Coated capsules and tablets of a fatty acid oil mixture

This application is incorporated herein by reference in its entirety, US Patent Provisional Application No. 61/254291 filed October 23, 2009, US Patent Provisional filed October 23, 2009. Claims priority under Application No. 61/254293 and US Patent Provisional Application No. 61/254296 filed October 23, 2009.

The present disclosure generally covers compositions and preconcentrates containing a fatty acid oil mixture in the form of coated capsules or coated tablets suitable for oral administration, and how they are used. The capsules and tablets disclosed herein include, for example, abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neuronal development, hypertriglyceridemia, hypercholesterolemia, etc. It can be administered to a subject for therapeutic treatment and / or regulation of at least one health problem, including mixed dyslipidemia, heart failure, and post-myocardial infarction (MI).

In humans, cholesterol and triglycerides are part of the lipoprotein complex in the bloodstream, by ultracentrifugation, high density lipoprotein (HDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), And can be separated into very low density lipoprotein (VLDL) fractions. Cholesterol and triglyceride are synthesized in the liver, incorporated into VLDL and released into plasma. High levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (membrane complex for LDL-C and VLDL-C) promote atherosclerosis in humans and HDL-C And lowering the level of its transport complex, apolipoprotein A is also associated with the development of atherosclerosis. In addition, cardiovascular morbidity and mortality in humans can vary directly in proportion to total-C and LDL-C levels and inversely in HDL-C levels. In addition, studies suggest that non-HDL cholesterol is an indicator of hypertriglyceridemia, vascular disease, arteriosclerosis, and related conditions. In fact, NCEP ATP III specifies that lowering non-HDL cholesterol is a therapeutic goal.

Omega-3 fatty acids can regulate plasma lipid levels, cardiovascular and immune function, insulin action, neural development, as well as visual function. Marine oils, commonly referred to as fish oils, are sources of omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and have been found to regulate lipid metabolism. .. Plant-based oils and microbial oils are also sources of omega-3 fatty acids. Omega-3 fatty acids may have beneficial effects on risk factors for cardiovascular diseases such as hypertension and hypertriglyceridemia, and on the activity of coagulation factor VII phospholipid complexes. Omega-3 fatty acids can also lower serum triglycerides, increase serum HDL cholesterol, lower systolic and diastolic blood pressure and / or pulse rate, and blood coagulation factor VII-phosphorus. May reduce the activity of the lipid complex. In addition, omega-3 fatty acids are generally well tolerated and do not cause serious side effects.

Several formulations of omega-3 fatty acids have been developed. For example, one form of omega-3 fatty acid oil mixture is DHA and EPA, such as those sold under the trademarks Omacor® / Lovaza® / Zodin® / Seacor®. It is a concentrate of long-chain polyunsaturated fatty acids, mainly omega-3, derived from the contained fish oil. See, for example, US Pat. Nos. 5502077, 5656667, 5689594 and 7732488. Specifically, each 1000 mg capsule of Lovaza contains at least 90% omega-3 fatty acid ethyl ester (84% EPA / DHA); that is, approximately 465 mg of EPA ethyl ester and approximately 375 mg of DHA ethyl ester. ..

But the evidence is at least C₂₄It suggests that long-chain fatty acids and alcohols up to are reversibly interconverted. Enzymatic systems that convert fatty alcohols to fatty acids are present in the liver, fibroblasts, and brain. In some tissues, fatty acids can be reduced back to alcohol. The carboxylic acid functional group of a fatty acid molecule targets binding, but this ionizable group can prevent the molecule from crossing cell membranes such as the intestinal wall. As a result, carboxylic acid functional groups are often protected as esters. Esters are less polar than carboxylic acids and can cross fatty cell membranes more easily. Once in the bloodstream, the ester can be hydrolyzed by the esterase enzyme in the blood back to free carboxylic acid. Plasma enzymes do not hydrolyze esters fast enough, but conversion of esters to free carboxylic acids can occur primarily in the liver. Ethyl esters of polyunsaturated fatty acids can also be hydrolyzed in vivo to free carboxylic acids.

<p> Thus, in the art, compositions and compositions that improve the release of omega-3 fatty acids in vivo and enhance solubilization, digestion, bioavailability and / or absorption while maintaining the ability to cross cell membranes. / Or there remains a need for a method.</p><p> It should be understood that both the general description above and the detailed description below are for illustration and illustration purposes only and do not limit the disclosure of the claimed invention.</p>

<p> The present disclosure is a pharmaceutical composition in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one free fatty acid, wherein the fatty acid oil mixture is eicosapentaenoen at least 75% by weight of the fatty acid oil mixture. A pharmaceutical composition comprising an acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA present in a form selected from ethyl esters and triglycerides, and gelatin capsules or tablets comprising at least one coating. ..</p><p> The present disclosure is also a food supplement or nutritional supplement composition in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one free fatty acid, a fatty acid oil. The mixture contains from about 25% to about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), where EPA and DHA are present in a form selected from ethyl esters and triglycerides, gelatin. Capsules or tablets are intended for compositions that include at least one coating.</p><p> The present disclosure is also a pharmaceutical preconcentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture, at least one free fatty acid, and at least one surfactant, wherein the fatty acid oil mixture is , Contains at least 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in a form selected from ethyl esters, triglycerides, gelatin capsules or tablets are at least 1 Target pre-concentrates, including one coating.</p><p> The present disclosure is also a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, with a fatty acid oil mixture of about 45% to about 55% by weight based on the weight of the pre-concentrate and the weight of the pre-concentrate. Containing at least one free fatty acid of about 10% to about 15% by weight and at least one surfactant of about 30% to about 40% by weight based on the weight of the preconcentrate. The fatty acid oil mixture comprises from about 80% to about 88% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the EPA and DHA being present in the form of ethyl esters, the at least one of which is present. Free fatty acids contain from about 80% to about 88% by weight of the at least one free fatty acid, EPA and DHA are present in the form of free fatty acids, and the surfactant is selected from polysolvate 20. And gelatin capsules or tablets are intended for pre-concentrates, including at least one coating.</p><p> The present disclosure is also a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, with a fatty acid oil mixture of about 45% to about 55% by weight based on the weight of the pre-concentrate and the weight of the pre-concentrate. It contains at least about 10% to about 15% by weight of free fatty acids and at least about 30% to about 40% by weight of the surfactant with respect to the weight of the preconcentrate. The fatty acid oil mixture contains from about 80% to about 88% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in the form of ethyl esters, and free fatty acids are Selected from oleic acid, the surfactant is selected from polysolvate 20, and gelatin capsules or tablets are intended for pre-concentrates containing at least one coating.</p><p> The present disclosure is also a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, with a fatty acid oil mixture of about 65% to about 75% by weight based on the weight of the pre-concentrate and the weight of the pre-concentrate. Containing at least one free fatty acid from about 15% to about 20% by weight and at least one surfactant from about 10% to about 15% by weight based on the weight of the preconcentrate. The fatty acid oil mixture contains from about 80% to about 88% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in the form of ethyl esters, and free fatty acids are Selected from oleic acid, the surfactant is selected from polysolvate 20, and gelatin capsules or tablets are intended for pre-concentrates containing at least one coating.</p><p> The present disclosure is also a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, with a fatty acid oil mixture of about 45% to about 55% by weight based on the weight of the pre-concentrate and the weight of the pre-concentrate. Containing at least one free fatty acid from about 10% to about 15% by weight and at least two surfactants from about 40% to about 50% by weight based on the weight of the preconcentrate. The fatty acid oil mixture comprises from about 80% to about 88% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the EPA and DHA being present in the form of ethyl esters, at least one of which. Free fatty acids contain from about 80% to about 88% by weight of the at least one free fatty acid, EPA and DHA are present in the form of free fatty acids, and the surfactants are polysorbate 20 and lecithin. Selected from, gelatin capsules or tablets are intended for pre-concentrates, including at least one coating.</p><p> The present disclosure is also a pharmaceutical preconcentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one surfactant, wherein the fatty acid oil mixture is at least 75 weight by weight of the fatty acid oil mixture. Includes% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in the form of free acids, and gelatin capsules or tablets are intended for pre-concentrates containing at least one coating.</p><p> The present disclosure is also a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, with a fatty acid oil mixture of about 60% to about 70% by weight based on the weight of the pre-concentrate and the weight of the pre-concentrate. Containing from about 30% to about 40% by weight of at least two surfactants, the fatty acid oil mixture is about 80% to about 88% by weight of the fatty acid oil mixture with eikosapentaenoic acid (EPA) and Pre-concentrates containing docosahexaenoic acid (DHA), EPA and DHA present in the form of free acids, surfactants selected from polysolvate 20 and lecithin, gelatin capsules or tablets containing at least one coating. set to target.</p><p> The present disclosure is also a pharmaceutical preconcentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one surfactant, wherein the fatty acid oil mixture is at least 75 weight by weight of the fatty acid oil mixture. Pre-concentrate containing% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA present in a form selected from ethyl esters and triglycerides, gelatin capsules or tablets containing at least one coating Is targeted.</p><p> The present disclosure is also a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, wherein the fatty acid oil mixture is about 75% to about 85% by weight of the weight of the pre-concentrate and the weight of the pre-concentrate. Containing from about 15% to about 25% by weight of at least one surfactant, the fatty acid oil mixture is about 80% to about 88% by weight of the fatty acid oil mixture with eikosapentaenoic acid (EPA) and Includes docosahexaenoic acid (DHA), EPA and DHA are present in the form of ethyl esters, surfactants are selected from polysolvate 80, gelatin capsules or tablets are intended for pre-concentrates containing at least one coating. do.</p><p> The disclosure also comprises a food supplement or dietary supplement preconcentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture, at least one free fatty acid, and at least one surfactant. The fatty acid oil mixture contains from about 25% to about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are present in a form selected from ethyl esters and triglycerides. , Gelatin capsules or tablets are intended for pre-concentrates, including at least one coating.</p><p> The present disclosure also comprises a food supplement pre-concentrate or nutritional supplement pre-concentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one surfactant, wherein the fatty acid oil mixture is: Contains about 25% to about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in the form of free acids, and at least one gelatin capsule or tablet Target pre-concentrates, including coatings.</p><p> The present disclosure also comprises a food supplement pre-concentrate or nutritional supplement pre-concentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one surfactant, wherein the fatty acid oil mixture is: It contains from about 25% to about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in a form selected from ethyl esters and triglycerides, gelatin capsules or Tablets are intended for pre-concentrates, including at least one coating.</p><p> The disclosure also relates to the treatment of at least one health problem selected from abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, nerve development, heart failure, and post-myocardial infarction. , A pharmaceutical composition in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one free fatty acid, the fatty acid oil mixture being at least 75% by weight eicosapentaenoic acid (EPA) of the fatty acid oil mixture. ) And docosahexaenoic acid (DHA), EPA and DHA are present in a form selected from ethyl esters and triglycerides, and gelatin capsules or tablets are intended for compositions comprising at least one coating.</p><p> The disclosure also relates to the treatment of at least one health problem selected from abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, nerve development, heart failure, and post-myocardial infarction. , Gelatin capsules or pharmaceutical preconcentrates in the form of tablets, comprising a fatty acid oil mixture, at least one free fatty acid and at least one surfactant, the fatty acid oil mixture is a fatty acid oil mixture. It contains at least 75% by weight eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in a form selected from ethyl esters and triglycerides, and gelatin capsules or tablets contain at least one coating. Target pre-concentrates.</p><p> The disclosure also relates to the treatment of at least one health problem selected from abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, nerve development, heart failure, and post-myocardial infarction. , A self-emulsifying drug delivery system (SNEDDS), a self-microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS), which comprises a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets. The pre-concentrate contains a fatty acid oil mixture, at least one free fatty acid, and at least one surfactant, and the fatty acid oil mixture is at least 75% by weight of eikosapentaenoic acid (EPA) of the fatty acid oil mixture. ) And docosahexaenoic acid (DHA), EPA and DHA are present in a form selected from ethyl esters and triglycerides, gelatin capsules or tablets contain at least one coating, and pre-concentrates emulsion in aqueous solution. Target the drug delivery system that forms.</p><p> The disclosure also relates to the treatment of abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neurodevelopment, heart failure, and at least one health problem selected from post-myocardial infarction. , Gelatin capsules or pharmaceutical preconcentrates in the form of tablets, comprising a fatty acid oil mixture and at least one surfactant, the fatty acid oil mixture is at least 75% by weight of eicosapentaenoic acid in the fatty acid oil mixture. Pre-concentrates that contain (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in the form of free acids, and gelatin capsules or tablets contain at least one coating.</p><p> The disclosure also relates to the treatment of at least one health problem selected from abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, nerve development, heart failure, and post-myocardial infarction. , Self-nano-emulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) containing pharmaceutical pre-concentrates in the form of gelatin capsules or tablets. The pre-concentrate contains a fatty acid oil mixture and at least one surfactant, and the fatty acid oil mixture contains at least 75% by weight of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of the fatty acid oil mixture. , EPA and DHA are present in the form of free acids, gelatin capsules or tablets contain at least one coating, and preconcentrates are intended for drug delivery systems that form emulsions in aqueous solutions.</p><p> The disclosure also relates to the treatment of abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, neurodevelopment, heart failure, and at least one health problem selected from post-myocardial infarction. , Gelatin capsules or pharmaceutical preconcentrates in the form of tablets, comprising a fatty acid oil mixture and at least one surfactant, the fatty acid oil mixture is at least 75% by weight of eicosapentaenoic acid in the fatty acid oil mixture. Containing (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in a form selected from ethyl esters and triglycerides, and gelatin capsules or tablets are intended for pre-concentrates containing at least one coating.</p><p> The disclosure also relates to the treatment of abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, nerve development, heart failure, and at least one health problem selected from post-myocardial infarction. , Self-nano-emulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery system (SEDDS) containing pharmaceutical pre-concentrates in the form of gelatin capsules or tablets. The pre-concentrate contains a fatty acid oil mixture and at least one surfactant, and the fatty acid oil mixture contains at least 75% by weight of ecosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of the fatty acid oil mixture. , EPA and DHA are present in forms selected from ethyl esters and triglycerides, gelatin capsules or tablets contain at least one coating, and preconcentrates form emulsions in aqueous solutions, targeting drug delivery systems. do.</p>

<figref num="1">It is a figure which shows the viscosity of the pre-concentrates A to L.</figref><figref num="2">It is a figure which shows the average particle size distribution of the preliminary concentrates A to F, I and J in the gastric medium (media) and the intestinal medium (media).</figref><figref num="3">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate A was measured four times in succession in a gastric medium.</figref><figref num="4">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate B was measured four times in succession in a gastric medium.</figref><figref num="5">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate C was measured four times in succession in a gastric medium.</figref><figref num="6">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate D was measured four times in succession in a gastric medium.</figref><figref num="7">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate E was measured four times in succession in a gastric medium.</figref><figref num="8">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate F was measured four times in succession in a gastric medium.</figref><figref num="9">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate I was measured four times in succession in a gastric medium.</figref><figref num="10">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate J was measured four times in succession in a gastric medium.</figref><figref num="11">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate A was measured four times in succession in an intestinal medium.</figref><figref num="12">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate B was measured four times in succession in an intestinal medium.</figref><figref num="13">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate C was measured four times in succession in an intestinal medium.</figref><figref num="14">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate D was measured four times in succession in an intestinal medium.</figref><figref num="15">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate E was measured four times in succession in an intestinal medium.</figref><figref num="16">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate F was measured four times in succession in an intestinal medium.</figref><figref num="17">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate I was measured four times in succession in an intestinal medium.</figref><figref num="18">It is a figure which shows the reading data obtained from the Malvern zetasizer when the pre-concentrate J was measured four times in succession in an intestinal medium.</figref><figref num="19">It is a figure which shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA at the time of lipolysis of Omacor (registered trademark).</figref><figref num="20">It is a figure which shows the recovery percentage of EPA + DHA at different time point about Omacor (registered trademark).</figref><figref num="21">FIG. 5 shows the percentage of lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for Omacor®.</figref><figref num="22">It is a figure which shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA at the time of lipolysis of pre-concentrate A.</figref><figref num="23">It is a figure which shows the recovery percentage of EPA + DHA at a different time point about a pre-concentrate A.</figref><figref num="24">EPA-EE at different time points regarding preconcentrate A, DHA-EE Oyo illustrates lipolysis% of beauty all K85EE.</figref><figref num="25">It is a figure which shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA at the time of lipolysis of pre-concentrate B.</figref><figref num="26">It is a figure which shows the recovery percentage of EPA + DHA at different time points with respect to a pre-concentrate B.</figref><figref num="27">FIG. 5 shows the percentage of lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for pre-concentrate B.</figref><figref num="28">It is a figure which shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA at the time of lipolysis of pre-concentrate C.</figref><figref num="29">It is a figure which shows the recovery percentage of EPA + DHA at a different time point about a pre-concentrate C.</figref><figref num="30">FIG. 5 shows the percentage of lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for pre-concentrate C.</figref><figref num="31">It is a figure which shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA at the time of lipolysis of pre-concentrate D.</figref><figref num="32">It is a figure which shows the recovery percentage of EPA + DHA at different time points with respect to a pre-concentrate D.</figref><figref num="33">FIG. 5 shows the percentage of lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for pre-concentrate D.</figref><figref num="34">It is a figure which shows the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA at the time of lipolysis of pre-concentrate E.</figref><figref num="35">It is a figure which shows the recovery percentage of EPA + DHA at different time points with respect to a pre-concentrate E.</figref><figref num="36">FIG. 5 shows the percentage of lipolysis of EPA-EE, DHA-EE and total K85EE at different time points for pre-concentrate E.</figref><figref num="37">It is a figure which shows the time profile of the plasma concentration | total lipid concentration of EPA about Example 14.</figref><figref num="38">FIG. 5 shows serum EPA levels over time following administration of coated and uncoated tablets as described in Example 22.</figref><figref num="39">FIG. 5 shows serum DHA levels over time following administration of coated and uncoated tablets as described in Example 22.</figref>

Specific embodiments of the present disclosure will be described in more detail below. The terms and definitions used in this application and made clear herein are to be construed as explaining their meaning within the present disclosure. Patents and scientific literature that apply and is referenced herein are incorporated herein by reference. If inconsistent with the terms and / or definitions incorporated by reference, the terms and definitions provided herein supersede.

The singular forms "a", "an" and "the" include references to multiples unless the context requires otherwise.

The terms "almost" and "about" mean that they are almost the same as the numbers or values mentioned. As used herein, it is generally understood that the terms "almost" and "about" include ± 10% of a specified amount, frequency or value.

The terms "administer," "administer," or "administer," as used herein, (1) the book by a sound practitioner or his authorized agent, or under its direction. It refers to providing, granting, dosing and / or prescribing a composition according to the disclosure, and (2) accepting, taking or consuming the composition according to the present disclosure by the patient or the person.

The present disclosure provides a pharmaceutical composition and a supplement composition comprising a fatty acid oil mixture and at least one free fatty acid, which may be coated, such as gelatin capsules, and formulated as tablets.

Also disclosed herein is a pre-concentrate containing a fatty acid oil mixture and at least one surfactant. In some embodiments, the pre-concentrate comprises a fatty acid oil mixture, at least one free fatty acid, and at least one surfactant. The pre-concentrates of the present disclosure can result in dispersions of small or very small average particle size when mixed with an aqueous medium. Such dispersions can be characterized as nanoemulsions, microemulsions, or emulsions. For example, by delivery, the pre-concentrate produces a dispersion with gastric or other physiological fluid, self-emulsifying drug delivery system (SNEDDS), self-microemulsifying drug delivery system (SMEDDS), or self-emulsifying drug delivery. It is believed to generate a system (SEDDS).

Fatty Acid Oil Mixture The compositions of the present disclosure include at least one fatty acid oil mixture. The fatty acid oil mixture contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). As used herein, the term "fatty acid oil mixture" refers to fatty acids such as unsaturated (eg, monounsaturated, polyunsaturated) or saturated fatty acids, as well as pharmaceutically acceptable esters, free acids thereof. Includes mono-, di- and triglycerides, derivatives, complexes, precursors, salts, and mixtures thereof. In some embodiments, the fatty acid oil mixture comprises a fatty acid, such as an omega-3 fatty acid, in a form selected from ethyl esters and triglycerides. In other embodiments, the fatty acids in the fatty acid oil mixture are present in the form of free acids.

The term "omega-3 fatty acid" refers to natural and synthetic omega-3 fatty acids, as well as pharmaceutically acceptable esters, free acids, triglycerides, derivatives and complexes thereof (eg, each incorporated herein by reference). See US Patent Application Publication No. 2004/0254357 of Zaloga et al. And US Pat. No. 6245811 of Horrobin et al.), Precursors, salts, and mixtures thereof. Examples of omega-3 fatty acid oils include, but are not limited to, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA). , Omega-3 polyunsaturated long-chain fatty acids such as eikosatetraenoic acid (ETA), eikosatrienic acid (ETE) and octadecatetetraenoic acid (ie stearidonic acid, STA); with omega-3 fatty acids and glycerol Includes esters such as mono-, di- and triglycerides; and esters of omega-3 fatty acids with primary, secondary and / or tertiary alcohols such as fatty acid methyl esters and fatty acid ethyl esters. Omega-3 fatty acids, their esters, triglycerides, derivatives, complexes, precursors, salts and / or mixtures thereof according to the present disclosure are in their pure form and / or, for example, marine oils (eg, fish oil and refined). It can be used as a component of oils such as fish oil concentrates), algae oils, microbial oils, and plant-based oils.

In some embodiments of the present disclosure, the fatty acid oil mixture comprises EPA and DHA. Further, for example, in some embodiments, the fatty acid oil mixture comprises forms of EPA and DHA selected from ethyl esters and triglycerides. In other embodiments, the fatty acid oil mixture comprises EPA and DHA in the form of free acids.

The fatty acid oil mixture of the present disclosure may further contain at least one fatty acid other than EPA and DHA. Examples of such fatty acids include, but are not limited to, omega-3 fatty acids and omega-6 fatty acids other than EPA and DHA. For example, in some embodiments of the present disclosure, the fatty acid oil mixture is α-linolenic acid (ALA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eico. Contains at least one fatty acid other than EPA and DHA, selected from satrienoic acid (ETE) and stearidonic acid (STA). In some embodiments, at least one fatty acid other than EPA and DHA is linoleic acid, gamma-linolenic acid (GLA), arachidonic acid (AA), docosapentaenoic acid (ie, osbondic acid), and these. Selected from the mixture. In some embodiments, at least one fatty acid other than EPA and DHA is present in a form selected from ethyl esters and triglycerides. In other embodiments, at least one fatty acid other than EPA and DHA is present in the form of a free acid.

Examples of additional fatty acids, or mixtures thereof (fatty acid oil mixtures), included in the present disclosure are, but not limited to, the fatty acids specified in the European Pharmacopoeia, omega-3 ethyl ester 90 and refined marine oils, such as Europe. Includes Pharmacopoeia omega-3 acid triglyceride, European Pharmacopoeia omega-3 acid ethyl ester 60, European Pharmacopoeia omega-3 acid-rich fish oil monograph, and / or, for example, the US Pharmacopoeia fish oil monograph.

Commercial examples of fatty acid oil mixtures containing various fatty acids suitable for the present disclosure include, but are not limited to, Incromega TG7010SR, Incromega E7010SR, Incromega TG6015, Incromega EPA500TGSR, Incromega . ) E400200SR, Incromega E4010, Incromega DHA700TGSR, Incromega DHA700ESR, Incromega DHA500TGSR, Incromega TG3322SR, Incromega E3322SR, Incromega TG3322, Incromega E3322 , Incromega Trio TG / EE, etc. Incromega Omega-3 Marine Oil Concentrate (Croda International) PLC, Yorksia, UK); EPAX2050TG, EPAX5500EE, EPAX5500TG, EPAX5000EE, EPAX5000TG, EPAX6000EE, EPAX6000TG, EPAX6000FA, EPAX6500EE, EPAX6500TG, EPAX4510TG, EPAX1050TG, EPAX6015TG / EE, EPAX4020TG, EPAX6015TG / EE, EPAX4020TG Omacor® / Lovaza® / Zodin® / Seacor®, K85EE, and AGP103 (Pronova BioPharma Norge AS); MEG-3 EPA / DHA Fish Oil Concentrate (Ocean Nutrition, Canada); DHA FNO "Functional Nutritional Oil" and DHA CL "Clear" Liquid) "(Lonza); Superba Omega Oil (Aker); Omega-3 products containing DHA made on the market; Neptune Omega Oil (Neptune); Cod liver oil products and anti-cod liver oil manufactured by Mollers Anti-reflux fish oil (TG); Lysi Omega-3 Fish Oil; Seven Seas Triomega® Cod Liver Oil Blend (Seven Seas); Fri Flyt Omega-3 (Vesteralens); and Epadel ( Mochida) is included. These commercial embodiments are the result of transesterification or preparation methods for obtaining omega-3 fatty acids from various sources such as aquatic, algae, microbial and plant-based sources. 3 Provides fatty acids, combinations, and other ingredients.

The fatty acid oil mixture according to the present disclosure may be derived from animal oils and / or non-animal oils. In some embodiments of the disclosure, the fatty acid oil mixture is derived from at least one oil selected from marine oils, algal oils, plant-based oils, and microbial oils. Examples of marine oils include fish oil, krill oil, and fish-derived lipid compositions. Plant-based oils include, for example, flaxseed oil, canola oil, caracina seed oil, and soybean oil. Examples of the microbial oil include products manufactured by Martek. In at least one embodiment of the present disclosure, the fatty acid oil mixture is derived from a marine oil such as fish oil. In at least one embodiment, the marine oil is refined fish oil.

In some embodiments of the present disclosure, fatty acids such as omega-3 fatty acids in fatty acid oil mixtures are esterified to alkyl esters and the like. Alkyl esters include, but are not limited to, ethyl, methyl, propyl, butyl esters, and mixtures thereof. In other embodiments, the fatty acid is selected from mono-, di- and triglycerides.

In some embodiments, the fatty acid oil mixture comprises ester exchange of a body oil derived from a fatty fish species, such as sardine oil or tuna oil, followed by a urea fraction followed by molecular distillation. Obtained by a specific purification step. In some embodiments, the crude oil mixture can also be subjected to a stripping step to reduce the amount of environmental pollutants and / or cholesterol prior to transesterification.

In another embodiment, the fatty acid oil mixture is, for example, supercritical CO.₂It is obtained by concentrating the major EPA and DHA from the fish oil concentrate using extraction or chromatography techniques. Commercial embodiments of fatty acids in the form of ethyltriglycerides included in the present disclosure include, but are not limited to, K85TG (Pronova BioPharma Norge AS). Commercial embodiments of ethyl ester forms of fatty acids included in the present disclosure include, but are not limited to, K85EE (Pronova BioPharma Norge AS).

In another embodiment, the fatty acid oil mixture is obtained by hydrolyzing the fatty acid oil mixture in the form of an ethyl ester. Commercial embodiments of free acid forms of fatty acids included in the present disclosure include, but are not limited to, K85FA (Pronova BioPharma Norge AS).

In some embodiments of the present disclosure, at least one omega-3 fatty acid in a fatty acid oil mixture has a cis-steric configuration. As an example, but not limited to, (all-Z) -9,12,15-octadecatorenoic acid (ALA), (all-Z) -6,9,12,15-octadecatetraenoic acid (STA) , (All-Z) -11,14,17-Eicosatrienoic acid (ETE), (all-Z) -5,8,11,14,17-Eicosapentaenoic acid (EPA), (all-Z)- 4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z) -8,11,14,17-eicosatetraenoic acid (ETA), (all-Z) -7,10 , 13,16,19-docosapentaenoic acid (DPA), (all-Z)-6,9,12,15,19-heneicosapentaenoic acid (HPA), (all-Z) -5,8,11, 14-Eicosatetraenoic acid, (all-Z) -4,7,10,13,16-docosapentaenoic acid (osbondic acid), (all-Z) -9,12-octadecadienoic acid (linoleic acid) ), (All-Z) -5,8,11,14-Eicosatetraenoic acid (AA), (all-Z) -6,9,12-octadecatolic acid (GLA), (Z) -9 Includes -octadecenoic acid (oleic acid), 13 (Z) -docosenoic acid (ercaic acid), (R- (Z))-12-hydroxy-9-octadecenoic acid (ricinolic acid).

In some embodiments of the present disclosure, the weight ratio of EPA: DHA in the fatty acid oil mixture is from about 1:10 to about 10: 1, about 1: 8 to about 8: 1, and about 1: 6 to about. It ranges from 6: 1, about 1: 5 to about 5: 1, about 1: 4 to about 4: 1, about 1: 3 to about 3: 1, or about 1: 2 to about 2: 1. In at least one embodiment, the weight ratio of EPA: DHA in the fatty acid oil mixture ranges from about 1: 2 to about 2: 1. In at least one embodiment, the weight ratio of EPA: DHA in the fatty acid oil mixture ranges from about 1: 1 to about 2: 1. In at least one embodiment, the weight ratio of EPA: DHA in the fatty acid oil mixture ranges from about 1.2 to about 1.3.

In some embodiments of the present disclosure, the composition and / or pre-concentrate comprises one or more fatty acids in free acid form or a mixture thereof. Without being bound by theory, it is believed that fatty acids in the free acid form can enhance or ameliorate lipolysis in the body. For example, the addition of at least one fatty acid in the free acid form can enhance or improve the interconversion of fatty acid esters and / or triglycerides to the free fatty acid form for efficient uptake. Free fatty acids can provide, for example, in vivo hydrolysis of fatty acids, solubility, bioavailability, absorption, or enhancement or improvement of any combination thereof.

Examples of free fatty acids are, but not limited to, polyunsaturated fatty acids in the form of free acids such as EPA, DHA, α-linolenic acid (ALA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), eicosapentaenoic acid. Satetraenoic acid (ETA), eicosapentaenoic acid (ETE), stearidonic acid (STA), linoleic acid, γ-linolenic acid (GLA), arachidonic acid (AA), osbondic acid, oleic acid, ricinoleic acid, erucic acid , And mixtures thereof.

In some embodiments of the present disclosure, the composition comprises a fatty acid oil mixture in a form selected from ethyl esters and triglycerides, and at least one free fatty acid, wherein the at least one free fatty acid is, for example, the said. It contains at least 80% by weight of omega-3 fatty acids of at least one free fatty acid and at least 90% by weight of omega-3 fatty acids of at least one free fatty acid. In some embodiments, the composition comprises a fatty acid oil mixture in a form selected from ethyl esters and triglycerides, and at least one free fatty acid is selected from oleic acid, ricinoleic acid, linoleic acid, and erucic acid. Will be done. In one embodiment, the at least one free fatty acid comprises oleic acid or linoleic acid.

In some embodiments, the at least one free fatty acid comprises at least 75% by weight of EPA and DHA of the at least one free fatty acid. For example, in some embodiments, at least one free fatty acid contains at least 80% by weight, at least 85% by weight, at least 90% by weight, or at least 95% by weight of EPA and DHA of the at least one free fatty acid. include. In some embodiments, the at least one free fatty acid is such as about 85% by weight, about 90% by weight, about 95% by weight, or any number sandwiched between the at least one free fatty acid. Contains about 80% by weight of EPA and DHA of at least one of its free fatty acids. At least one free fatty acid can be used in pure form and / or as a component of oils such as marine oils (eg fish oils and refined fish oil concentrates), microbial oils and plant-based oils.

In some embodiments, the at least one free fatty acid is from about 75% to about 95% by weight of the at least one free fatty acid, eg, about 75% to about 75% by weight of the at least one free fatty acid. 90% by weight, about 75% by weight to about 85% by weight, about 75% by weight to about 80% by weight, about 80% by weight to about 95% by weight, about 80% by weight to about 90% by weight, about 80% by weight 85% by weight, about 85% to about 95% by weight, about 85% to about 90% by weight, and further, for example, about 90% to about 95% by weight of at least one of the free fatty acids, or sandwiched between them. Includes EPA and DHA such as any number. In at least one embodiment, the at least one free fatty acid comprises from about 80% to about 85% by weight of the at least one free fatty acid EPA and DHA, eg, about 80% of the at least one free fatty acid. Includes EPA and DHA from% to about 88% by weight, such as about 84% by weight.

Medicine In some embodiments of the present disclosure, the fatty acid oil mixture acts as an active pharmaceutical ingredient (API). In some embodiments, the fatty acid oil mixture is present in a pharmaceutically acceptable amount. As used herein, the term "pharmaceutically effective amount" is sufficient to treat, eg, attenuate and / or alleviate at least one health problem, such as action, symptoms, etc. in a subject in need thereof. Means quantity. In at least some embodiments of the present disclosure, the fatty acid oil mixture is free of additional active agents.

When the composition is a pharmaceutical composition, the fatty acid oil mixture comprises at least 75% by weight of EPA and DHA of the fatty acid oil mixture. For example, in one embodiment, the fatty acid oil mixture comprises at least 80% by weight of the fatty acid oil mixture, eg, at least 85% by weight, at least 90% by weight, or at least 95% by weight of the fatty acid oil mixture of EPA and DHA. In some embodiments, the fatty acid oil mixture is about 80% by weight of the fatty acid oil mixture, eg, about 85% by weight, about 90% by weight, about 95% by weight, or any number in between. Includes EPA and DHA.

For example, in some embodiments, the fatty acid oil mixture contains about 75% to about 95% by weight of EPA and DHA of the fatty acid oil mixture, eg, about 75% to about 90% by weight of the fatty acid oil mixture, about 90% by weight. 75% to about 88% by weight, about 75% to about 85% by weight, about 75% to about 80% by weight, about 80% to about 95% by weight, about 80% to about 90% by weight, about 80% to about 85% by weight, about 85% to about 95% by weight, about 85% to about 90% by weight, and even, for example, about 90% to about 95% by weight, or any number of EPAs in between. And DHA included. In at least one embodiment, the fatty acid oil mixture is about 80% to about 85% by weight of the fatty acid oil mixture, eg, about 80% to about 88% by weight of the fatty acid oil mixture, eg, about 84% by weight of EPA and Including DHA.

In some embodiments, the fatty acid oil mixture comprises at least 95% by weight of EPA or DHA, or EPA and DHA, of the fatty acid oil mixture.

In a further embodiment, the fatty acid oil mixture can include other omega-3 fatty acids. For example, the present disclosure includes at least 90% by weight of an omega-3 fatty acid in a fatty acid oil mixture.

In one embodiment, for example, the fatty acid oil mixture comprises from about 75% to about 88% by weight of the fatty acid oil mixture EPA and DHA, wherein the fatty acid oil mixture is at least 90% by weight of the fatty acid oil mixture. Contains omega-3 fatty acids.

In another embodiment, the fatty acid oil mixture comprises from about 75% to about 88% by weight of EPA and DHA of the fatty acid oil mixture, wherein the fatty acid oil mixture is at least 90% by weight of omega of the fatty acid oil mixture. -3 contains fatty acids, the fatty acid oil mixture contains α-linolenic acid (ALA).

In one embodiment, the fatty acid oil mixture comprises from about 80% to about 88% by weight of the fatty acid oil mixture EPA and DHA, and further comprises docosapentaenoic acid (DPA).

In another embodiment, the fatty acid oil mixture comprises from about 80% to about 88% by weight of the fatty acid oil mixture EPA and DHA, and further from about 1% to about 4% by weight of the fatty acid oil mixture (all-Z). ) Omega-3) -6,9,12,15,18-Contains heneicosapentaenoic acid (HPA).

In another embodiment, the fatty acid oil mixture comprises about 80% to about 88% by weight of EPA and DHA of the fatty acid oil mixture, and 1% to about 4% by weight of fatty acids other than EPA and DHA of the fatty acid oil mixture. Containing, where fatty acids other than EPA and DHA are C₂₀, C₂₁Or C₂₂Has a carbon atom of.

In one embodiment, the fatty acid oil mixture can include K85EE or AGP103 (Pronova BioPharma Norge AS). In another embodiment, the fatty acid oil mixture can include K85TG (Pronova BioPharma Norge AS). In yet another embodiment, the fatty acid oil mixture can include K85FA (BioPharma Norge AS).

In some embodiments of the disclosure, the pharmaceutical composition provides an enhancement of bioavailability, eg, an enhancement of bioavailability greater than about 40%, such as an enhancement of about 80%.

EPA and DHA Products In at least one embodiment, the fatty acid oil mixture comprises at least 75% by weight EPA and DHA of the fatty acid oil mixture, of which at least 95% is EPA. In another embodiment, the fatty acid oil mixture comprises at least 80% by weight of EPA and DHA of the fatty acid oil mixture, of which at least 95% is EPA. In yet another embodiment, the fatty acid oil mixture comprises at least 90% by weight of EPA and DHA of the fatty acid oil mixture, of which at least 95% is EPA.

In another embodiment, the fatty acid oil mixture comprises at least 75% by weight of EPA and DHA of the fatty acid oil mixture, of which at least 95% is DHA. For example, in one embodiment, the fatty acid oil mixture comprises at least 80% by weight of EPA and DHA of the fatty acid oil mixture, of which at least 95% is DHA. In another embodiment, the fatty acid oil mixture comprises at least 90% by weight of EPA and DHA of the fatty acid oil mixture, of which at least 95% is DHA.

Supplements The present disclosure further provides food supplements or dietary supplements comprising a fatty acid oil mixture, wherein the fatty acid oil mixture comprises less than 75% by weight of EPA and DHA of the fatty acid oil mixture. In some embodiments, for example, the fatty acid oil mixture is less than 70% by weight of the fatty acid oil mixture, eg, less than 65% by weight, less than 60% by weight, less than 55% by weight, less than 50% by weight, 45 of the fatty acid oil mixture. Contains less than% by weight, less than 40% by weight, and even less than 35% by weight of EPA and DHA.

In some embodiments, the fatty acid oil mixture contains about 25% to about 75% by weight of EPA and DHA of the fatty acid oil mixture, eg, about 30% to about 75% by weight of the fatty acid oil mixture, about 30% by weight. % ~ About 70% by weight, about 30% by weight ~ about 65% by weight, about 30% by weight ~ about 55% by weight, about 30% by weight ~ about 50% by weight, about 30% by weight ~ about 45% by weight, about 30% by weight Includes% ~ about 40% by weight, and further, for example, about 30% to about 35% by weight of EPA and DHA.

Surfactant / Pre-Concentrate The present disclosure provides a pre-concentrated composition, wherein the term "pre-concentrated" refers to a composition comprising at least one fatty acid oil mixture and at least one surfactant. Point to. In some embodiments, for example, the preconcentrate comprises a fatty acid oil mixture in a form selected from ethyl esters and triglycerides, at least one free fatty acid, and at least one surfactant. In other embodiments, the pre-concentrate comprises a fatty acid oil mixture in free acid form and at least one surfactant. In yet another embodiment, the pre-concentrate comprises a fatty acid oil mixture in a form selected from ethyl esters and triglycerides and at least one surfactant.

Surfactants can, for example, reduce the surface tension of liquids, or the surface tension between two liquids. For example, the surfactants according to the present disclosure can reduce the surface tension between a fatty acid oil mixture and an aqueous solution.

Chemically speaking, a surfactant is a molecule having at least one hydrophilic moiety and at least one hydrophobic (ie, lipophilic) moiety. The properties of a surfactant can be expressed in terms of the hydrophilic-lipophilic balance (HLB) of the surfactant, where the HLB value is a measure of the hydrophilicity of the surfactant with respect to its lipophilic properties. HLB values are usually in the range 0-20, an HLB value of 0 means high hydrophilicity and an HLB value of 20 means high lipophilicity. Surfactants are often used in combination with other surfactants, in which case the HLB value is additive. The HLB value of the surfactant mixture can be calculated as follows: HLB_A(Surfactant A fraction) + HLB_B(Surfactant B fraction) = HLB_{A + B}_mixture

Surfactants are generally classified as ionic surfactants, such as anionic or cationic surfactants, and nonionic surfactants. If the surfactant contains two oppositely charged groups, the surfactant is named a zwitterionic surfactant. Other categories of surfactants include, for example, phospholipids.

In at least one embodiment of the present disclosure, the composition comprises at least one surfactant selected from non-ionic, anionic, cationic, and zwitterionic surfactants.

Non-limiting examples of non-ionic surfactants suitable for the present disclosure are referred to below.

Pluronic® surfactants consist of a central hydrophobic polymer (polyoxypropylene (poly (propylene oxide))) with a hydrophilic polymer (polyoxyethylene (poly (ethylene oxide))) on each side. It is a non-ionic polymer. A variety of commercially available Pluronic® products are listed in Table 1.

<tables num="1"><img file="JP6835664B2_D0001.tif" /></tables>

Brij® is a non-ionic surfactant containing polyethylene ether. A variety of commercially available Brij® products are listed in Table 2.

<tables num="2"><img file="JP6835664B2_D0002.tif" /></tables>

Span® is a nonionic surfactant containing a sorbitan ester. Span® is available from a variety of sources, including Aldrich. Table 3 lists the various commercial Span® products.

<tables num="3"><img file="JP6835664B2_D0003.tif" /></tables>

Tween® (polysorbate) is a nonionic surfactant containing a polyoxyethylene sorbitan ester. Table 4 lists the various commercial Tween® products.

<tables num="4"><img file="JP6835664B2_D0004.tif" /></tables>

Myrj® is a nonionic surfactant containing a polyoxyethylene fatty acid ester. A variety of commercially available Myrj® products are listed in Table 5.

<tables num="5"><img file="JP6835664B2_D0005.tif" /></tables>

Cremophor® is a non-ionic surfactant. A variety of commercially available Cremophor® products are listed in Table 6.

<tables num="6"><img file="JP6835664B2_D0006.tif" /></tables>

According to the present disclosure, other typical nonionic surfactants include, but are not limited to, diacetylmonoglyceride, diethylene glycol monopalmitostearate, polyethylene glycol monopalmitostearate, glyceryl behate, glyceryl distearate, Glyceryl monolinolate, glyceryl monooleate, glyceryl monostearate, macrogol cetostearyl ether (such as seto macrogol 1000 and polyoxy 20 setostearyl ether), macrogol 15 hydroxystearate, macrogol lauryl ether (laures 4 and lauro) Macrogol 400, etc.), Macrogol monomethyl ether, Macrogol oleyl ether (polyoxyl 10 oleyl ether, etc.), Macrogol stearate (polyoxyl 40 stearate, etc.), menfegol, mono and diglyceride, nonoxinol (nonoxynol-9, nonoxinol-10, etc.) And nonoxynol-11 etc.), Octoxinol (octoxinol 9 and octoxinol 10 etc.), polyoxamer (polyoxalen etc.), polyoxamer 188, polyoxamer 407, polyoxyl bean oil (polyoxyl 35 bean oil etc.), polyoxyl hydrogenation Includes castor oil (such as polyoxyl 40 hydrogenated castor oil), propylene glycol diacetate, and propylene glycol laurate (such as propylene glycol dilaurate and propylene glycol monolaurate). Further examples include propylene glycol monopalmitostearate, Kiraya, sorbitan ester, and sucrose ester.

Examples of anionic surfactants suitable for the present disclosure include salts of carboxylic acid perfluoride and sulfonic acid perfluoride, alkyl sulfates (sodium dodecyl sulfate and ammonium lauryl sulfate, etc.), ether sulfate (sodium lauryl ether sulfate, etc.). ), And alkylbenzene sulfonates.

Cationic surfactants suitable for the present disclosure include, for example, quaternary ammonium compounds (such as benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride and cetyltrimethylammonium bromide) or other trimethylalkylammonium salts. ..

Zwitterionic surfactants include, but are not limited to, dodecyl betaine, cocoamphoglycinate, and cocamidopropyl betaine.

In some embodiments of the present disclosure, surfactants can include phospholipids, derivatives thereof, or analogs thereof. Such surfactants can be selected from, for example, natural, synthetic, semi-synthetic phospholipids, derivatives thereof, and analogs thereof. Typical phospholipid-based surfactants include phosphatidylcholine containing saturated, unsaturated and / or polyunsaturated lipids (dioreoil phosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, etc. Distearoyl phosphatidylcholine, etc.), dieicopentaenoyl (EPA) choline, didocosahexaenoyl (DHA) choline, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, and phosphatidylinositol. Other typical phospholipid surfactants include soy lecithin, egg lecithin, diorail phosphatidylcholine, distearoylphosphatidylglycerol, PEGylated phospholipids, and dimyristylphosphatidylcholine.

Phospholipids may be "natural" or derived from aquatic origin, selected from, for example, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol. Fatty acid moieties are 14: 0, 16: 0, 16: 1n-7, 18: 0, 18: 1n-9, 18: 1n-7, 18: 2n-6, 18: 3n-3, 18: 4n- You can choose from 3, 20: 4n-6, 20: 5n-3, 22: 5n-3 and 22: 6n-3, or any combination thereof. In one embodiment, the fatty acid moiety is selected from palmitic acid, EPA and DHA.

Table 7 lists other typical surfactants suitable for this disclosure.

<tables num="7"><img file="JP6835664B2_D0007.tif" /></tables>

In some embodiments of the present disclosure, at least one surfactant does not include Labrasol, Cremophor RH40, or a combination of Cremophor and Tween-80.

In some embodiments, at least one surfactant has a hydrophilic-lipophilic balance (HLB) of less than about 10, for example less than about 9, or less than about 8.

The weight ratio of EPA + DHA to at least one surfactant can vary depending on the detergent choice, the ratio of EPA to DHA, and the general formulation. In some embodiments of the present disclosure, the weight ratio of EPA + DHA: surfactant is from about 10: 5 to about 10: 0.001, about 10: 4 to about 10: 0.005, about 10: 3 to about 10 :. It is in the range of 0.01, about 10: 2 to about 0.015, about 10: 2 to about 10: 0.02, or about 10:15 to about 10: 0.03.

Co-surfactant In some embodiments, the pre-concentrate of the present disclosure further comprises at least one co-surfactant. As used herein, the term "auxiliary surfactant" is used to affect the emulsification and / or stability of preconcentrates, eg to increase or enhance them, eg to form emulsions. Means a substance added to a pre-concentrate, for example in combination with at least one surfactant, to help. In some embodiments, at least one auxiliary surfactant is hydrophilic.

Examples of co-surfactants suitable for the present disclosure include, but are not limited to, short chain alcohols containing 1-6 carbons (eg, ethanol), benzyl alcohols, alkanediols and triols (eg, propylene glycol, glycerol, etc.). Polyethylene glycols such as PEG and PEG400), glycol ethers such as tetraglycols and glycoflors (eg tetrahydrofurfuryl PEG ethers), N-methylpyrrolidones (eg Pharmasolve®) and 2-pyrrolidones (eg Solufor®). Includes pyrrolidine derivatives such as trademark) P), as well as bile salts, such as sodium deoxycholate. Further examples include ethyl oleate.

In some embodiments, the at least one co-surfactant constitutes from about 1% to about 10% by weight by weight of the pre-concentrate.

Solvents In some embodiments, the composition and / or preconcentrate further comprises at least one solvent. Hydrophilic solvents suitable for the present disclosure include, but are not limited to, alcohols including water-miscible alcohols, such as absolute ethanol and / or glycerol, and glycols (eg, glycols obtained from oxides such as ethylene oxide, 1,2. -Propylene glycol). Other non-limiting examples include polyols such as polyalkylene glycol, such as poly (C) such as polyethylene glycol.₂~₃) Includes alkylene glycol.

In some embodiments of the present disclosure, the preconcentrate comprises at least one substance that acts as both a co-surfactant and a solvent, such as an alcohol such as ethanol. In other embodiments, the pre-concentrate comprises at least one co-surfactant and at least one solvent which is a different substance. For example, in some embodiments, the preconcentrate comprises ethanol as a co-surfactant and glycerol as a solvent.

Super Disintegrant In some embodiments of the present disclosure, the composition and / or preconcentrate may include at least one super disintegrant. Super disintegrants can, for example, improve disintegration efficiency and result in reduced levels of use compared to conventional disintegrants. Examples of superdisintegrants include, but are not limited to, croscarmellose (crosslinked cellulose), crospovidone (crosslinked polymer), sodium starch glycolate (crosslinked starch), and soybean polysaccharides. Commercial examples of super disintegrants include Kollidon® (BASF), Polyplasdone® XL (ISP), and Ac-Di-Sol (FMC BioPolymer).

The composition and / or pre-concentrate is about 1% to about 25% by weight of the composition and / or pre-concentrate, for example, about 1% to about 20% by weight, or about 1% to about 15% by weight. It can contain at least one super disintegrant by weight. In some embodiments, the composition and / or pre-concentrate containing at least one super disintegrant is present in the form of tablets.

In some embodiments, the weight ratio of fatty acid oil mixture: surfactant in the pre-concentrate is from about 1: 1 to about 10: 1, about 1.1 to about 8: 1, 1: 1 to about 7: 1. , 1: 1 to about 6: 1, 1: 1 to about 5: 1, 1: 1 to about 4: 1, 1: 1 to about 3: 1, or 1: 1 to about 2: 1 ..

In some embodiments, at least one surfactant constitutes from about 5% to about 55% by weight of the total weight of the preconcentrate. For example, in some embodiments, at least one surfactant is about 5% to about 35% by weight, about 10% to about 35% by weight, about 15% by weight, based on the total weight of the preconcentrate. It constitutes% to about 35% by weight, about 15% to about 30% by weight, or about 20% to about 30% by weight.

SNEDDS / SMEDDS / SEDDS The pre-concentrates of the present disclosure exist in the form of a self-emulsifying drug delivery system (SNEDDS), a self-microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS). The preconcentrate can now form an emulsion in an aqueous solution.

Without being bound by theory, the pre-concentrate forms SNEDDS, SMEDDS, and / or SEDDS when in contact with the gastric and / or intestinal medium in the body, and the pre-concentrate forms an emulsion containing micelle particles. It is thought that. Emulsions can, for example, result in increased or improved stability of fatty acids for uptake in the body and / or increased or improved surface area for absorption. SNEDDS / SMEDDS / SEDDS can therefore result in in vivo hydrolysis of fatty acids, solubility, bioavailability, absorption, or enhancement or improvement of any combination thereof.

In general, known SNEDDS / SMEDDS / SEDDS formulations contain about 10 mg of drug and about 500 mg of surfactant / co-surfactant. The SNEDDS / SMEDDS / SEDDS disclosed herein can have the opposite relationship, i.e., the amount of fatty acid oil mixture containing the active pharmaceutical ingredient (API) exceeds the amount of surfactant.

The SNEDDS / SMEDDS / SEDDS disclosed in the present invention can have a particle size (that is, a particle size) in the range of about 5 nm to about 10 μm. For example, in some embodiments, the particle size is in the range of about 5 nm to about 1 μm, such as about 50 nm to about 750 nm, about 100 nm to about 500 nm, or about 150 nm to about 350 nm.

Excipients The compositions, pre-concentrates, and / or SNEDDS / SMEDDS / SEDDS disclosed in the present invention can further include at least one inactive pharmaceutical ingredient, such as an excipient. The non-active ingredient solubilizes, suspends, thickens, dilutes, emulsifies, stabilizes, preservatives, protects, colors, flavors, and / or forms the active ingredient into an applicable and effective formulation, resulting in. , The formulation can be made safe, convenient, and / or otherwise acceptable for use. At least one non-active ingredient is colloidal silicon dioxide, crospovidone, lactic acid monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, and xanthan gum. You can choose from.

The compositions, pre-concentrates, and / or SNEDDS / SMEDDS / SEDDS disclosed in the present invention may further include at least one antioxidant. Examples of suitable antioxidants for the present disclosure are, but are not limited to, α-tocopherol (vitamin E), EDTA calcium disodium, α-tocopheryl acetate, butylhydroxytoluene (BHT), and butylhydroxyanisole (BHA). Is included.

Forms The compositions and / or preconcentrates disclosed in the present invention can be administered, for example, in capsules, tablets, sachets, or any other form suitable for drug delivery. The dosage form can have any shape suitable for oral administration, such as a sphere, egg, ellipse, cube shape, regular and / or irregular shape. Dosage forms can be prepared by methods known in the art and may include one or more additional pharmaceutically acceptable excipients as discussed previously.

In some embodiments of the present disclosure, the composition and / or pre-concentrate is present in the form of capsules or tablets. The material forming the capsule wall can include, for example, polysaccharides other than gelatin or alginate. In at least one embodiment, the capsule is a gelatin capsule. The capsule may be a hard capsule or a soft capsule.

When the dosage form is present in the form of tablets, the tablets may be, for example, disintegrating tablets, fast-dissolving tablets, foamable tablets, fast-dissolving tablets, and / or mini-tablets. Tablet formulations are described, for example, in WO 2006/000229. In some embodiments of the present disclosure, the tablet comprises Neusilin (eg, magnesium aluminometasilicate).

The capsules and / or tablets of the present disclosure may include at least one coating. Such coatings can delay the release of capsules or tablets (eg, release of EPA and / or DHA) for a predetermined period of time. For example, at least one coating can allow the dosage form to pass through the stomach without exposure to gastric acid or digestive juices and delay the release of EPA and / or DHA outside the stomach. In some embodiments, capsules and / or tablets release less than 30%, such as less than 25%, less than 20%, less than 15%, or less than 10% of total EPA and / or DHA in the stomach.

In some embodiments, the at least one coating is selected from enteric coatings, sublayers, top layers, and combinations thereof. As used herein, the term "sub-layer" means a capsule wall material (eg, a gelatin wall) or a coating layer that is placed between the tablet surface and an enteric coating. The term "top-layer" as used herein means a coating layer on an enteric coating that covers a capsule wall material or tablet surface. The chemical composition of the sublayer and top layer can be varied depending on the overall composition of the capsule or tablet. Typical materials for the sublayers and top layers disclosed in the present invention include film film forming agents such as polysaccharides, such as hydroxypropylmethylcellulose.

In embodiments of the present disclosure, capsules and / or tablets include at least one enteric coating. In some embodiments, the capsule and / or tablet comprises at least one enteric coating and at least one top layer covering the at least one enteric coating. In other embodiments, the capsule and / or tablet comprises at least one enteric coating and at least one sublayer between the capsule wall or tablet surface and at least one enteric coating. In yet other embodiments, the capsule and / or tablet comprises at least one enteric coating, at least one sublayer between the capsule wall or tablet surface and at least one top layer covering at least one enteric coating. including. In some embodiments, at least one sublayer (group) and / or top layer (group) comprises hydroxypropylmethylcellulose.

In some embodiments, the at least one sublayer comprises an encapsulant. Suitable encapsulants can include, for example, permeable or soluble agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, and xanthan gum. Other agents can be added to improve the processability of the encapsulant or barrier layer. Such agents include talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica, glycerol monostearate, magnesium trisilicate, and magnesium stearate, or mixtures thereof. The sealant or barrier layer can be applied from a solution (eg, aqueous) or suspension using any known means such as a fluidized bed coater (eg, Wurster coating) or a pan coating device. Suitable sealants or barriers include, for example, Opadry® products such as Opadry® II available from Colorcon.

In some embodiments, at least one coating is pH independent. Coatings with a pH-independent profile generally erode or dissolve after a predetermined period of time, which period is generally directly proportional to the thickness of the coating. In other embodiments, at least one coating is pH dependent. Coatings with a pH-dependent profile can generally maintain their integrity at the acidic pH of the stomach, but erode or dissolve when they enter the more basic upper intestine. In some embodiments, at least one coating is insoluble at a pH below about 5 and soluble at a pH above about 6.

Examples of coating materials suitable for the present disclosure include, but are not limited to, gelatin, film-forming agents, polymers, and copolymers. Examples of polymers and copolymers include, but are not limited to, acrylate-based polymers and copolymers (eg, methacrylic acid, copolymers of methacrylic acid and methyl methacrylate, copolymers of methacrylic acid and methyl acrylate, methacrylic acid and Copolymers with ethyl methacrylate and copolymers of methacrylic acid with ethyl acrylate), and polymers and copolymers based on polysaccharides and / or cellulose (eg, cellulose phthalate, hydroxypropylmethyl phthalate, and succinate acetate). Hydroxypropylmethyl Cellulate Acid) is included. Examples of other polymers include polyvinyl phthalate acetate. Additional materials suitable for at least one coating include pharmaceutically acceptable acidic compounds that cannot be dissolved at low pH in the stomach but can be dissolved at higher pH in the lower part of the gastrointestinal system. Can be mentioned.

Examples of commercially available polymers suitable for this disclosure include EUDRAGIT® products from Evonik. EUDRAGIT® polymers are acrylate and / or methacrylate-based polymeric lacquer materials that can be pH independent or pH dependent.

For example, EUDRAGIT® RL and EUDRAGIT® RS are acrylic resins containing copolymers of acrylic and methacrylic acid esters containing low content quaternary ammonium groups. The ammonium group exists as a salt and causes the lacquer coating to become permeable. EUDRAGIT® RL and EUDRAGIT® RS are free permeable (RL) and slightly permeable (RS), respectively, and are pH independent. The polymer swells in water and digestion fluid in a pH-independent manner. In the swollen state, they are permeable to water and dissolved active compounds. Specific examples include EUDRAGIT® RL30D, EUDRAGIT® RL PO, EUDRAGIT® RL100, EUDRAGIT® RL12,5, EUDRAGIT® RS30D, EUDRAGIT® RS PO, EUDRAGIT® RS100 and EUDRAGIT® RS Includes 12,5. Further examples of pH-independent polymers include EUDRAGIT® E100, EUDRAGIT® E12,5, and EUDRAGIT® EPO. In at least one embodiment of the present disclosure, at least one coating comprises EUDRAGIT® RS 30D.

Further, for example, EUDRAGIT® L and EUDRAGIT® S are anionic polymers synthesized from methacrylic acid and methyl methacrylate. They are insoluble in acids and pure water and become soluble in neutral to weakly alkaline conditions. The permeability of EUDRAGIT® L and EUDRAGIT S is pH dependent. Above pH 5.0, the polymer gradually becomes permeable. Specific examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT (registered trademark). Includes Trademarks) S12,5, and EUDRAGIT® FS30D. Further examples of pH-dependent polymers include EUDRAGIT® E100, EUDRAGIT® E12,5, and EUDRAGIT® PO. In at least one embodiment of the present disclosure, at least one coating comprises EUDRAGIT® L100-55.

At least one coating can contain at least one plasticizer. Plasticizers can, for example, improve the mechanical properties of pH-sensitive materials in at least one coating. Suitable plasticizers include, but are not limited to, triethyl citrate, triacetin, polyethylene glycol, propylene glycol, phthalates, sorbitol, and glycerin. The amount of plasticizer can vary depending on the chemical composition of at least one coating and the chemical composition and size of the capsule or tablet. In some embodiments, for example, the amount of the plasticizer is in the range of about 10% to about 60% by weight of at least one coating thereof.

The amount of coating material or the thickness of at least one coating thereof may vary depending on the chemical composition and number of different coating layers, as well as the chemical composition, size and shape of the capsule or tablet. Generally speaking, the coating must be thick enough to prevent the substantial release of EPA and / or DHA in the stomach, but it contributes significantly to the size of the capsule or tablet. Must not be. In some embodiments of the present disclosure, the thickness of at least one coating is in the range of about 10 μm to about 2 mm, eg, about 20 μm to about 1 mm. In some embodiments, at least one coating comprises from about 1% to about 50% dry capsule wall forming material (eg gelatin).

The capsules according to the present disclosure can be produced under low oxygen conditions in order to prevent oxidation during the production process. Capsules can be prepared, for example, by direct encapsulation using standard methods known in the art. Examples of such methods include, but are not limited to, the simple coagulation method (see, eg, ES2009346, EP0052510, and EP0346879), the composite coagulation method (see, eg, GB1393805), two. Includes heavy emulsification methods (see, eg, US Pat. No. 4,654,441), simple emulsification methods (see, eg, US Pat. No. 5,445,832), and solvent evaporation methods (see, eg, GB2209937). .. These methods can provide, for example, continuous processing and batch size flexibility. The present disclosure further provides to coat a pre-prepared capsule (eg, a gelatin capsule containing a fatty acid oil mixture). The coating of pre-prepared capsules can be, for example, sprayed using spray drying techniques, sprayed into a coating pan containing preformed capsules, or the capsules immersed in a coating solution. Can be carried out by.

In some embodiments of the present disclosure, the capsule filling amount is in the range of about 0.400 g to about 1.600 g. For example, in some embodiments, the capsule filling amounts are about 0.400 g ~ about 1.300 g, about 0.600 g ~ about 1.200 g, about 0.600 g ~ about 0.800 g, about 0.800 g ~ about 1.000 g, about 1.000 g ~. It is in the range of about 1.200 g, or any amount between them. For example, in some embodiments, the capsule filling amount is about 0.600 g, about 0.800 g, about 1.000 g, or about 1.200 g.

In some embodiments of the present disclosure, the composition and / or pre-concentrate comprises from about 300 mg to about 400 mg, eg, about 375 mg of DHA. In some embodiments, the composition and / or pre-concentrate comprises from about 400 mg to about 500 mg, eg, about 465 mg of EPA. In one embodiment, for example, the composition and / or pre-concentrate comprises about 375 mg DHA and about 465 mg EPA.

Methods or Uses The disclosure further includes methods of treating and / or regulating at least one health problem in a subject in need thereof. The compositions and pre-concentrates disclosed in the present invention include at least one including, for example, abnormal plasma lipid levels, cardiovascular function, immune function, visual function, insulin action, nerve development, heart failure, and post-myocardial infarction. It can be administered, for example, in capsules, tablets, or any other form suitable for drug delivery to a subject for the treatment and / or regulation of health problems.

In one embodiment, the disclosure comprises administering to a subject a pharmaceutical composition in the form of a gelatin capsule or tablet, a method of treating at least one health problem in a subject in need thereof. The composition comprises a pharmaceutically effective amount of the fatty acid oil mixture and at least one free fatty acid, the fatty acid oil mixture being at least 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are present in a form selected from ethyl esters and triglycerides, and gelatin capsules or tablets provide a method comprising at least one coating. In some embodiments, the method treats at least one of elevated triglyceride levels, non-HDL cholesterol levels, LDL cholesterol levels and / or VLDL cholesterol levels. For example, the method increases triglyceride levels by about 30% to about 80%, such as about 40% to about 70%, about 40% to about 60%, or about 30% to about 50 in subjects with elevated triglyceride levels. It can be reduced by%.

In another embodiment, the disclosure is a method of regulating at least one health problem in a subject in need thereof, wherein the supplement composition in the form of a gelatin capsule or tablet is administered to the subject. The composition comprises a fatty acid oil mixture and at least one free fatty acid, and the fatty acid oil mixture comprises about 25% to about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (EPA). Containing DHA), EPA and DHA are present in a form selected from ethyl esters and triglycerides, gelatin capsules or tablets contain at least one coating, and at least one health problem is abnormal plasma lipid levels, It provides a method selected from cardiovascular function, immune function, visual function, insulin action, nerve development, heart failure, and after myocardial infarction.

The present disclosure further provides a method of enhancing the hydrolysis, solubility, bioavailability, absorption of EPA and / or DHA, and at least one parameter selected from a combination thereof. Bioavailability can be increased, for example, by at least 40%, such as about 80% or at least 85%.

In one embodiment, the method of enhancing the hydrolysis, solubility, bioavailability, absorption of EPA and / or DHA, and at least one parameter selected from a combination thereof, is selected from ethyl esters and triglycerides. A fatty acid oil mixture containing forms of EPA and DHA; as well as combining at least one free fatty acid in the form of a gelatin capsule or tablet, the gelatin capsule or tablet comprising at least one coating.

In another embodiment, the method of enhancing the hydrolysis, solubility, bioavailability, absorption of EPA and / or DHA, and at least one parameter selected from a combination thereof, is selected from ethyl ester and triglyceride. Fatty acid oil mixture containing EPA and DHA in the form; at least one free fatty acid; and at least one surfactant in the form of gelatin capsules or tablets, the gelatin capsules or tablets at least. Includes one coating.

In other embodiments, the method of enhancing the hydrolysis, solubility, bioavailability, absorption of EPA and / or DHA, and at least one parameter selected from a combination thereof, is a method of enhancing EPA and DHA in free acid form. A mixture of fatty acid oils containing; as well as combining at least one free fatty acid in the form of gelatin capsules or tablets, the gelatin capsules or tablets comprising at least one coating.

In yet another embodiment, the method of enhancing the hydrolysis, solubility, bioavailability, absorption of EPA and / or DHA, and at least one parameter selected from a combination thereof, is selected from ethyl ester and triglyceride. A fatty acid oil mixture containing EPA and DHA in the form to be: and at least one surfactant combined in the form of a gelatin capsule or tablet, the gelatin capsule or tablet comprising at least one coating.

The pre-concentrates disclosed in the present invention are self-emulsifying drug delivery systems (SNEDDS), self-microemulsifying drug delivery systems (SMEDDS), or self-emulsifying types in aqueous solutions in the methods disclosed in the present invention. A drug delivery system (SEDDS) can be formed.

In some embodiments of the present disclosure, a pharmaceutical or supplemental composition, or pharmaceutical or supplemental preconcentrate, is intended for subjects who require it to treat and / or regulate at least one health problem. Can be administered.

In some embodiments, the pre-concentrates of the present disclosure are self-emulsifying drug delivery systems (SNEDDS), self-microemulsifying drug delivery systems (SMEDDS), or self-emulsifying drug delivery systems (SEDDS) in aqueous solutions. ) Is formed. In some embodiments, the aqueous solution is a gastric medium and / or an intestinal medium.

The total daily dose of the fatty acid oil mixture may be in the range of about 0.600 g to about 6.000 g. For example, in some embodiments, the total dose of the fatty acid oil mixture is about 0.800 g to about 4.000 g, about 1.000 g to about 4.000 g, about 0.5000 g to about 4.000 g, about 0.250 g to about 2.000 g, It is in the range of about 0.400g to about 2.000g, or about 1.000g to about 2.000g. In one embodiment, the fatty acid oil mixture is selected from the K85EE and AGP103 fatty acid oil compositions. In another embodiment, the fatty acid oil mixture comprises K85FA.

Administration may be oral or any other form of administration that provides a subject, such as a human, with a dose of fatty acid, such as an omega-3 fatty acid. For example, the compositions and pre-concentrates disclosed in the present invention, as capsules and / or tablets, at doses of 1 to 10 tablets per day, eg, 1 to 4 times daily, eg, daily. It can be administered once, twice, three times, or four times, and even once, for example, once, twice, or three times a day.

Formulation In some embodiments of the present disclosure, the pre-concentrate is a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, with a fatty acid oil mixture, at least one free fatty acid, and at least one interface. Including the activator, the fatty acid oil mixture contains at least 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA present in a form selected from ethyl ester and triglyceride. However, gelatin capsules or tablets are pre-concentrates containing at least one coating.

In one embodiment, the pharmaceutical pre-concentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture, at least one free fatty acid and at least one surfactant, and the fatty acid oil mixture is a fatty acid oil. Contains at least 95% by weight of the mixture EPA ethyl ester, DHA ethyl ester, or a mixture thereof, and the free fatty acid is selected from linoleic acid, α-linolenic acid (ALA), γ-linoleic acid (GLA), and oleic acid. Surfactants are selected from polysolvate 20, polysolvate 80, and mixtures thereof, and gelatin capsules or tablets contain at least one coating.

In another embodiment, the pharmaceutical pre-concentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture, at least one free fatty acid and at least one surfactant, and the fatty acid oil mixture is a fatty acid. It contains about 80% to about 88% by weight of EPA and DHA of the oil mixture, EPA and DHA are present in the form of ethyl esters, free fatty acids contain oleic acid, surfactants are polysolvate 20, polysolvate 80. , And a mixture thereof, the at least one surfactant comprises less than 40% by weight of the weight of the preconcentrate, and the gelatin capsule or tablet comprises at least one coating.

In another embodiment, the pharmaceutical pre-concentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture, at least one free fatty acid and at least one surfactant, and the fatty acid oil mixture is a fatty acid. It contains about 80% to about 88% by weight of EPA and DHA of the oil mixture, EPA and DHA are present in the form of ethyl esters, free fatty acids contain linoleic acid, surfactants are polysolvate 20, polysolvate 80. , And a mixture thereof, the at least one surfactant comprises less than 35% by weight of the weight of the preconcentrate, and the gelatin capsule or tablet comprises at least one coating.

In another embodiment, the pharmaceutical preconcentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture, at least one free fatty acid and at least one surfactant, the fatty acid oil mixture is a fatty acid. It contains from about 80% to about 88% by weight of EPA and DHA of the oil mixture, the EPA and DHA are present in the form of ethyl esters, and the at least one free fatty acid is about about 80% by weight of the at least one free fatty acid. Containing 80% to about 88% by weight of EPA and DHA, the EPA and DHA are present in the form of free acids, surfactants are selected from polysolvate 20, polysolvate 80, and mixtures thereof, gelatin capsules. Alternatively, the tablet contains at least one coating. For example, the pharmaceutical pre-concentrate should contain K85EE as a fatty acid oil mixture, K85FA as at least one free fatty acid, and at least one surfactant selected from polysorbate 20, polysorbate 80, and mixtures thereof. Can be done.

In another embodiment, the pharmaceutical pre-concentrate can contain K85EE as a fatty acid oil mixture; K85FA as at least one free fatty acid; and at least one surfactant selected from polysorbate 20 or polysorbate 80. Here, [K85EE]: [Tween]: [K85FA] is, for example, in the range of about 5: 2: 0.5 to 5: 4: 2. In a further embodiment, the ratio of [K85EE]: [Tween]: [K85FA] is about [4-5]: [3-4]: [1-1.5].

In another embodiment, a fatty acid oil mixture from a minimum value of about 5-10% to a maximum value of about 50% containing about 80% to about 88% by weight of EPA and DHA of the fatty acid oil mixture (where, said. EPA and DHA are present in the form of ethyl esters), K85-FA compositions (corresponding to the profile of K85-FA fatty acids achieved by hydrolyzing the K85-EE fatty acid ethyl ester composition), EPA, It is replaced by free fatty acids selected from DPA, DHA, and combinations thereof. For example, the content of EPA-EE and DHA-EE, which is 400 mg to 840 mg in 1 g of the total fatty acid oil mixture, is replaced by 40 to 440 mg in 1 g of free fatty acid selected from the K85-FA composition.

In other embodiments, the pre-concentrate in the form of gelatin capsules or tablets is a food supplement or dietary supplement pre-concentrate, a fatty acid oil mixture, at least one free fatty acid, and at least one surfactant. The fatty acid oil mixture comprises from about 25% to about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the EPA and DHA being selected from ethyl esters and triglycerides. Present in form, gelatin capsules or tablets contain at least one coating.

In some embodiments of the present disclosure, the pre-concentrate is a pharmaceutical pre-concentrate of a gelatin capsule or tablet form fatty acid oil mixture, which comprises a fatty acid oil mixture and at least one surfactant and is a fatty acid. The oil mixture contains at least 75% by weight eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in the form of free fatty acids, and gelatin capsules or tablets contain at least one coating.

In one embodiment, for example, a pharmaceutical preconcentrate in the form of a gelatin capsule or tablet comprises a fatty acid oil mixture and at least one surfactant, the fatty acid oil mixture being about 80% by weight of the fatty acid oil mixture. Containing ~ about 88% by weight of EPA and DHA, EPA and DHA are present in the form of free acids, surfactants are selected from polysolvate 20, polysolvate 80, and mixtures thereof, gelatin capsules or tablets are at least Includes one coating.

In one embodiment, the pharmaceutical pre-concentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture and at least one surfactant, the fatty acid oil mixture being from about 80% by weight to about 80% by weight of the fatty acid oil mixture. Containing 88% by weight of EPA and DHA, EPA and DHA are present in the form of free acids, surfactants are selected from polysolvate 20, polysolvate 80, and mixtures thereof, the at least one surfactant. Consists of less than 40% by weight of the preconcentrate, and the gelatin capsule or tablet contains at least one coating.

In another embodiment, for example, a pharmaceutical preconcentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture, oleic acid and at least one surfactant, the fatty acid oil mixture is a fatty acid oil mixture. Containing from about 80% to about 88% by weight of EPA and DHA, EPA and DHA are present in the form of free acids, surfactants are selected from polysolvate 20, polysolvate 80, and mixtures thereof, said at least. One surfactant constitutes less than 40% by weight of the weight of the pre-concentrate, and the gelatin capsule or tablet contains at least one coating.

In another embodiment, the pharmaceutical pre-concentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture, α-linoleic acid and at least one surfactant, and the fatty acid oil mixture is a fatty acid oil mixture. Containing from about 80% to about 88% by weight of EPA and DHA, EPA and DHA are present in the form of free acids, surfactants are selected from polysolvate 20, polysolvate 80, and mixtures thereof, said at least. One surfactant constitutes less than 35% by weight of the weight of the preconcentrate, and the gelatin capsule or tablet contains at least one coating.

In another embodiment, the pharmaceutical pre-concentrate in the form of gelatin capsules or tablets comprises a mixture of K85FA fatty acid oil and at least one surfactant selected from polysorbate 20 and polysorbate 80, gelatin capsules or The tablet contains at least one coating.

In other embodiments, the pre-concentrate is a food supplement pre-concentrate or nutritional supplement pre-concentrate in the form of gelatin capsules or tablets, which comprises a fatty acid oil mixture and at least one surfactant, and is a fatty acid. The oil mixture contains from about 25% to about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are present in the form of free acids, gelatin capsules or tablets. Includes at least one coating.

In some embodiments of the disclosure, the pre-concentrate is a pharmaceutical pre-concentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one surfactant, wherein the fatty acid oil mixture is , Contains at least about 75% by weight of the fatty acid oil mixture eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), EPA and DHA are present in a form selected from ethyl esters and triglycerides, gelatin capsules or tablets are at least Includes one coating.

In one embodiment, the pharmaceutical pre-concentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture and at least one surfactant, the fatty acid oil mixture being at least about 95% by weight of the fatty acid oil mixture. Includes EPA ethyl ester, DHA ethyl ester, or mixtures thereof, surfactants are selected from polysolvate 20, polysolvate 80, and mixtures thereof, and gelatin capsules or tablets contain at least one coating.

In another embodiment, the pharmaceutical preconcentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture and at least one surfactant, the fatty acid oil mixture being from about 80% by weight of the fatty acid oil mixture. Containing about 88% by weight of EPA and DHA, EPA and DHA are present in the form of ethyl esters, the surfactant is selected from polysolvate 20, polysolvate 80, and mixtures thereof, the at least one surfactant. Consists of less than 40% by weight of the weight of the pre-concentrate, and gelatin capsules or tablets contain at least one coating.

In another embodiment, the pharmaceutical preconcentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture and at least one surfactant, the fatty acid oil mixture being from about 80% by weight of the fatty acid oil mixture. Containing about 88% by weight of EPA and DHA, EPA and DHA are present in the form of ethyl esters, the surfactant is selected from polysolvate 20, polysolvate 80, and mixtures thereof, the at least one surfactant. Consists of less than 35% by weight of the weight of the pre-concentrate, and gelatin capsules or tablets contain at least one coating.

In some embodiments, for example, the pharmaceutical preconcentrate in the form of gelatin capsules or tablets is K85EE as a fatty acid oil mixture; and at least one surfactant selected from polysorbate 20, polysorbate 80, and mixtures thereof. Contains an activator, gelatin capsules or tablets include at least one coating.

In another embodiment, the pharmaceutical preconcentrate in the form of gelatin capsules or tablets comprises a fatty acid oil mixture, at least one surfactant and at least one co-surfactant, and the fatty acid oil mixture is , Containing from about 80% to about 88% by weight of EPA and DHA of fatty acid oil mixture, EPA and DHA are present in the form of ethyl ester, the surfactant is selected from Polysolvate 80, the auxiliary surfactant is Contains ethanol, gelatin capsules or tablets include at least one coating.

In other embodiments, the pre-concentrate is a food supplement pre-concentrate or nutritional supplement pre-concentrate in the form of gelatin capsules or tablets, comprising a fatty acid oil mixture and at least one surfactant, fatty acids. The oil mixture contains from about 25% to about 75% by weight of EPA and DHA of the fatty acid oil mixture, EPA and DHA are present in a form selected from ethyl esters and triglycerides, and gelatin capsules or tablets are at least one. Includes coating.

The following examples are intended to illustrate, but are not limited to, the present disclosure. Those skilled in the art will appreciate further embodiments that are consistent with the disclosures provided herein.

[Example]

<p> Pre-concentrates Various pre-concentrates were prepared as shown in Table 9. To prepare the pre-concentrate, the ingredients were mixed on a weight-to-weight basis according to the scheme shown below. The pre-concentrate was visually inspected again after mixing and after storage at room temperature for 24 hours. In the pre-concentrate section, the indication "clear" means a transparent homogeneous mixture; the indication "non-clear" means a non-uniform mixture in which some turbidity can be observed by visual inspection. The degree of turbidity was not measured.</p><p> All clear pre-concentrates were emulsified in the gastric medium by adding gastric medium (2 mL) to nearly 100 mg of pre-concentrate. The composition of the gastric medium is shown in Table 8.</p><p><tables num="8"><img file="JP6835664B2_D0008.tif" /></tables></p><p> Emulsification results were recorded approximately 3 hours after mixing. Most pre-concentrates formed an emulsion immediately after mixing. Emulsions that remain milky and uniform after 3 hours are referred to as "emulsion" in the emulsion section. Emulsions that have separated, become non-uniform, or have oil droplets observed are referred to as "separation" in the emulsion section.</p><p> The selected emulsion was further characterized by measuring the particle size. The particle size was measured using a Malvern Zetasizer (Malvern Instrument, Ustersia, UK) with a zeta potential in the particle size measurement range of 0.5 to 6000 nm and the particle range of 3 nm to 10 μm. The particle size was measured in triplets. The K85EE (EE = ethyl ester) fatty acid composition used herein is sold in gelatin capsules and is primarily trademarked under the trade name Lovaza or Omacor .</p><p><tables num="9"><img file="JP6835664B2_D0009.tif" /></tables><img file="JP6835664B2_D0010.tif" /><img file="JP6835664B2_D0011.tif" /><img file="JP6835664B2_D0012.tif" /><img file="JP6835664B2_D0013.tif" /><img file="JP6835664B2_D0014.tif" /><img file="JP6835664B2_D0015.tif" /><img file="JP6835664B2_D0016.tif" /><img file="JP6835664B2_D0017.tif" /></p><p> Among the prepared pre-concentrates, formulation number 85 facilitates the loading of 60% K85EE into the pre-concentrate and provides a stable emulsion with a particle size measured in the gastric medium of about 275 nm. rice field. Attempts to prepare pre-concentrates with saturated fatty acids, stearic acid and decanoic acid have failed. A uniform pre-concentrate could be obtained by heating, but when the pre-concentrate was cooled to room temperature, precipitation of stearic acid or decanoic acid was observed.</p>

<p> Further Pre-Concentrates Further pre-concentrates were prepared using K85EE and K85FA to determine the optimum amount of surfactant. The pre-concentrates listed in Table 10 were prepared as shown in Example 1. The pre-concentrate was visually inspected again after mixing and after storage at room temperature for 24 hours. In the item of pre-concentrate, the indication "clear" means a transparent homogeneous mixture, and the indication "turbidity" means a heterogeneous mixture in which some turbidity can be observed by visual inspection. The degree of turbidity was not measured.</p><p><tables num="10"><img file="JP6835664B2_D0018.tif" /></tables><img file="JP6835664B2_D0019.tif" /><img file="JP6835664B2_D0020.tif" /></p>

<p> Compatibility of the pre-concentrate with the solvent The compatibility of the solvent with the pre-concentrate containing a certain amount of K85EE and Tween-80 was evaluated. The pre-concentrates listed in Table 11 were prepared, however, with the addition of the following solvents, as shown in Example 1. The pre-concentrate was visually inspected again after mixing and after storage at room temperature for 24 hours. In the item of pre-concentrate, the indication "clear" means a transparent homogeneous mixture, and the indication "turbidity" means a heterogeneous mixture in which some turbidity can be observed by visual inspection. The degree of turbidity was not measured.</p><p><tables num="11"><img file="JP6835664B2_D0021.tif" /></tables><img file="JP6835664B2_D0022.tif" /><img file="JP6835664B2_D0023.tif" /><img file="JP6835664B2_D0024.tif" /><img file="JP6835664B2_D0025.tif" /></p>

<p> Characterization of pre-concentrates and SNEDDS / SMEDDS / SEDDS Pre-concentrates A to L shown in Table 12 were prepared in the same manner as shown in Example 1.</p><p><tables num="12"><img file="JP6835664B2_D0026.tif" /></tables></p><p> In Table 12 above, all the pre-concentrates were apparently clear and uniform except for the preparation using erucic acid. Thus, the pre-concentrates can be mixed in any ratio and these mixtures will also form a uniform and clear pre-concentrate.</p><p> In addition, the preliminary concentrates A to L were screened for compatibility with various solvents. The results of this screening are shown in Table 13 below. Approximately 50 mg of each solvent was added to a 500 mg pre-concentrate. For pre-concentrate A, all solvents were used. For ethanol, all pre-concentrates were tested. The pre-concentrate was visually inspected again after mixing and after storage at room temperature for 24 hours. In the pre-concentrate section, the indication "clear" means a transparent homogeneous mixture, and the indication "non-clear" means a heterogeneous mixture in which some turbidity can be observed by visual inspection. The degree of turbidity was not measured.</p><p><tables num="13"><img file="JP6835664B2_D0027.tif" /></tables></p><p> Viscosity can be used as a parameter for physical characterization. Viscosity measurements were performed on the pre-concentrates A to L in triplets. In general, the viscosity showed greater sensitivity to the type of fatty acid than to the type of surfactant. FIG. 1 is a graph showing the viscosities of the preliminary concentrates A to L. Viscosity measurements are indistinguishable between Tween 20 and Tween 80, but free acids can affect viscosity.</p><p> Pre-concentrates A through F, I, and J were diluted with gastric and intestinal medium to form an emulsion (ie, SNEDDS / SMEDDS / SEDDS). The composition of the gastric medium is shown in Table 14, and the composition of the intestinal medium is shown in Table 15.</p><p><tables num="14"><img file="JP6835664B2_D0028.tif" /></tables></p><p><tables num="15"><img file="JP6835664B2_D0029.tif" /></tables></p><p> The particle size was measured using a Malvern zetasizer (Malvern Instrument, Ustersia, UK) with a zeta potential measurement range of 0.5 to 6000 nm particle size and a particle range of 3 nm to 10 μm. The particle size was measured in triplets.</p><p> For gastric medium, an emulsion was prepared by adding 1 mL of gastric medium to a 50 mg preconcentrate. Table 16 below shows the particle size measurements of the pre-concentrates A to F, I and J in the gastric medium. In addition, the measured values of particle size in the gastric medium are illustrated graphically in FIG.</p><p><tables num="16"><img file="JP6835664B2_D0030.tif" /></tables></p><p> For intestinal medium, an emulsion was prepared by adding the previously obtained gastric medium (100 μL) to the intestinal medium (900 μL). Table 17 below shows the particle size measurements of the pre-concentrates A to F, I and J in the intestinal medium. In addition, the measured values of particle size in the intestinal medium are illustrated graphically in FIG.</p><p><tables num="17"><img file="JP6835664B2_D0031.tif" /></tables></p><p> As shown in Figure 2, the intestinal medium has a greater effect on the particle size distribution, especially the pre-concentrate containing Tween80. The observations are visualized in Figures 3-18. Figures 3-18 show readings from the Malvern Zetasizer for four consecutive measurements of each preconcentrate in the same sample. All pre-concentrates are close to a monomodal particle size distribution in the gastric medium, while only pre-concentrates containing Tween 20 remain monomodal when converted to intestinal medium.</p>

<p> Lipolysis and solubilization Studies were conducted to analyze the rate of lipolysis (ie, hydrolysis) and solubilization of K85EE and various preconcentrates containing various free fatty acids and detergents. In particular, four experiments were planned to determine how the amount of detergent affects the rate and extent of lipolysis and solubilization. Lipolysis was performed with SMEDDS preparation containing K85EE.</p><p> Ingredients Bile acids, porcine bile extracts (Sigma); containing glycine and taurine conjugates of hyodeoxycholic acid and other bile acids, Pancreatic lipase, porcine pancreates (Sigma); amylases, trypsins , Contains many enzymes including lipases, ribonucleases and proteases, · Lecithin; Phospholipids (LIPOID S PC from LIPOID AG), · Trizumamaleart (Sigma Aldrich), · Tween20, Molecular Biological Grade (AppliChem) , Darmstadt), Tween80 (Fluka), . α-phosphoric acid (Sigma, 60% product), oleic acid (Aldrich, 90% product), . K85-EE and K85-FA</p><p> Pre-concentrates A-E were prepared as summarized in Table 18.</p><p><tables num="18"><img file="JP6835664B2_D0032.tif" /></tables></p><p>General Lipolysis Method A minor modification of the in vitro dynamic lipolysis model developed by Zangenberg et al. (Zangenberg, NH et al., Eur.J.Pharm.Sci.14,237-244,2001; Zangenberg, NH et al. , Eur.J.Pharm.Sci.14,115 ~ 122,2001). Lipid decomposition was carried out in a thermostat-controlled 600 mL glass container with a jacket, with the continuous addition of calcium chloride in the presence of porcine bile extract. The lipase source was porcine panclearin, which was hydrolyzed and then titrated with pH stat (pH 6.5) and sodium hydroxide solution (1.0 N). The initial composition of the lipolytic medium is shown in Table 19.</p><p><tables num="19"><img file="JP6835664B2_D0033.tif" /></tables></p><p> The final volume was 300 mL in all experiments and the calcium addition rate during the experiment was 0.045 mmol / min (0.09 mg / min). In all experiments, the amount of K85-EE added corresponds to 5.58 mg / mL.</p><p> To measure the process of lipolysis of K85-EE by HPLC, crude samples were taken and acidified with dilute hydrochloric acid. The concentrations of EPA-EE, DHA-EE, EPA-FA and DHA-FA were measured by HPLC in triplets. Experiments were performed using the LC Agilent Technologies 1200 series with a column temperature of 30 ° C, mobile phases of (A) water (0.1% acetic acid) and (B) MeCN (0.1% acetic acid), 70% from 0 to 8 minutes. Conducted from B to 100% B, 100% B from 8 to 15 minutes, 100% B to 70% B from 16 to 16 minutes, 70% B from 16 to 20 minutes .. The flow rate was 0.5 mL / min, UV (210 nm), injection volume: 5 μL, and analysis execution time: 20 minutes.</p><p> Monitor the concentrations of EPA ethyl ester (EPA-EE), DHA ethyl ester (DHA-EE), EPA free acid (EPA-FA), and DHA free acid (DHA-FA) over time to control the rate of lipid degradation. Calculated as shown in Table 20 and compared with Omacor®.</p><p><tables num="20"><img file="JP6835664B2_D0034.tif" /></tables></p><p> Figures 19, 22, 25, 28, 31 and 34 graphically illustrate the disappearance of EPA-EE and DHA-EE and the appearance of EPA-FA and DHA-FA during lipolysis of the respective test samples. The graph included sampling time points from 2 minutes to 233 minutes. In addition, a linear regression line was included.</p><p> Figures 20, 23, 26, 29, 32 and 35 show the percentage of EPA + DHA recovered at different time points for each test sample. Data are obtained as the sum of EPA-EE, DHA-EE, EPA-FA and DHA-FA and are shown as a percentage of the theoretical amount of 5580 μg / mL.</p><p> Figures 21, 24, 27, 30, 33 and 36 graphically show the percentage of lipolysis at different time points for EPA-EE, DHA-EE and total K85EE. Values are calculated for the total amount of EPA-EE and DHA-EE measured by HPLC after 2 minutes of lipolysis.</p>

<p> Fatty Acid Oil Mixture in Pharmaceutical Composition / Pre-Concentrate Table 21 shows the fatty acid oil mixture in the pharmaceutical composition or pre-concentrate (where the fatty acid oil mixture is the K85-EE composition).</p><p><tables num="21"><img file="JP6835664B2_D0035.tif" /></tables></p>

<p> Tablet formulation Tablets were prepared by immersing the tablets shown in Table 22 in K85EE oil. The average liquid load was 160 mg oil / tablet, which corresponds to about 72 v / v%. Also, tablets can be prepared without super disintegrants.</p><p><tables num="22"><img file="JP6835664B2_D0036.tif" /></tables></p>

<p> New K85 Tablet Formula The tablet formulation containing the ingredients shown in Table 23 was prepared by immersing the tablet in K85EE or AGP oil and in the oil in the free acid form.</p><p><tables num="23"><img file="JP6835664B2_D0037.tif" /></tables></p>

<p> Preparation of SEDDS and SMEDDS Pre-concentrates can be prepared by mixing a fatty acid oil mixture with at least one surfactant and free fatty acid.</p><p> The pre-concentrate can be visually inspected again after mixing and after storage at room temperature for 24 hours to obtain a clear and clear pre-concentrate.</p><p> An aqueous medium can then be added to the pre-concentrate to form an oil-in-water emulsion. The dispersion rate for forming an oil-in-water emulsion is extremely fast, less than 1 minute.</p><p> The formed microemulsion can then be tested for hydrolysis, also called lipolysis.</p><p> For example, in order to measure the hydrolysis process of KE85-EE by HPLC, a crude sample can be taken and acidified with dilute hydrochloric acid. The concentrations of EPA-ethyl ester, DHA ethyl ester, EPA free fatty acid and DHA free fatty acid can then be measured by HPLC.</p><p> All samples can be withdrawn from the non-uniform phase and some recovery variability can be expected, especially at an early stage.</p><p><tables num="24"><img file="JP6835664B2_D0038.tif" /></tables></p><p> An example HPLC analysis method can include the following parameters: Use of LC-MS manufactured by Agilent Technologies, including 1200 Series LC and 6140 Quadrupole MS running ChemStation B.04.01 software; -Column: Eclipse XDB C18, 2.1 x 150 mm, 5 μm, Agilent; -Column temperature: 25 ° C; -Mobile phase: water (0.1% acetic acid), B: MeCN (0.1% acetic acid); -Gradient: 0 to 8 minutes 70% B to 100% B, 8 to 15 minutes 100% B, 16 to 16 minutes 100% B to 70% B, 16 to 20 minutes 70% B;. UV 210nm; . Injection volume: 25 μL; and . Analysis execution time: 20 minutes</p><p> The oil-in-water emulsion can then be further analyzed to measure the particle size of the oil droplets. The particle size can be measured using a Malvern zeta potential measuring range (Malvern Instrument, Ustersia, UK) having a particle size measuring range of 0.6 to 6000 nm and a zeta potential measuring range of a particle range of 3 nm to 10 μm.</p><p> Table 25 shows the ingredients that can be included in the pharmaceutical compositions and food supplement compositions according to the present disclosure.</p><p><tables num="25"><img file="JP6835664B2_D0039.tif" /></tables></p><p> Further, for example, Table 26 illustrates free fatty acids selected from K85EE omega-3 fatty acid oil and K85FA having an EPA: DHA-FA ratio approximately equal to the EPA: DHA-EE ratio in K85EE.</p><p><tables num="26"><img file="JP6835664B2_D0040.tif" /></tables></p><p> In addition, the entire amount of the oil mixture shown above can be mixed with the surfactant Tween® 20.</p><p> Further, for example, the K85EE mixed fatty acid composition contains at least 90% omega-3 ethyl ester fatty acid, wherein the mixed fatty acid composition is from about 80% to about 88% by weight of the fatty acid composition. Includes icosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester.</p><p> Table 27 exemplifies a set of ratios of [oil]: [surfactant]: [free fatty acid] (a): b): c)). For example, K85EE or AGP103 oils can be combined with surfactants and co-surfactants in a ratio of [K85EE]: [surfactant]: [free fatty acid] in the range of approximately 4: 2: 0.5 to 4: 4: 2. Used together. Therefore, the range of surfactants may be 2 to 4, and the range of free fatty acids may be 0.5 to 2.</p><p> It is also included herein that the K85EE oil mixture shown in Table 27 can be replaced with a K85TG oil mixture and a commercially available omega-3 oil concentrate in the form of ethyl ester and / or triglyceride.</p><p><tables num="27"><img file="JP6835664B2_D0041.tif" /></tables></p>

<p> Pharmaceutical Pre-Concentrate Composition A pharmaceutical pre-concentrate composition was prepared by mixing the following components. . K85-EE as a fatty acid oil mixture in an amount of 10.80 g; . Tween-20 (molecular biology grade, AppliChem, Darmstadt, A4974,0250, Lot.5N004174) in an amount of 7.44 g as a surfactant; EPA-FA in an amount of 1.53 g as at least one fatty acid; and DHA-FA in an amount of 1.24 g.</p><p> Mixing gave a clear uniform solution. The density of the formulation was measured to be 1.02 g / mL. The composition was then filled into vials (vial size = 4 mL) to prepare vials containing 1.25 x 1670 mg = 2087 mg each, blown with nitrogen and sealed with parafilm.</p>

<p> In vivo studies in mini pigs Two different formulations were prepared and shipped for in vivo studies. Formulation 1 was prepared according to Example 10 by mixing specified amounts of the following ingredients: K85EE, Tween20, EPA-FA and DHA-FA, and Formulation 2 was an OMACOR gelatin capsule.</p><p> The study was performed on 8 male Gottingen SPF mini pigs from Ellegaard Gottingen Minipigs ApS. Animals are floor pen (1.2 m) using sawdust (Jelu Werk, Josef Ehrler, Ludwigsmuhle, D-73494 Rosenberg, "Jeluxyl" from Germany) as a bed.²) Individually housed in.</p><p> Treatment was performed by the cross method. The dose was 2 g per animal. The first day of treatment is called the first day. Treatment was performed with a washout period of at least 10 days between each dose. A blood sample (n = 8) was collected after administration. Plasma samples were analyzed within 2 weeks for total lipid content of EPA and DHA by validated LC-MS / MS method. The results shown in Figure 37 show the plasma concentration-to-time profile of the total lipid concentration of EPA and support the excellent bioavailability (eg, greater than 40%) for the K85 SMEDDS formulation. Similar results were shown for the time profile of total lipid concentration in DHA (not shown in Figure 37).</p>

<p> Pharmaceuticals, SMEDDS and SEDDS Table 28 illustrates the pharmaceuticals, SMEDDS and SEDDS that can be prepared.</p><p><tables num="28"><img file="JP6835664B2_D0042.tif" /></tables></p><p> In embodiments, the surfactant is selected from Tween® surfactants such as 20, 40, 60, 80 and 85. For example, the compositions according to the present disclosure can include at least one surfactant selected from Tween® 20 and 40.</p>

<p> Pre-concentrate preparation for emulsion / microemulsion The following pre-concentrate preparation for emulsion / microemulsion according to the present disclosure was prepared.</p><p>Pharmaceutical Formulation 1: Composition for SEDDS A pharmaceutical composition was prepared by mixing the following ingredients: a) Fatty acid oil mixture of 5.5 g EPA-FA and 4.5 g DHA-FA (K85EE or FA fatty acid) The ratio of EPA: DHA in the mixture is almost achieved), b) EE form of the secondary fatty acid mixture, ie 5.0 g of ethyl oleate: Fluka, 75100, 13704450308P14, and c) as a surfactant. 10.0 g amount of Tween® 20, molecular biology grade, AppliChem, Darmstadt, A4974,0250, Lot.5N004174.</p><p> A clear uniform solution was obtained. The density of the formulation was measured to be 1.03 g / mL. The composition was then filled into vials (vial size = 4 mL) to prepare vials containing each (2450 mg x 1.25) = 3063 mg, blown with nitrogen and sealed with parafilm.</p><p>Pharmaceutical Formulation 2 A formulation similar to the one exemplified above was prepared using Tween® 80 instead of Tween® 20. Therefore, it was prepared using mixed fatty acids, namely EPA-FA (110 mg) + DHA-FA (90 mg), ethyl oleate (100 mg), and Tween 80 (200 mg). A clear uniform solution was obtained.</p>

<p> Emulsion in pure water The oil content in one capsule of Omacor® containing EPA ethyl ester (465 mg), DHA ethyl ester (375 mg) and α-tocopherol (4 mg) is as shown in Table 29. The detergent was mixed in a scintillation vial. Water (10 mL) was added at 37 ° C and the mixture was shaken for 15 seconds using a vortex mixer. The mixture was observed after 1 and 5 minutes. The visual scores for emulsion uniformity were scored as follows: non-emulsion = score 0, emulsion but not uniform emulsion = score 1, uniform emulsion = score 2.</p><p> The mixture was also spun in a roller mixer for 5 minutes after mixing. The visual scoring for this roller test was similarly scored.</p><p><tables num="29"><img file="JP6835664B2_D0043.tif" /></tables><img file="JP6835664B2_D0044.tif" /><img file="JP6835664B2_D0045.tif" /></p>

<p> Emulsion in Artificial Gastric Fluid The oil content in one capsule of OMACOR® containing EPA ethyl ester (465 mg), DHA ethyl ester (375 mg) and α-tocopherol (4 mg) is as shown in Table 30. The surfactant was mixed in a scintillation vial. The experiment was set up as described in Example 14, except that pepsin-free artificial gastric juice (European Pharmacopoeia 6.0, p. 274) was used instead of water.</p><p><tables num="30"><img file="JP6835664B2_D0046.tif" /></tables></p>

<p> Emulsion in simulated intestinal fluid The oil content in one capsule of Omacor® containing EPA ethyl ester (465 mg), DHA ethyl ester (375 mg) and α-tocopherol (4 mg) is as shown in Table 31. The surfactant was mixed in a scintillation vial. The experiment was set up as described in Example 14, except that simulated intestinal juice (pH 6.8) without pancreatic powder (European Pharmacopoeia 6.0, p. 274) was used instead of water.</p><p><tables num="31"><img file="JP6835664B2_D0047.tif" /></tables></p>

<p> Microscopic examination of emulsions Emulsions derived from Reference No. 52 (gastric fluid) of Example 15 and Reference No. 58 (intestinal juice) of Example 16 were examined under a microscope 24 hours after roller treatment. Both emulsions were found to be oil-in-water suspensions that did not tend to aggregate.</p>

<p> Pharmaceutical Formulas Table 32 exemplifies the pharmaceutical formulations that can be prepared.</p><p><tables num="32"><img file="JP6835664B2_D0048.tif" /></tables></p><p> In embodiments, the surfactant or combination of surfactants is a Tween® surfactant, ie Tween® 20, Tween® 40, Tween® 60, Tween®. It is selected from 65, Tween® 80 and Tween® 85.</p><p> In another embodiment, the surfactant is selected from a combination of a Tween® surfactant and a surfactant selected from Cremphor®, eg, Tween® 20 and Cremphor. It is a combination with EL. Furthermore, in a further embodiment, Tween® 20 and Solutol HS15 surfactants can be used together as well as Tween® 20 and Tween® 40.</p><p> The fatty acid oil mixture in the pharmaceutical pre-concentrate, where the fatty acid oil mixture is a K85EE or AGP-103 oil composition, is shown in Table 33.</p><p><tables num="33"><img file="JP6835664B2_D0049.tif" /></tables></p>

<p> Additional Emulsion Pre-Concentrates 1-23 in Artificial Gastric Juice and Simulated Intestinal Juice were prepared with EPA / DHA ethyl ester (1000 mg K85EE) and various detergent and detergent mixtures as shown in Table 34. .. Emulsions were prepared in both artificial gastric juice and simulated intestinal juice as described in Examples 15 and 16. The results were similar to those for emulsions in artificial gastric juice and simulated intestinal juice, as described in Table 34.</p><p><tables num="34"><img file="JP6835664B2_D0050.tif" /></tables><img file="JP6835664B2_D0051.tif" /></p><p> Emulsions 4 to 15 prepared in both artificial gastric juice and simulated intestinal juice were uniform (milky) for several hours when left to stand. Emulsions 1-3 separated slightly after preparation (ie, after a few hours of standing). Microscopic examination of emulsions 1-15 showed that the average particle size was less than 100 μm. A 20 second homogenization of Emulsion 4 (Ultra Rurrax (IKA)) resulted in a substantial increase in the formation of small particles (&lt;10 μm).</p><p> Based on the prepared pre-concentrate, 0.5% nonionic detergent (eg, Cremophor®) can emulsify EPA / DHA ethyl ester in both artificial gastric juice and simulated intestinal juice. can. In addition, the inclusion of more than one surfactant appears to stabilize the emulsion. Furthermore, the particle size can be changed according to the emulsification method.</p>

<p> Gelatin capsules coated with cellulose acetate phthalate (A) Gelatin capsules containing EPA ethyl ester and DHA ethyl ester Preformed gelatin capsules containing EPA ethyl ester and DHA ethyl ester The agent (Omacor®, Pfizer, Norway) was coated with an acetone solution of cellulose phthalate acetate (6%) and triethyl citrate (3%). The capsules were dried at room temperature for 24 hours. The coating material on one capsule (cellulose phthalate + triethyl citrate) increased the capsule weight by 15 mg.</p><p>(B) Gelatin capsules containing EPA ethyl ester, DHA ethyl ester and Brij® 96V and coated with cellulose acetate phthalate EPA ethyl ester (463mg), DHA ethyl ester (375mg), Brij® Preformed gelatin capsules containing 96 V (60 mg) and tocopherol (4 mg) were coated with an acetone solution of cellulose phthalate acetate (6%) and triethyl citrate (3%). The capsules were dried at room temperature for 24 hours.</p>

<p> Eudragit® RS30D coated gelatin capsule (A) Preformed containing EPA ethyl ester and DHA ethyl ester, Eudragit® RS30D coated gelatin capsule containing EPA ethyl ester and DHA ethyl ester The gelatin capsules (Omacor®, Pfizer, Norway) were coated with an aqueous solution of Eudragit® RS30D from Degussa, Germany. The capsules were dried at room temperature for 24 hours.</p><p>(B) Gelatin capsules containing EPA ethyl ester, DHA ethyl ester and Brij® 96V and coated with Eudragit® RS30D EPA ethyl ester (463 mg), DHA ethyl ester (375 mg), Brij (registered) Preformed gelatin capsules containing 96 V (60 mg) and tocopherol (4 mg) were coated with an aqueous solution of Eudragit® RS30D from Degussa, Germany. The capsules were dried at room temperature for 24 hours.</p>

<p> Enteric coated tablets Coated tablets were prepared and administered to animal models (mini pigs), and serum levels of EPA and DHA were measured over time.</p><p> Two tablets were pretreated as follows: Tablets 31: 20% PEG, 10% Ac-Di-Sol (disintegrant) Tablets 32: 20% PEG, 0.5M KH₂PO₄, 10% Ac-Di-Sol (disintegrant).</p><p> The pretreatment was carried out in a fluidized bed, where the solution was sprayed onto the Neusilin granules, followed by heating and / or compressing the granules, incubating in nitrogen overnight and then loading with K85EE oil.</p><p> Tablets with an inner layer of aqueous PVA sublayer coating (Opadry® II) and an outer layer of aqueous enteric coating (acyl EZE Eudragit® L100-55 enteric coating). Covered.</p><p> Results on serum EPA levels are shown in Table 35 and illustrated in Figure 38. Results on serum DHA levels are shown in Table 36 and illustrated in FIG.</p><p><tables num="35"><img file="JP6835664B2_D0052.tif" /></tables></p><p><tables num="36"><img file="JP6835664B2_D0053.tif" /></tables></p><p> The tablets according to the present disclosure are K85EE oil + FFA + at least one surfactant (eg, Tween® 20 or Tween® 80), K85FA oil + at least one surfactant, and K85EE + at least one. It can be preloaded with a pre-concentrate selected from the various surfactants.</p>