weight of the active ingredient based on the total weight of the lipid (oil) phase.

16. The delivery system according to any one of claims 1 to 4, wherein the second phase is an aqueous phase, and the aqueous phase contains 0.1% to 80% by weight, typically 1% to 75% by weight, and more typically 3% to 70% by weight of the active ingredient based on the total weight of the aqueous phase.

17. The delivery system according to any one of claims 1 to 4, wherein the active ingredient provides coloration to at least one of the phases.

18. A method of forming a two-phase liquid capsule-filled composition containing a lipid phase and an aqueous phase, wherein the lipid phase and the aqueous phase are separated from each other and different, and the method comprises: a. forming a lipid phase containing an active ingredient; b. forming an aqueous phase containing a water-soluble active ingredient; c. mixing the lipid phase with the aqueous phase using a high shear rate mixer to form a combined liquid phase; d. disposing the combined liquid phase in a container or capsule; e. separating the lipid phase and the aqueous phase in the container or capsule, the method comprising.

19. The method according to claim 18, wherein the mixing is carried out with a high shear mixer at a mixing speed of 100 RPM (revolutions per minute) to 15,000 RPM.

20. The delivery system according to any one of claims 1 to 4, wherein the container is coated or banded.