Modified-release pharmaceutical composition and use thereof

Abstract

Provided in the present disclosure is a modified-release pharmaceutical composition. The pharmaceutical composition comprises: a self-emulsifying pharmaceutical composition; a capsule shell, used for encapsulating the self-emulsifying pharmaceutical composition; and a modified-release coating, applied on the outer surface of the capsule shell.

Description

A modulated-release pharmaceutical composition and its use Cross-references to related applications

[0001] This application claims the benefit of Chinese Patent Application No. 202410952194.9, filed on July 16, 2024, and Chinese Patent Application No. 202411533658.9, filed on October 31, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure relates to the field of pharmaceutical technology, and in particular to a modulated-release pharmaceutical composition and its use in the preparation of a medicament for treating and / or preventing dyslipidemia, hypertriglyceridemia, cardiovascular disease, or reducing triglyceride levels in the blood above normal levels. Background Technology

[0003] n-3 (ω-3 or Ω-3) is a polyunsaturated fatty acid (PUFA) commonly found in deep-sea fish and is highly beneficial to human health. In the pharmaceutical field, drug compositions rich in n-3 polyunsaturated fatty acids can be used to treat and / or prevent various clinical indications, such as hypertriglyceridemia and coronary heart disease.

[0004] Bioavailability is an important indicator of the extent to which the active ingredient of a drug is absorbed by the human body. For drug compositions containing n-3 polyunsaturated fatty acids, bioavailability is a key factor affecting therapeutic efficacy, and most current research focuses on this aspect.

[0005] Some drugs have excessively high intra-individual coefficients of variation for one or more pharmacokinetic parameters due to factors such as acid instability, extensive metabolism before absorption, and formulation factors. The coefficient of variation reflects the differences in the absorption, distribution, metabolism, and excretion of a drug among different individuals or under different conditions. Because of the existence of the coefficient of variation, the same drug may produce different therapeutic effects in different patients. Therefore, the coefficient of variation is also an important indicator for measuring the therapeutic effect of a drug.

[0006] Bioavailability and coefficient of variation are important indicators for jointly measuring the therapeutic effect of drugs. However, current research on n-3 polyunsaturated fatty acids, especially high-purity EPA-FFA (Eicosapentaenoic Acid Free Fatty Acid), has paid almost no attention to the combined effects of different formulations on coefficient of variation and bioavailability. Summary of the Invention

[0007] In view of this, the purpose of this disclosure is to provide a modulated-release pharmaceutical composition and its pharmaceutical use. In some embodiments of this disclosure, the pharmaceutical composition prepared by using self-emulsification and modulated-release coating significantly reduces the in vivo coefficient of variation of high-purity EPA-FFA, while improving its bioavailability and reducing gastrointestinal side effects.

[0008] One embodiment of this specification provides a pharmaceutical composition of high-purity EPA-FFA, which may include EPA-FFA with a purity of about 90% or higher. Herein, EPA-FFA with a purity of about 90% or higher means that, based on the total mass of all fatty acids in the pharmaceutical composition, the mass fraction of EPA-FFA is about 90% or higher, about 91% or higher, about 92% or higher, about 93% or higher, about 94% or higher, about 95% or higher, about 95.5% or higher, about 96% or higher, about 96.5% or higher, about 97% or higher, about 97.5% or higher, about 98% or higher, about 98.5% or higher, or about 99% or higher.

[0009] In some embodiments, the pharmaceutical composition may include no more than about 10% by mass of fatty acids other than EPA-FFA.

[0010] In some embodiments, the pharmaceutical composition may include an EPA-FFA trans isomer with a mass fraction of not more than about 5%.

[0011] One embodiment of this specification provides a pharmaceutical composition of high-purity EPA-FFA, which may include EPA-FFA with a purity of about 95% or higher. Herein, EPA-FFA with a purity of about 95% or higher means that, based on the total mass of all fatty acids in the pharmaceutical composition, the mass fraction of EPA-FFA is about 95% or higher, about 95.5% or higher, about 96% or higher, about 96.5% or higher, about 97% or higher, about 97.5% or higher, about 98% or higher, about 98.5% or higher, or about 99% or higher.

[0012] In some embodiments, the pharmaceutical composition may include no more than about 5% by mass of fatty acids other than EPA-FFA.

[0013] In some embodiments, the pharmaceutical composition may include an EPA-FFA trans isomer with a mass fraction of not more than about 5%.

[0014] One embodiment of this specification provides a pharmaceutical composition of high-purity EPA-FFA, comprising contents and a capsule shell, the contents comprising EPA-FFA with a purity of about 95% or higher, and the capsule shell for encapsulating the contents. In some embodiments, the capsules disclosed herein may be soft capsules or hard capsules, preferably soft capsules.

[0015] In some embodiments, the pharmaceutical composition includes a release coating (or “release coating layer”) coated on the outer surface of the capsule shell.

[0016] In some embodiments, the modulating coating comprises a modulating polymer and an acid-swellable coating film-forming agent. Unless otherwise specified, the polymers disclosed herein are long-chain molecules formed by the covalent bonding of multiple repeating monomer units, typically with a molecular weight in the range of 10. 4 above.

[0017] In some embodiments, the modulated coating comprises a modulated polymer and an acid-swellable coating film-forming agent that expands in volume in a buffer salt medium at pH 3.0-4.5.

[0018] In some embodiments, the modulating polymer includes at least one of a water-poorly soluble coating film-forming agent and an enteric coating film-forming agent. A water-poorly soluble coating film-forming agent is a polymer film-forming agent that is poorly soluble or insoluble in water within the pH range of the human gastrointestinal tract. Unless otherwise specified, the human gastrointestinal tract pH range in this disclosure refers to acidic media with pH = 1.0-3.0 and buffered salt media with pH > 3.0 (e.g., pH = 3.5, 4.5, 6.8). These media are formulated with reference to the Chinese Pharmacopoeia, the Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms, and the United States Pharmacopeia. Further descriptions of exemplary acidic media and buffered salt media can be found in other parts of this disclosure. Unless otherwise specified, "poorly soluble" in this disclosure means that 1 g of solute dissolves in 1000 mL to less than 10000 mL of solvent, for example, 1 g of a water-poorly soluble coating film-forming agent dissolves in 1000 mL to less than 10000 mL of water within the pH range of the human gastrointestinal tract. Unless otherwise specified, "insoluble" in this disclosure means that 1g of solute cannot be completely dissolved in 10000mL of solvent. For example, 1g of a water-insoluble coating film-forming agent cannot be completely dissolved in 10000mL of water within the pH range of the human gastrointestinal tract. In some embodiments, the water-insoluble coating film-forming agent may include at least one of ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer, and ethylene-vinyl acetate copolymer. In some embodiments, the water-insoluble coating film-forming agent may include cellulose acetate, cellulose propionate, etc. In some embodiments, the water-insoluble coating film-forming agent may include at least one of ethyl cellulose and ethyl acrylate-methyl methacrylate copolymer. Enteric coating film-forming agents are polymeric film-forming agents that are insoluble in acidic media within the pH range of the human stomach (pH 1.0-3.0) but mostly or completely soluble in buffer salt media within the pH range of the human intestinal tract (pH ≥ 6.8). Unless otherwise specified, the preparation of acidic media with pH = 1.0-3.0 and buffered salt media with pH ≥ 6.8 in this disclosure is based on the Chinese Pharmacopoeia, the Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms, and the United States Pharmacopeia. Further descriptions of exemplary acidic media and buffered salt media can be found in other parts of this disclosure. Unless otherwise specified, "substantially dissolved" in this disclosure means that the dissolved amount accounts for more than 95%, 96%, 97%, 98%, or 99% of the total mass. In some embodiments, the enteric coating film-forming agent may include at least one of cellulose acetate phthalate (CAP), acrylic resin, and hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the enteric coating film-forming agent may include at least one of cellulose acetate phthalate (CAP) and acrylic resin.

[0019] In some embodiments, the acid-swellable coating film-forming agent is a polymeric film-forming agent that expands in volume in a buffered salt medium with pH = 3.0-4.5. In other embodiments, the acid-swellable coating film-forming agent is a polymeric film-forming agent that expands in volume in a buffered salt medium with pH = 3.5-4.5. Volume expansion refers to an increase in volume to a multiple of the original volume, such as an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 1x, 1.5x, 2x, 3x, 4x, 5x, 6x, 8x, 10x, 12x, 15x, 18x, or 20x. The release-modifying coating is placed in an aqueous medium (e.g., an acidic medium with pH ≥ 3.0, a buffered salt medium, or gastrointestinal digestive fluid). The acid-swellable coating film-forming agent absorbs water and expands in volume, causing the release-modifying coating to rupture. Cracks and pores form on the release-modifying coating. Water in the medium enters the interior of the release-modifying coating through the cracks and pores, causing the capsule shell to dissolve and rupture. This allows the contents to be continuously released into the medium through the ruptured capsule shell and release-modifying coating until the capsule shell and release-modifying coating disintegrate, and the contents are completely released into the medium. In some embodiments, the acid-swellable coating film-forming agent may include at least one of alginate and pectin. In some embodiments, the acid-swellable coating film-forming agent may include at least one of sodium alginate, potassium alginate, ammonium alginate, and pectin. In some embodiments, the acid-swellable coating film-forming agent may include at least one of sodium alginate and potassium alginate.

[0020] Unless otherwise specified, the "acid-swellable coating film-forming agent" in this disclosure refers to a polymer film-forming agent that expands in volume in a buffer salt medium with pH ≥ 3.0.

[0021] In some embodiments, the modulated coating comprises a water-insoluble film-forming agent and alginate. In some embodiments, the modulated coating comprises a water-insoluble film-forming agent and sodium alginate.

[0022] In some embodiments, the mass ratio of the water-insoluble coating film-forming agent to alginate is (60-95):(5-40), preferably 65:35 to 90:10, 70:30 to 85:15, or 70:30 to 80:20. In some embodiments, the mass ratio of the water-insoluble coating film-forming agent to sodium alginate is about (60-95):(5-40), preferably 65:35 to 90:10, 70:30 to 85:15, or 70:30 to 80:20.

[0023] In some embodiments, the release coating comprises ethyl cellulose and sodium alginate. In some embodiments, the release coating comprises ethyl acrylate-methyl methacrylate copolymer and sodium alginate.

[0024] Coating weight gain can affect drug release behavior and improve the stability of drug formulations, and is one of the important indicators for measuring coating quality. In some embodiments, the coating weight gain of the release-modifying coating includes about 1% to about 15%, about 2% to about 10%, about 2% to about 9%, about 3% to about 8%, and about 3% to about 7%. In some embodiments, the coating weight gain of the release-modifying coating is preferably about 3.25% to about 6.15%, about 3.5% to about 6%, about 4% to about 5.5%, and about 4.5% to about 5%. In this document, the coating weight gain of the release-modifying coating is the percentage of the mass of the release-modifying coating to the mass of the capsule, which does not contain a coating and includes the contents and the capsule shell encapsulating the contents.

[0025] In some embodiments, the capsule shell comprises gelatin and a plasticizer; wherein, based on the total mass of the capsule shell, the gelatin comprises about 50% to about 80% by mass; and based on the total mass of the capsule shell, the plasticizer comprises about 20% to about 50% by mass. In some embodiments, the plasticizer is selected from glycerol, sorbitol, propylene glycol, and PEG. In some embodiments, the plasticizer is glycerol.

[0026] One embodiment of this specification provides a self-emulsifying pharmaceutical composition comprising: EPA-FFA with a purity of about 90% or higher and an emulsifier.

[0027] One embodiment of this specification provides a self-emulsifying pharmaceutical composition comprising: EPA-FFA with a purity of about 95% or higher and an emulsifier.

[0028] In some embodiments, the emulsifier has a mass fraction of about 1% to about 40% based on the total mass of the self-emulsifying pharmaceutical composition. The range of emulsifier types is well known in the art. In some embodiments, the emulsifier may include surfactant-based emulsifiers and / or hydrophilic polymeric emulsifiers.

[0029] In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 0-40. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 0-20. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 0.5-18. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 1-16. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 3-14. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 4-12. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 4-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 5-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 6-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 8-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 10-12. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 12-14.

[0030] In some embodiments, the emulsifier may include at least one of the following: polyoxyethylene fatty alcohol ethers, polyoxyethylene-polyoxypropylene copolymers, gum arabic, tragacanth gum, Bletilla striata gum, apricot gum, pectin, peach gum, sodium alginate, agar, casein, sodium cholate, cholesterol, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene dehydrated sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid esters, sucrose fatty acid esters, lecithin, glyceryl mono- and di-stearate esters, glyceryl fatty acid esters, glycerol, propylene glycol, poloxamer 188, poloxamer 407, sodium oleate, Tween 20, Tween 80, and 15-hydroxystearic acid polyethylene glycol ester. In some embodiments, the emulsifier may include at least one of the following: polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil), polyoxyethylene castor oil (e.g., polyoxyethylene (35) castor oil, polyoxyethylene (40) castor oil), Span derivatives (e.g., Span 20, Span 40, Span 60, Span 80), Tween derivatives (e.g., Tween 20, Tween 40, Tween 60, Tween 80), lecithin, glyceryl monostearate and glyceryl distearate, poloxamer (e.g., poloxamer 188, poloxamer 407), and polyethylene glycol 15-hydroxystearate.

[0031] In some embodiments, the emulsifier includes at least one of poloxamer 188, sodium oleate, Tween 80, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, glyceryl monooleate, PEG-glyceryl caprylate, glycerol, propylene glycol, and lecithin.

[0032] In some embodiments, the emulsifier includes at least one of polyoxyethylene (35) castor oil and lecithin.

[0033] In some embodiments, lecithin includes egg yolk lecithin or soy lecithin.

[0034] In some embodiments, the lecithin mass fraction is about 0 to about 20%, about 1% to about 18%, about 2% to about 15%, about 3% to about 12%, about 4% to about 10%, about 5% to about 8%, about 0.5% to about 5%, about 0.5% to about 3%, about 1% to about 2%, or any single value or subrange thereof, based on the total mass of the pharmaceutical composition.

[0035] In some embodiments, the mass fraction of polyoxyethylene (35) castor oil is about 1% to about 40%, about 3% to about 38%, about 5% to about 35%, about 7% to about 32%, about 10% to about 30%, about 15% to about 30%, about 17% to about 28%, about 20% to about 30%, about 20% to about 28%, about 20% to about 25%, about 22% to about 25%, about 22% to about 23%, or any single value or subrange thereof, based on the total mass of the pharmaceutical composition.

[0036] One embodiment of this specification provides a modulated-release pharmaceutical composition comprising: a capsule shell for encapsulating the self-emulsifying pharmaceutical composition as described in any embodiment of this disclosure; and a modulated-release coating applied to the outer surface of the capsule shell. In some embodiments, the modulated-release pharmaceutical composition further comprises the self-emulsifying pharmaceutical composition described in this disclosure. In some embodiments, this disclosure provides a modulated-release pharmaceutical composition comprising: (1) EPA-FFA and an emulsifier; (2) an encapsulation layer (e.g., a capsule shell) for encapsulating the EPA-FFA and the emulsifier; and (3) a modulated-release coating applied to the outer surface of the encapsulation layer.

[0037] In some embodiments, the modulated coating comprises a modulated polymer and an acid-swellable coating film-forming agent.

[0038] In some embodiments, the modulating polymer includes at least one of water-poorly soluble coating film-forming agents and enteric coating film-forming agents. Water-poorly soluble coating film-forming agents are polymeric film-forming agents that are poorly soluble or insoluble in water in media within the pH range of the human gastrointestinal tract. In some embodiments, water-poorly soluble coating film-forming agents may include at least one of ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer, and ethylene-vinyl acetate copolymer. In some embodiments, water-poorly soluble coating film-forming agents may include cellulose acetate, cellulose propionate, etc. In some embodiments, water-poorly soluble coating film-forming agents may include at least one of ethyl cellulose and ethyl acrylate-methyl methacrylate copolymer. Enteric coating film-forming agents are polymeric film-forming agents that are insoluble in acidic media within the pH range of the human stomach (pH 1.0-3.0) but mostly or completely soluble in buffer salt media within the pH range of the human intestinal tract (pH ≥ 6.8). In some embodiments, enteric coating film-forming agents may include at least one of cellulose acetate phthalate (CAP), acrylic resin, and hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the enteric coating film-forming agent may include at least one of cellulose acetate phthalate (CAP) and acrylic resin.

[0039] In some embodiments, the acid-swellable coating film-forming agent is a polymeric film-forming agent that expands in volume in a buffered salt medium with pH = 3.0-4.5. In some embodiments, the acid-swellable coating film-forming agent is a polymeric film-forming agent that expands in volume in a buffered salt medium with pH = 3.5-4.5. In some embodiments, the volume expansion is an increase relative to the original volume of, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, or 20 times. The release-modifying coating is placed in an aqueous medium (e.g., an acidic medium with pH ≥ 3.0, a buffered salt medium, or gastrointestinal digestive fluid). The acid-swellable coating film-forming agent absorbs water and expands in volume, causing the release-modifying coating to rupture. Cracks and pores form on the release-modifying coating. Water in the medium enters the interior of the release-modifying coating through the cracks and pores, causing the capsule shell to dissolve and rupture. This allows the contents to be continuously released into the medium through the ruptured capsule shell and release-modifying coating until the capsule shell and release-modifying coating disintegrate, and the contents are completely released into the medium. In some embodiments, the acid-swellable coating film-forming agent may include at least one of alginate and pectin. In some embodiments, the acid-swellable coating film-forming agent may include at least one of sodium alginate, potassium alginate, ammonium alginate, and pectin. In some embodiments, the acid-swellable coating film-forming agent may include at least one of sodium alginate and potassium alginate.

[0040] In some embodiments, the modulated coating comprises a water-insoluble film-forming agent and alginate. In some embodiments, the modulated coating comprises a water-insoluble film-forming agent and sodium alginate.

[0041] In some embodiments, the mass ratio of the water-insoluble coating film-forming agent to alginate is (60-95):(5-40), preferably 65:35 to 90:10, 70:30 to 85:15, or 70:30 to 80:20. In some embodiments, the mass ratio of the water-insoluble coating film-forming agent to sodium alginate is (60-95):(5-40), preferably 65:35 to 90:10, 70:30 to 85:15, or 70:30 to 80:20.

[0042] In some embodiments, the release coating comprises ethyl cellulose and sodium alginate. In some embodiments, the release coating comprises ethyl acrylate-methyl methacrylate copolymer and sodium alginate.

[0043] In some embodiments, the weight gain of the release coating includes about 1% to about 15%, about 2% to about 10%, about 2% to about 9%, about 3% to about 8%, and about 3% to about 7%. In some embodiments, the weight gain of the release coating is preferably about 3.25% to about 6.15%, about 3.5% to about 6%, about 4% to about 5.5%, and about 4.5% to about 5%.

[0044] The weight gain of the release coating is the percentage of the mass of the release coating to the mass of the capsule. The capsule does not contain the coating, but includes the contents and the capsule shell that encapsulates the contents.

[0045] In some embodiments, the capsule shell comprises gelatin and a plasticizer; wherein, based on the total mass of the capsule shell, the gelatin comprises about 50% to about 80% by mass; and the plasticizer comprises about 20% to about 50% by mass, based on the total mass of the capsule shell. In some embodiments, the plasticizer is selected from glycerol, sorbitol, propylene glycol, and PEG. In some embodiments, the plasticizer is glycerol.

[0046] One embodiment of this specification provides a modulated-release pharmaceutical composition comprising a modulated-release coating. The modulated-release coating does not disintegrate within 120 min in an acidic dissolution medium with pH 1.0-3.0 or within 120 min in a 0.1 mol / L hydrochloric acid solution, but disintegrates within 1 h in a buffer salt medium with pH ≥ 3.5. The buffer salt medium with pH = 3.5 may be a phosphate-potassium dihydrogen phosphate buffer solution.

[0047] In some embodiments, the modulating coating does not disintegrate for 120 minutes in an acidic dissolution medium with pH 1.0-3.0 or in a 0.1 mol / L hydrochloric acid solution, but disintegrates within 1 hour in a buffer salt medium with pH 3.5-4.5. For example, the modulating coating disintegrates within 1 hour in buffer salt media with pH 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5. Buffer salt media with different pH values ​​can be prepared according to the preparation methods specified in General Chapter 8004 of Part IV of the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia. If the required pH buffer salt media is not listed in the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia, a buffer salt media with a close pH can be selected, and acid or alkali can be added to adjust it to the required pH. Buffer salt media with different pH values ​​can also be prepared according to the preparation methods specified in the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms". If the required pH dissolution media is not listed in the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms", a dissolution media with a close pH can be selected, and acid or alkali can be added to adjust it to the required pH.

[0048] In some embodiments, the release coating disintegrates within 1 hour in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 50 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 48 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating preferably disintegrates within 45 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 43 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating preferably disintegrates within 40 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 38 minutes in a buffer medium at pH 3.5. The buffer medium at pH 3.5 may be a phosphate-potassium dihydrogen phosphate buffer solution.

[0049] In some embodiments, the release coating disintegrates within 1 hour in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 50 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 40 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 38 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating preferably disintegrates within 35 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 32 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating preferably disintegrates within 30 minutes in a buffer medium at pH 4.0. The buffer medium at pH 4.0 may be an acetate buffer.

[0050] In some embodiments, the release coating disintegrates within 1 hour in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 50 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 40 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 38 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating preferably disintegrates within 35 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating preferably disintegrates within 30 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 28 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 25 minutes in a buffer medium at pH 4.5. The buffer medium at pH 4.5 may be an acetate-sodium acetate buffer solution.

[0051] In some embodiments, the release-modifying coating disintegrates within 60 minutes, preferably within 30 minutes, in a buffered salt medium at pH 6.8. In some embodiments, the release-modifying coating disintegrates within 28 minutes in a buffered salt medium at pH 6.8. In some embodiments, the release-modifying coating disintegrates within 26 minutes in a buffered salt medium at pH 6.8. The buffered salt medium at pH 6.8 may be a phosphate buffer solution.

[0052] One embodiment of this specification provides a modulated-release pharmaceutical composition comprising a modulated-release coating. The modulated-release coating exhibits no disintegration within 120 min in an acidic dissolution medium with pH 1.0-3.0 or in a 0.1 mol / L hydrochloric acid solution for 120 min, and disintegrates within 1 h in a buffer salt medium with pH ≥ 3.5. The buffer salt medium with pH = 3.5 may be a phosphate-potassium dihydrogen phosphate buffer solution.

[0053] In some embodiments, the release-modifying coating shows no disintegration for 120 minutes in an acidic dissolution medium with pH 1.0-3.0 or in 0.1 mol / L hydrochloric acid solution, but disintegrates within 1 hour in a buffer salt medium with pH 3.5-4.5. For example, the release-modifying coating disintegrates within 1 hour in buffer salt media with pH 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5. The buffer salt media with different pH values ​​can be prepared according to the buffer salt media preparation methods specified in General Chapter 8004 of the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia. If the required pH buffer is not specified in the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia, a buffer with the closest pH can be selected, and acid or alkali can be added to adjust it to the desired pH. Buffers with different pH values ​​can also be prepared according to the dissolution media preparation methods specified in the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms." If the required pH dissolution media is not specified in the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms," ​​a dissolution media with a close pH can be selected, and acid or alkali can be added to adjust it to the desired pH.

[0054] In some embodiments, the release coating disintegrates within 1 hour in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 50 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 48 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating preferably disintegrates within 45 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 43 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating preferably disintegrates within 40 minutes in a buffer medium at pH 3.5. In some embodiments, the release coating disintegrates within 38 minutes in a buffer medium at pH 3.5. The buffer medium at pH 3.5 may be a phosphate-potassium dihydrogen phosphate buffer solution.

[0055] In some embodiments, the release coating disintegrates within 1 hour in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 50 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 40 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 38 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating preferably disintegrates within 35 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating disintegrates within 32 minutes in a buffer medium at pH 4.0. In some embodiments, the release coating preferably disintegrates within 30 minutes in a buffer medium at pH 4.0. The buffer medium at pH 4.0 may be an acetate buffer.

[0056] In some embodiments, the release coating disintegrates within 1 hour in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 50 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 40 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 38 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating preferably disintegrates within 35 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating preferably disintegrates within 30 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 28 minutes in a buffer medium at pH 4.5. In some embodiments, the release coating disintegrates within 25 minutes in a buffer medium at pH 4.5. The buffer medium at pH 4.5 may be an acetate-sodium acetate buffer solution.

[0057] In some embodiments, the release-modifying coating disintegrates within 60 minutes, preferably within 30 minutes, in a buffered salt medium at pH 6.8. In some embodiments, the release-modifying coating disintegrates within 28 minutes in a buffered salt medium at pH 6.8. In some embodiments, the release-modifying coating disintegrates within 26 minutes in a buffered salt medium at pH 6.8. The buffered salt medium at pH 6.8 may be a phosphate buffer solution.

[0058] In some embodiments, the pharmaceutical composition further includes: a capsule shell, a release-modifying coating coated on the outer surface of the capsule shell; and contents encapsulated by the capsule shell.

[0059] In some embodiments, the contents include EPA-FFA with a purity of about 90% or higher. In some embodiments, the contents include EPA-FFA with a purity of about 95% or higher. In some embodiments, the contents include EPA-FFA with a purity of about 90% or about 95% or higher and an emulsifier.

[0060] One embodiment of this specification provides a modulated-release pharmaceutical composition comprising a capsule shell coated with a modulated-release coating. The capsule shell coated with the modulated-release coating shows no disintegration for 120 minutes in an acidic dissolution medium with a pH of 1.0-3.0 or in a 0.1 mol / L hydrochloric acid solution for 120 minutes, and disintegrates within 1 hour in a buffer salt medium with a pH ≥ 3.5. The buffer salt medium with a pH of 3.5 may be a phosphate-potassium dihydrogen phosphate buffer solution.

[0061] In some embodiments, the capsule shell shows no disintegration for 120 minutes in an acidic dissolution medium with pH 1.0-3.0 or in 0.1 mol / L hydrochloric acid solution, and disintegrates within 1 hour in a buffer salt medium with pH 3.5-4.5. For example, the capsule shell disintegrates within 1 hour in buffer salt media with pH 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5. The buffer salt media with different pH values ​​can be prepared according to the buffer salt media preparation methods specified in General Chapter 8004 of the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia. If the required pH buffer is not specified in the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia, a buffer with the closest pH can be selected, and acid or alkali can be added to adjust it to the desired pH. Buffers with different pH values ​​can also be prepared according to the dissolution media preparation methods specified in the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms." If the required pH dissolution media is not specified in the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms," ​​a dissolution media with a close pH can be selected, and acid or alkali can be added to adjust it to the desired pH.

[0062] In some embodiments, the release-modifying coating disintegrates within 1 hour in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coating disintegrates within 50 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell disintegrates within 40 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coating disintegrates within 38 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell preferably disintegrates within 35 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coating disintegrates within 33 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell preferably disintegrates within 30 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coating disintegrates within 28 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coating disintegrates within 25 minutes in a buffered salt medium at pH 4.5. The buffer salt medium with pH=4.5 can be an acetate-sodium acetate buffer solution.

[0063] In some embodiments, the capsule shell disintegrates within 60 minutes, preferably within 30 minutes, in a buffered salt medium at pH 6.8. In some embodiments, the release-modifying coating disintegrates within 28 minutes in a buffered salt medium at pH 6.8. In some embodiments, the release-modifying coating disintegrates within 26 minutes in a buffered salt medium at pH 6.8. The buffered salt medium at pH 6.8 may be a phosphate buffer solution.

[0064] In some embodiments, the pharmaceutical composition further includes: contents encapsulated within a capsule shell.

[0065] In some embodiments, the contents include EPA-FFA with a purity of about 90% or higher. In some embodiments, the contents include EPA-FFA with a purity of about 95% or higher. In some embodiments, the contents include EPA-FFA with a purity of about 90% or about 95% or higher and an emulsifier.

[0066] One embodiment of this specification provides the use of self-emulsifying pharmaceutical compositions and / or modulated-release pharmaceutical compositions as described in any embodiment of this disclosure in the preparation of medicaments for treating and / or preventing dyslipidemia, hypertriglyceridemia, or cardiovascular disease, or for reducing triglyceride levels in the blood above normal levels. In some embodiments, the cardiovascular disease includes myocardial infarction, stroke, coronary revascularization, or angina pectoris.

[0067] One embodiment of this specification provides the use of a self-emulsifying pharmaceutical composition and / or modulated-release pharmaceutical composition as described in any embodiment of this disclosure in the preparation of a medicament for lowering triglyceride levels.

[0068] One embodiment of this specification provides the use of the self-emulsifying pharmaceutical composition and / or modulated-release pharmaceutical composition described herein for the treatment and / or prevention of dyslipidemia, hypertriglyceridemia, or cardiovascular disease, or for reducing triglyceride levels in the blood above normal levels. One embodiment of this specification provides the self-emulsifying pharmaceutical composition and / or modulated-release pharmaceutical composition described herein for the treatment and / or prevention of dyslipidemia, hypertriglyceridemia, or cardiovascular disease, or for reducing triglyceride levels in the blood above normal levels. One embodiment of this specification provides a method for treating and / or preventing dyslipidemia, hypertriglyceridemia, or cardiovascular disease, or for reducing triglyceride levels in the blood above normal levels, comprising administering the self-emulsifying pharmaceutical composition and / or modulated-release pharmaceutical composition described herein to a subject in need. In some embodiments, the subject is given a therapeutically effective amount of the self-emulsifying pharmaceutical composition and / or modulated-release pharmaceutical composition described herein. The therapeutically effective amount described herein can be determined by those skilled in the art or by a clinician based on the patient's weight, age, sex, health status, etc.

[0069] The beneficial effects that some embodiments of this specification may bring include, but are not limited to, the following: by preparing capsules encapsulating the active ingredient EPA-FFA into specific release-modifying coating formulations, which can disintegrate within 1 hour in buffered salt media with pH ≥ 3.5, the release-modifying coating formulation can significantly reduce intestinal side effects such as diarrhea and abdominal pain, and control the coefficient of variation. Furthermore, by preparing high-purity EPA-FFA into a self-emulsifying composition and encapsulating it in soft capsules, and then coating the outer surface of the capsule shell with a specific release-modifying coating to prepare a release-modifying drug composition, self-emulsification and release-modifying coating can exhibit a synergistic effect, significantly reducing the in vivo coefficient of variation of high-purity EPA-FFA, while improving bioavailability and reducing gastrointestinal side effects. It should be noted that different embodiments may produce different beneficial effects. In different embodiments, the beneficial effects that may occur can be any one or a combination of the above, or any other possible beneficial effects. Detailed Implementation

[0070] To more clearly illustrate the technical solutions of this disclosure, embodiments will be used to describe them below. It should be understood that the description of the embodiments is only for ease of understanding and is not intended to limit this disclosure to the specific embodiments shown. The headings in this disclosure are provided for convenience only and should not be construed as limiting this disclosure in any way. Embodiments shown under any heading can be combined with embodiments shown under any other heading. For those skilled in the art, various modifications, improvements, and corrections can be made to these embodiments without creative effort. Therefore, such modifications, improvements, and corrections still fall within the spirit and scope of the exemplary embodiments in this specification.

[0071] In order to improve the therapeutic effect of n-3 polyunsaturated fatty acid pharmaceutical compositions, ensure the stability of therapeutic effect among different individuals, and avoid gastrointestinal side effects, the applicant has studied different active ingredients and formulations in order to obtain n-3 polyunsaturated fatty acid pharmaceutical compositions with fewer gastrointestinal side effects, higher bioavailability, and more stable bioavailability among different individuals. This is accompanied to a certain extent by higher safety and more stable efficacy of the pharmaceutical compositions.

[0072] (1) Active component: EPA-FFA

[0073] With the goal of improving therapeutic efficacy and reducing the influence of food, the applicant investigated the bioavailability, coefficient of variation, and food effects of different active ingredients. Specifically, by studying the differences in pharmacokinetics between gastric-coated formulations of the active ingredients EPA-EE (Eicosapentaenoic Acid Ethyl Ester) and EPA-FFA in humans, rats, and beagle dogs, it was found that gastric-coated formulations with EPA-FFA as the active ingredient have improved bioavailability and can reduce the influence of food compared to EPA-EE.

[0074] (2) Adjusting the coating

[0075] Considering that gastric-soluble fish oil formulations, if released in the stomach, can irritate the stomach and cause significant gastric side effects such as hiccups and nausea, the applicant investigated formulations that do not release into the stomach in some embodiments of this disclosure, such as conventional enteric-coated formulations and delayed-release formulations. It was found that although conventional enteric-coated or delayed-release formulations solved gastric side effects such as hiccups and nausea, conventional enteric-coated or delayed-release formulations containing the active ingredient EPA-FFA could not maintain high bioavailability while controlling the coefficient of variation, and new intestinal side effects such as diarrhea and abdominal pain also occurred.

[0076] In light of the above results, the applicant further investigated other formulations and unexpectedly discovered that: when capsules encapsulating the active ingredient EPA-FFA are prepared into a specific modulated-release coating formulation, this specific modulated-release coating can disintegrate within 1 hour in a buffered salt medium with pH ≥ 3.5, but does not disintegrate within 120 minutes at pH 1.0-3.0 (the pH of the human stomach environment). This modulated-release coating formulation not only solves gastric side effects such as hiccups and nausea, but also significantly reduces intestinal side effects such as diarrhea and abdominal pain, and can control the coefficient of variation.

[0077] (3) Self-emulsifying and release-regulating coating

[0078] In some embodiments of this disclosure, in order to further reduce the inter-individual coefficient of variation and improve bioavailability, the applicant studied numerous factors, noting that self-emulsification affects the bioavailability and coefficient of variation of the active ingredient EPA-FFA. The applicant found that, on an empty stomach, the coefficient of variation of the self-emulsified gastric-soluble formulation of EPA-FFA was significantly higher than that of the conventional gastric-soluble formulation of the active ingredient EPA-FFA.

[0079] Furthermore, the applicant further investigated other formulations and unexpectedly discovered that when the active ingredient EPA-FFA is prepared into a self-emulsifying content and packaged into a specific release-modifying coating, due to the synergistic effect between the self-emulsification of EPA-FFA and the specific release-modifying coating, the formulation can not only significantly reduce the coefficient of variation, improve bioavailability, reduce intestinal side effects such as diarrhea and abdominal pain, and reduce gastric side effects such as hiccups and nausea when fasting, but also reduce the coefficient of variation and maintain high bioavailability after feeding.

[0080] Therefore, certain embodiments of this disclosure, by encapsulating the contents in soft capsules and coating the outer surface of the capsule shell with a specific release-modifying coating to prepare a modulated-release pharmaceutical composition, can reduce gastric side effects such as acid reflux and hiccups, and gastrointestinal side effects such as diarrhea and abdominal pain. Furthermore, certain embodiments of this disclosure, by preparing high-purity EPA-FFA into self-emulsifying soft capsules and coating the outer surface of the capsule shell with a specific release-modifying coating to prepare a modulated-release pharmaceutical composition, can significantly reduce the in vivo coefficient of variation of high-purity EPA-FFA, while simultaneously improving bioavailability and reducing gastric side effects such as acid reflux and hiccups, and gastrointestinal side effects such as diarrhea and abdominal pain.

[0081] In some embodiments, the pharmaceutical compositions of this disclosure comprise EPA-FFA as an active ingredient. As used herein, “EPA-FFA” refers to eicosapentaenoic acid (EPA) free fatty acid, or “eicosapentaenoic acid free acid” or “EPA free acid”. As used herein, “EPA-EE” refers to eicosapentaenoic acid ethyl ester, or “EPA ethyl ester”.

[0082] In some embodiments, the high-purity EPA-FFA disclosed herein can be used to prepare drugs for the treatment and / or prevention of cardiovascular diseases such as dyslipidemia, hypertriglyceridemia, myocardial infarction, stroke, coronary revascularization, and angina pectoris, or to reduce the level of triglycerides in the blood that exceeds normal levels.

[0083] The term "treatment" in relation to a given disease or condition includes, but is not limited to, suppressing the disease or condition, such as preventing its development; alleviating the disease or condition, such as causing its remission or reduction; or alleviating symptoms caused by the disease or condition, such as relieving, preventing, or treating the symptoms of the disease or condition. The term "prevention" in relation to a given disease or condition means, if it has not occurred, preventing the onset of the disease or condition, preventing the occurrence of the disease or condition in a subject who may be susceptible to it but has not yet been diagnosed with it; and / or, if it already exists, preventing further development of the disease / condition, or preventing recurrence of the disease or condition in a subject who has been treated.

[0084] In some embodiments, the pharmaceutical compositions disclosed herein may be used in combination with other drugs. In some embodiments, the pharmaceutical compositions disclosed herein may be used in combination with statins.

[0085] In some embodiments, this disclosure provides a pharmaceutical composition comprising EPA-FFA.

[0086] In some embodiments, EPA-FFA is present in the pharmaceutical compositions disclosed herein at a mass of about 5 mg to about 5000 mg.In some embodiments, the amount of EPA-FFA can be from about 7 mg to about 4800 mg, for example, about 7 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about... 425mg, approximately 450mg, approximately 475mg, approximately 500mg, approximately 525mg, approximately 550mg, approximately 575mg, approximately 600mg, approximately 625mg, approximately 650mg, approximately 675mg, approximately 700mg, approximately 725mg, approximately 750mg, approximately 775mg, approximately 800mg, approximately 825mg, approximately 850mg, approximately 875mg, approximately 900mg, approximately 925mg, approximately 950mg, approximately 975mg, approximately 1000mg, approximately 1025mg, approximately 1050mg, approximately 1075mg, approximately 1100mg, approximately 1125mg, approximately 1150mg, approximately 1175mg, approximately 1200mg, approximately 1225mg Approximately 1250mg, approximately 1275mg, approximately 1300mg, approximately 1325mg, approximately 1350mg, approximately 1375mg, approximately 1400mg, approximately 1425mg, approximately 1450mg, approximately 1475mg, approximately 1500mg, approximately 1525mg, approximately 1550mg, approximately 1575mg, approximately 1600mg, approximately 1625mg, approximately 1650mg, approximately 1675mg, approximately 1700mg, approximately 1725mg, approximately 1750mg, approximately 1775mg, approximately 1800mg, approximately 1825mg, approximately 1850mg, approximately 1875mg, approximately 1900mg, approximately 1925mg, approximately 1950mg, approximately 1975mg Approximately 2000mg, approximately 2025mg, approximately 2050mg, approximately 2075mg, approximately 2100mg, approximately 2125mg, approximately 2150mg, approximately 2175mg, approximately 2200mg, approximately 2225mg, approximately 2250mg, approximately 2275mg, approximately 2300mg, approximately 2325mg, approximately 2350mg, approximately 2375mg, approximately 2400mg, approximately 2425mg, approximately 2450mg, approximately 2475mg, approximately 2500mg, approximately 2700mg, approximately 3000mg, approximately 3200mg, approximately 3500mg, approximately 3800mg, approximately 4000mg, approximately 4200mg, approximately 4500mg, or approximately 4800mg.

[0087] In some embodiments, the pharmaceutical compositions disclosed herein may contain EPA-FFA as the sole active ingredient.

[0088] In some embodiments, the pharmaceutical compositions of this disclosure may comprise high-purity EPA-FFA. As used herein, the term "high-purity EPA-FFA" means that the mass fraction of EPA-FFA is at least about 80% based on the total mass of all fatty acids in the pharmaceutical composition. In some embodiments, in this high-purity EPA-FFA, the mass fraction of EPA-FFA, based on the total mass of all fatty acids, may be not less than about 80%, not less than about 85%, not less than about 90%, not less than about 95%, not less than about 96%, not less than about 96.2%, not less than about 96.5%, not less than about 96.7%, not less than about 97%, not less than about 97.3%, not less than about 97.5%, not less than about 97.8%, not less than about 98%, not less than about 98.3%, not less than about 98.5%, not less than about 98.7%, not less than about 99%, not less than about 99.2%, or not less than about 99.5%. In some embodiments, the high-purity EPA-FFA preferably comprises about 90% EPA-FFA by mass fraction based on the total mass of all fatty acids. In some embodiments, the high-purity EPA-FFA preferably comprises about 93% EPA-FFA by mass fraction based on the total mass of all fatty acids. In some embodiments, the high-purity EPA-FFA preferably comprises about 95% EPA-FFA by mass fraction based on the total mass of all fatty acids. In some embodiments, the high-purity EPA-FFA preferably comprises about 96.5% EPA-FFA by mass fraction based on the total mass of all fatty acids. In some embodiments, the high-purity EPA-FFA preferably comprises about 97% EPA-FFA by mass fraction based on the total mass of all fatty acids. In some embodiments, the high-purity EPA-FFA preferably comprises about 97.8% EPA-FFA by mass fraction based on the total mass of all fatty acids. Unless otherwise specified, the purity of EPA-FFA in this disclosure refers to the mass fraction of EPA-FFA based on the total mass of all fatty acids in the pharmaceutical composition.

[0089] In some embodiments, the high-purity EPA-FFA of this disclosure may further contain fatty acids other than EPA-FFA. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure may further contain fatty acids other than EPA-FFA in mass fractions not exceeding 20%, 18%, 16%, 14%, 12%, 11.5%, 11.25%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 1.5%, 1%, 0.5%, or 0.25%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably includes fatty acids other than EPA-FFA at a mass fraction of no more than about 5%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably includes fatty acids other than EPA-FFA at a mass fraction of no more than about 4%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably includes fatty acids other than EPA-FFA at a mass fraction of no more than about 3.5%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably includes fatty acids other than EPA-FFA at a mass fraction of no more than about 3%. In some embodiments, "fatty acids other than EPA-FFA" may include C21:5n-3. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure comprises C21:5n-3 with a mass fraction not exceeding about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.05%, about 0.045%, about 0.04%, or about 0.03%. In some embodiments, "fatty acids other than EPA-FFA" may include C22:6n-3. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure comprises C22:6n-3 with a mass fraction not exceeding about 0.3%, about 0.2%, about 0.1%, about 0.05%, about 0.04%, or about 0.03%.

[0090] In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure comprises EPA-FFA trans isomers with a mass fraction not exceeding about 5%, 4.5%, 4%, 3.5%, 3%, 2.8%, 2.5%, 2.2%, 2%, 1.8%, 1.5%, 1.2%, 1%, 0.8%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably comprises EPA-FFA trans isomers with a mass fraction not exceeding about 2.2%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably comprises EPA-FFA trans isomers with a mass fraction not exceeding about 2%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably includes an EPA-FFA trans isomer with a mass fraction not exceeding about 1%. In some embodiments, based on the total mass of all fatty acids, the high-purity EPA-FFA of this disclosure preferably includes an EPA-FFA trans isomer with a mass fraction not exceeding about 0.6%. In some embodiments, the high-purity EPA-FFA of this disclosure preferably does not contain an EPA-FFA trans isomer.

[0091] In some embodiments, the pharmaceutical composition of high-purity EPA-FFA can be prepared as an oral dosage form. In some embodiments, since EPA-FFA itself is an oily liquid with a fishy odor and is easily oxidized, the pharmaceutical composition of this disclosure is preferably prepared in capsule form. The capsule form of the pharmaceutical composition can mask the unpleasant fish oil odor and protect EPA-FFA from oxidation. In some embodiments, the capsule shell encapsulates contents containing high-purity EPA-FFA. In some embodiments, the contents containing high-purity EPA-FFA may include high-purity EPA-FFA and pharmaceutically acceptable excipients. More information about high-purity EPA-FFA and pharmaceutically acceptable excipients can be found in the description of other parts of this disclosure.

[0092] In some embodiments, the capsule shell of this disclosure may include a soft capsule shell, and suitable formulations for soft capsule shells are well known in the art. In some embodiments, the capsule shell of this disclosure may include a film-forming agent and a plasticizer.

[0093] In some embodiments, the film-forming agent for the capsule shell of this disclosure may be gelatin. In some embodiments, the gelatin in this disclosure is not particularly limited and may include type A gelatin, type B gelatin, enzymatic gelatin, hide gelatin (e.g., calfskin, pigskin) and / or bone gelatin (e.g., calf bone, pig bone) used alone or in combination.

[0094] In some embodiments, the mass fraction of gelatin, based on the total mass of the gelatin capsule shell, can be about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 55% to about 80%, about 55% to about 75%, about 55% to about 70%, about 55% to about 65%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 65% to about 75%, or any single value or subrange thereof. In some embodiments, the mass fraction of gelatin, based on the total mass of the gelatin capsule shell, can preferably be about 60% to about 75%, more preferably about 65% to about 75%.

[0095] In some embodiments, gelatin is present in the pharmaceutical compositions of this disclosure at a mass of about 50 mg to about 500 mg. In some embodiments, the mass of gelatin may be about 60 mg to about 490 mg, about 70 mg to about 460 mg, about 90 mg to about 450 mg, about 100 mg to about 430 mg, about 110 mg to about 400 mg, about 115 mg to about 390 mg, about 120 mg to about 380 mg, about 125 mg to about 370 mg, about 130 mg to about 350 mg, about 135 mg to about 330 mg, about 140 mg to about 310 mg, about 145 mg to about 300 mg, about 150 mg to about 500 mg. 280mg, about 155mg-about 270mg, about 160mg-about 250mg, about 165mg-about 230mg, about 170mg-about 200mg, about 175mg-about 220mg, about 180mg-about 240mg, about 183mg-about 250mg, about 183mg-about 255mg, about 190mg-about 280mg, about 200mg-about 300mg, about 230mg-about 300mg, about 250mg-about 310mg, or about 255mg-about 350mg.

[0096] In some embodiments, the thickness of the gelatin capsule shell in the pharmaceutical composition disclosed herein may include, but is not limited to, any one of the following: about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 0.2-1.0 mm, about 0.2-0.6 mm, about 0.2-0.5 mm, about 0.4-1.6 mm, about 0.5-1.0 mm, about 0.6-0.9 mm, and about 0.5-1.2 mm.

[0097] In some embodiments, the mass fraction of the plasticizer, based on the total mass of the capsule shell, can be about 10% to about 40%, 10% to 50%, 20% to 50%, 20% to 40%, 10% to about 30%, 10% to about 20%, about 15% to about 40%, about 15% to about 30%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 25% to about 40%, about 25% to about 35%, or about 30% to about 40%, or any single value or subrange thereof. In some embodiments, the mass fraction of the plasticizer, based on the total mass of the capsule shell, can preferably be about 20% to about 35%, more preferably about 30% to about 35%.

[0098] In some embodiments, the plasticizer for the gelatin capsule shell in this disclosure may include glycerin. In some embodiments, other exemplary plasticizers may include, but are not limited to, polyol plasticizers (e.g., diglyceride, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, sorbitol, polyethylene glycol, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, and ethanolamines and mixtures thereof). In some embodiments, other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small molecule organic compounds, low molecular weight polyols having aliphatic hydroxyl groups, ester plasticizers, ethylene glycol ethers, polypropylene glycol, multiblock polymers, monoblock polymers, citrate plasticizers, and triacetin.

[0099] In some embodiments, the mass fraction of glycerol, based on the total mass of the capsule shell, can be about 10% to about 40%, 10% to 50%, 20% to 50%, 20% to 40%, 10% to about 30%, 10% to about 20%, about 15% to about 40%, about 15% to about 30%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 25% to about 40%, about 25% to about 35%, or about 30% to about 40%, or any single value or subrange thereof. In some embodiments, the mass fraction of glycerol, based on the total mass of the capsule shell, can preferably be about 20% to about 35%, more preferably about 30% to about 35%.

[0100] In some embodiments, the mass fraction of other plasticizers, based on the total mass of the capsule shell, can be about 10% to about 40%, 10% to 50%, 20% to 50%, 20% to 40%, 10% to about 30%, 10% to about 20%, about 15% to about 40%, about 15% to about 30%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 25% to about 40%, about 25% to about 35%, or about 30% to about 40%, or any single value or subrange thereof. In some embodiments, the mass fraction of other plasticizers, based on the total mass of the capsule shell, can preferably be about 20% to about 35%, more preferably about 30% to about 35%.

[0101] In some embodiments, the capsule shell may further comprise monosaccharides, such as glucose, and / or disaccharides, such as maltose or lactose. These substances may suitably enhance the strength of the capsule shell. In some embodiments, based on the total mass of the capsule shell, the mass fraction of monosaccharides and / or disaccharides in the capsule shell may be about 0.01% to about 4%, or about 0.1% to about 3%, or about 0.2% to about 2%, or about 0.01% to about 0.1%, or about 0.05% to about 0.5%, or about 0.1% to about 0.2%, or any single value or subrange thereof.

[0102] In some embodiments, the capsule shell may further include a stabilizer. In some embodiments, the stabilizer may include at least one of an antioxidant, an antibacterial agent, and a crosslinking inhibitor. In some embodiments, the mass fraction of the stabilizer may be about 0.05% to about 5%, about 0.1% to about 3%, or about 0.2% to about 2%, or any single value or subrange thereof, based on the total mass of the capsule shell. In some embodiments, the capsule shell of this disclosure may not include a stabilizer.

[0103] In some embodiments, the capsule shell may also optionally contain additives, such as colorants, flavorings, sweeteners, fillers, diluents, pH adjusters, or other pharmaceutically acceptable excipients or additives (e.g., synthetic dyes and inorganic oxides).

[0104] Exemplary colorants may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown. In some embodiments, the color of the dosage form may indicate the ingredients contained therein (e.g., one or more active ingredients).

[0105] In some embodiments, the capsule shell may comprise: (a) gelatin, in a mass fraction of about 50%-about 80%, about 50%-about 75%, about 50%-about 70%, about 50%-about 65%, about 50%-about 60%, about 55%-about 80%, about 55%-about 75%, about 55%-about 70%, about 55%-about 65%, about 60%-about 80%, about 60%-about 75%, about 60%-about 70%, about 65%-about 75%; and (b) a plasticizer, in a mass fraction of 10%-about 40%, about 15%-about 40%, about 20%-about 40%, based on the total weight of the capsule shell. 20% to about 35%, about 20% to about 30%, about 25% to about 40%, about 25% to about 35%, about 30% to about 35%, or about 30% to about 40%, and (c) a solvent (e.g., water) having a mass fraction of about 1% to about 15%, about 2% to about 14%, about 3% to about 13%, about 4% to about 12%, about 5% to about 11%, about 6% to about 12%, about 6% to about 10%, about 7% to about 9%, about 8% to about 9%, about 8% to about 10%, about 8% to about 11%, about 8% to about 12%, about 8% to about 13%, about 9% to about 14%, or about 10% to about 15%, based on the total weight of the capsule shell. In some embodiments, the capsule shell preferably comprises: (a) gelatin, in a mass fraction of about 60% to about 75% based on the total weight of the capsule shell, more preferably about 65% to about 75%; (b) a plasticizer, in a mass fraction of about 20% to about 35% based on the total weight of the capsule shell, more preferably about 30% to about 35%; and (c) water, in a mass fraction of about 6% to about 12% based on the total weight of the capsule shell, more preferably about 7% to about 9%.

[0106] In some embodiments, the disintegration time of the uncoated soft capsule is approximately 3 min to approximately 20 min, approximately 4 min to approximately 18 min, approximately 5 min to approximately 16 min, approximately 6 min to approximately 15 min, approximately 7 min to approximately 14 min, approximately 8 min to approximately 13 min, approximately 9 min to approximately 12 min, or approximately 10 min to approximately 12 min. Here, uncoated soft capsule refers to a soft capsule without a coating.

[0107] In one embodiment, the capsule containing the contents is prepared by a method comprising the following steps: (a) preparing the contents, said contents comprising high-purity EPA-FFA; and (b) encapsulating the contents of step (a) in a capsule shell. In one embodiment, the encapsulation method according to step (b) may further include a sub-step of preparing the capsule, such as mixing gelatin and a plasticizer. In one embodiment, the gelatin and plasticizer are stirred and mixed in a suitable solvent (e.g., water, propylene glycol, a mixture of water and an organic acid, etc.) to form a gel solution.

[0108] Encapsulation of the contents can be accomplished using any conventional method, such as drop encapsulation and compression encapsulation. In drop encapsulation, the soft capsule material (generally referred to as a gel) and the drug solution (i.e., the contents) are dripped separately from the inner and outer layers of a double-layered dropper, allowing a measured amount of gel to encapsulate a measured amount of drug solution. The drops are then poured into a cooling liquid to form spherical or near-spherical shapes, and after cooling and solidification, capsules are obtained. In compression encapsulation, the gel is first formed into a film of a certain thickness, and then the drug solution is injected through a spray nozzle between two layers of film and compressed. Exemplary compression encapsulation methods can include roll-to-roll encapsulation and flat-plate encapsulation. The aforementioned roll-to-roll encapsulation and flat-plate encapsulation can be performed using commercially available rotary soft capsule preparation devices or flat-plate soft capsule preparation devices.

[0109] In some embodiments, the thickness of the tape used in the capsule preparation process (e.g., in a compression process) can be adjusted to control the thickness of the capsule shell. More information regarding capsule shell thickness can be found above.

[0110] In some embodiments, the capsules (e.g., after encapsulation of contents) may be dried. The purpose of drying is to remove excess water from the capsule shell after encapsulation of contents. In some embodiments, drying may be carried out at a relative humidity of about 5% to about 40%, about 10% to about 30%, or about 15% to about 25%, at a temperature of about 15% to about 40%, about 10% to about 30%, or about 15% to about 25%. In some embodiments, the duration of drying may be about 12 hours to about 168 hours, about 18 hours to about 120 hours, about 24 hours to about 72 hours, about 24 hours, about 48 hours, about 72 hours, or any subrange or single value thereof. In some embodiments, the drying of the capsules may be carried out in air (without any specific control over the nitrogen or oxygen content).

[0111] Fish oil softgels, when released into the stomach, can irritate the stomach, causing noticeable hiccups and a fishy odor. According to the product information for the marketed drug LOAAZA, the incidence of belching as an adverse reaction is 4%, higher than the 1% in the placebo group. Since the active pharmaceutical ingredients in fish oil softgels are all fats, poor or insufficient absorption can easily lead to intestinal side effects, similar to steatorrhea, including increased intestinal motility, abdominal pain, and diarrhea. According to the product information for the enteric-coated fish oil product Epanova, at a daily dose of 2g, 7% of patients experienced diarrhea, and 3% experienced abdominal pain or discomfort; at a daily dose of 4g, these side effects increased to 15% and 5%, respectively. At both daily doses, upper gastrointestinal related side effects such as nausea (4% and 6%, respectively) and belching (3% and 3%) were relatively minor.

[0112] Some embodiments of this disclosure aim to address the gastric side effects of the aforementioned gastric-coated fish oil products and the intestinal side effects of the aforementioned enteric-coated fish oil products. In some embodiments, this disclosure provides a modulated-release pharmaceutical composition.

[0113] The 2020 edition of the Chinese Pharmacopoeia, Part IV, Guideline 9013, stipulates that enteric-coated preparations are preparations that do not release or release almost no drug in a specified acidic medium (pH 1.0-3.0), but release most or all of the drug in a pH 6.8 phosphate buffer solution within a required time. Therefore, conventional enteric-coated preparations generally have the following characteristics: (1) No gastric release: They remain stable under the action of gastric acid and will not be released in the stomach; (2) Release in the small intestine: When the drug reaches the small intestine, the enteric coating will dissolve in the pH environment of the small intestine, releasing the drug.

[0114] In some embodiments, the modulated-release pharmaceutical compositions of this disclosure differ from conventional enteric-coated formulations. These compositions do not release or release almost no drug in an acidic dissolution medium with pH 1.0-3.0 or in 0.1 mol / L hydrochloric acid solution for 120 min, but release the drug completely or substantially completely within 1 h in a buffered salt medium with pH ≥ 3.5. The buffered salt medium with pH = 3.5 can be a phosphate-potassium dihydrogen phosphate buffer. Therefore, some pharmaceutical compositions of this disclosure have a lower pH value for complete or substantial release than conventional enteric-coated formulations, making them unconventional enteric-coated formulations.

[0115] In some embodiments, the modulated-release pharmaceutical composition releases the drug completely or almost completely within 1 hour in a buffered salt medium with a pH of 3.5-4.5. For example, the pharmaceutical composition releases the drug completely or almost completely within 1 hour in buffered salt media with pH values ​​of 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5. The buffered salt media with different pH values ​​can be prepared according to the buffered salt media preparation methods specified in General Chapter 8004 of the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia. If a buffered salt medium with the required pH is not specified in the 2020 edition of the Chinese Pharmacopoeia or the United States Pharmacopeia, a buffered salt medium with the closest pH can be selected, and acid or alkali can be added to it to prepare a buffered salt medium with the required pH. Buffer salt media with different pH values ​​can also be prepared according to the preparation method of dissolution media specified in the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms". If the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms" does not specify a dissolution medium with the required pH, a dissolution medium with a close pH can be selected, and acid or alkali can be added to it to prepare a dissolution medium with the required pH.

[0116] In some embodiments, the modulated-release drug composition preferably releases the drug completely or almost completely within 40 min, 38 min, 35 min, 30 min, 28 min, or 25 min in a buffered salt medium at pH 4.5. The buffered salt medium at pH 4.5 may be an acetate-sodium acetate buffer solution.

[0117] In some embodiments, the modulated-release drug composition releases the drug completely or almost completely within 60 minutes in a buffered salt medium at pH 6.8, preferably within 50 minutes, 40 minutes, or 30 minutes. The buffered salt medium at pH 6.8 may be a phosphate buffer.

[0118] The reason why the modulated-release pharmaceutical composition disclosed herein achieves its technical effect is related to the modulated-release coating. The modulated-release coating, to a certain extent, prevents the release of the pharmaceutical composition in the acidic environment of the stomach (pH 1.0-3.0), or at least almost prevents it from releasing the drug, while in the human body at a higher pH environment (pH ≥ 3.5), it begins to release the drug more rapidly. It is believed that this relatively higher pH environment in the human body may be below the pylorus or in the upper intestinal tract (e.g., the duodenum). This causes the pharmaceutical composition to rapidly disintegrate and release its contents after passing through the stomach, and to completely disintegrate within 1 hour, allowing the contents to be completely released into the body. This drug release characteristic of the present disclosure enables the pharmaceutical composition to avoid gastric side effects such as acid reflux and belching, as well as intestinal side effects such as diarrhea and abdominal pain caused by incomplete absorption of the active ingredient.

[0119] In some embodiments, the modulated-release pharmaceutical composition may include a modulated-release coating applied to the outer surface of a capsule shell. In some embodiments, the capsule shell may encapsulate contents containing high-purity EPA-FFA. In some embodiments, the contents containing high-purity EPA-FFA may include high-purity EPA-FFA and pharmaceutically acceptable excipients. Further details regarding high-purity EPA-FFA, pharmaceutically acceptable excipients, and capsule shells can be found in other parts of this disclosure.

[0120] In some embodiments, the release-modifying coating of this disclosure can remain undisintegrated for 120 minutes in an acidic dissolution medium with a pH of 1.0-3.0 or in a 0.1 mol / L hydrochloric acid solution for 120 minutes, and disintegrate within 1 hour in a buffer salt medium with a pH ≥ 3.5, thereby simultaneously avoiding gastric and intestinal side effects. In some embodiments, the capsule shell coated with the release-modifying coating remains undisintegrated for 120 minutes in an acidic dissolution medium with a pH of 1.0-3.0 or in a 0.1 mol / L hydrochloric acid solution for 120 minutes, and disintegrates within 1 hour in buffer salt media with pH = 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, and 4.5.

[0121] In some embodiments, the release-modifying coating can disintegrate within 1 hour in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with the release-modifying coating can disintegrate within 50 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with the release-modifying coating can disintegrate within 40 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with the release-modifying coating can disintegrate within 38 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with the release-modifying coating can disintegrate within 35 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with the release-modifying coating can disintegrate within 30 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with the release-modifying coating can disintegrate within 28 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with the release-modifying coating can disintegrate within 25 minutes in a buffered salt medium at pH 4.5. In some embodiments, the capsule shell coated with a release modulating coating can disintegrate within 20 minutes in a buffered salt medium at pH 4.5.

[0122] In some embodiments, the release-modifying coated capsule shells exhibit no disintegration for 120 minutes in an acidic dissolution medium with pH 1.0-3.0 or in a 0.1 mol / L hydrochloric acid solution, and disintegrate within 1 hour in a buffer salt medium with pH ≥ 3.5. In other embodiments, the release-modifying coated capsule shells exhibit no disintegration for 120 minutes in an acidic dissolution medium with pH 1.0-3.0 or in a 0.1 mol / L hydrochloric acid solution, and disintegrate within 1 hour in buffer salt media with pH = 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5.

[0123] In some embodiments, the release-modifying coated capsule shell can disintegrate within 1 hour in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coated capsule shell can disintegrate within 50 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coated capsule shell can disintegrate within 40 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coated capsule shell can disintegrate within 38 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coated capsule shell can disintegrate within 35 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coated capsule shell can disintegrate within 30 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coated capsule shell can disintegrate within 28 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-modifying coated capsule shell can disintegrate within 25 minutes in a buffered salt medium at pH 4.5. In some embodiments, the release-coated capsule shell can disintegrate within 20 minutes in a buffered salt medium at pH 4.5.

[0124] In some embodiments, the release coating and the capsule shell coated with the release coating can disintegrate simultaneously.

[0125] This disclosure describes methods for preparing dissolution media under different pH conditions. For example, methods for preparing buffer salt media are well-known in the art, and the preparation methods disclosed in the *Chinese Pharmacopoeia* or the *Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms* can be used as references. An exemplary method for preparing a dissolution media is as follows:

[0126] Acidic media with a pH of 1.0-2.9 can be hydrochloric acid, citric acid, or acetic acid solutions. Acidic media with a pH of 3.0 can be buffer salt media with a pH of 3.0.

[0127] An acidic medium with a pH of 1.0-2.2 can be a hydrochloric acid solution. The "Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms" specifies the following preparation method for the dissolution medium: Take the amount of hydrochloric acid specified in the table below, dilute with water to 1000 mL, and shake well. Table 1: Preparation of Hydrochloric Acid Solution

[0128] If a dissolution medium with pH = 2.3-2.9 is not specified in the "Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms", a dissolution medium with pH = 2.2 can be selected. Alkali can be added to adjust the pH to the required level (e.g., pH = 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9).

[0129] A buffer salt medium with pH=3.0 can be a potassium phthalate-hydrochloric acid solution. The United States Pharmacopeia (USP) specifies: place 50 mL of potassium phthalate solution in a 200 mL volumetric flask, add 22.3 mL of 0.2 mol / L hydrochloric acid solution, and then add water to a final volume of 200 mL to obtain a potassium phthalate-hydrochloric acid solution with pH=3.0.

[0130] A buffer salt medium with pH=3.5 can be a phosphate-potassium dihydrogen phosphate buffer. The European Pharmacopoeia specifies: dissolve 68.0 g of potassium dihydrogen phosphate in water, and dilute to 1000.0 mL with the same solvent. Adjust the pH with phosphate to obtain a phosphate-potassium dihydrogen phosphate buffer with pH=3.5.

[0131] Acetate buffers can be prepared using buffer salts with pH values ​​of 4.0 and 4.5. The "Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms" specifies the preparation of acetate buffers as follows: Take 120.0 g (114 mL) of glacial acetic acid and dilute it with water to 1000 mL to obtain a 2 mol / L acetic acid solution; take the amount of sodium acetate specified in the table below, dissolve it in water and dilute it to 1000 mL, shake well, and mix it with the acetic acid solution to obtain the acetate buffer. Table 2: Preparation of Acetate Buffers

[0132] In some embodiments, the buffer salt medium with pH=4.5 can be an acetate-sodium acetate buffer solution. The 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 8004, specifies: Take 18g of sodium acetate, add 9.8mL of glacial acetic acid, and then dilute with water to 1000mL to obtain an acetate-sodium acetate buffer solution (pH 4.5).

[0133] A phosphate buffer medium with a pH of 6.8 can be used. The 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 8004, specifies: 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, 118 mL of 0.2 mol / L sodium hydroxide solution, diluted with water to 1000 mL, and shaken well, yields a phosphate buffer solution (pH 6.8).

[0134] The term "non-release" in this disclosure means that the drug is not detected in the dissolution medium (release amount is 0). The term "virtually non-release" in this disclosure means that the release amount is very small (e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%).

[0135] The term "substantially complete release" in this disclosure means a release of more than 90%, such as 93%, 95%, 98%, 99%, or 99.5%. The term "release amount" in this disclosure refers to the proportion of the mass of the drug released from the capsule shell into the dissolution medium relative to the total mass of the drug in the capsule shell.

[0136] This disclosure reveals that capsule shells with modulated-release coatings and / or modulated-release coatings possessing the specific disintegration characteristics of this disclosure can be prepared using coating film-forming agents with the following characteristics: the modulated-release coating may contain two types of coating film-forming agents, one being a water-poorly soluble coating film-forming agent or an enteric coating film-forming agent, wherein the water-poorly soluble coating film-forming agent is poorly soluble or insoluble in media within the pH range of the gastrointestinal tract of an animal (e.g., human body), and the enteric coating film-forming agent is insoluble in acidic media within the pH range of the stomach of an animal (e.g., human body) (pH 1.0-3.0) and is mostly or completely soluble in buffer salt media within the pH range of the intestinal tract (pH ≥ 6.8). Unless otherwise specified, the media within the human gastrointestinal pH range of this disclosure refer to acidic media with pH = 1.0-3.0 and buffered salt media with pH > 3.0 (e.g., pH = 3.5, 4.5, 6.8). The preparation of these media is based on the *Chinese Pharmacopoeia*, the *Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms*, and the *United States Pharmacopeia*. Further descriptions of exemplary acidic and buffered salt media can be found in other parts of this disclosure. Further descriptions of poorly soluble, insoluble, and largely soluble media can be found in other parts of this disclosure. Another type is an acid-swellable coating film-forming agent, which swells and expands in buffered salt media with pH = 3.0-4.5 or pH = 3.5-4.5, leading to disintegration of the release-modifying coating and / or the capsule shell coated with the release-modifying coating. For example, the volume expansion is an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, or 20 times relative to the original volume. When the release-modifying coating is placed in an aqueous medium (e.g., an acidic medium with pH ≥ 3.0, a buffered salt medium, or gastrointestinal digestive fluid), the acid-swellable coating film-forming agent absorbs water and expands in volume, causing the release-modifying coating to rupture. Cracks and pores form on the release-modifying coating, and water in the medium enters the interior of the release-modifying coating through the cracks and pores, causing the capsule shell to dissolve and rupture. This allows the contents to be continuously released into the medium through the ruptured capsule shell and release-modifying coating until the capsule shell and release-modifying coating disintegrate, and the contents are completely released into the medium.

[0137] In some embodiments, the modulated coating of this disclosure comprises a modulated polymer and an acid-swellable coating film-forming agent. The modulated polymer comprises at least one of a water-poorly soluble coating film-forming agent and an enteric coating film-forming agent. The water-poorly soluble coating film-forming agent is a polymeric film-forming agent that is poorly soluble or insoluble in water in media within the pH range of the human gastrointestinal tract. In some embodiments, the water-poorly soluble coating film-forming agent may comprise at least one of ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer, and ethylene-vinyl acetate copolymer. In some embodiments, the water-poorly soluble coating film-forming agent may comprise at least one of ethyl cellulose and ethyl acrylate-methyl methacrylate copolymer. In some embodiments, the enteric coating film-forming agent is a polymeric film-forming agent that is insoluble in acidic media within the pH range of the human stomach (pH 1.0-3.0) but soluble in buffer salt media within the pH range of the human intestinal tract (pH ≥ 6.8). In some embodiments, the enteric coating film-forming agent may comprise at least one of cellulose acetate phthalate (CAP), acrylic resin, and hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the enteric coating film-forming agent may include at least one of cellulose acetate phthalate (CAP) and acrylic resin. In some embodiments, the acid-swellable coating film-forming agent is a polymeric film-forming agent that expands in volume after absorbing water in an acidic medium with pH = 3.0-4.5. In some embodiments, the acid-swellable coating film-forming agent is a polymeric film-forming agent that expands in volume after absorbing water in an acidic medium with pH = 3.5-4.5. In some embodiments, the acid-swellable coating film-forming agent may include at least one of alginate and pectin. In some embodiments, the acid-swellable coating film-forming agent may include at least one of sodium alginate, potassium alginate, ammonium alginate, and pectin. In some embodiments, the acid-swellable coating film-forming agent may include at least one of sodium alginate and potassium alginate.

[0138] In some embodiments, the acid-swellable coating film-forming agent expands in volume after absorbing water in an acidic medium with pH = 3.0-4.5. In some embodiments, the acid-swellable coating film-forming agent is a polymeric film-forming agent that expands in volume after absorbing water in an acidic medium with pH = 3.5-4.5. In some embodiments, the acid-swellable coating film-forming agent expands in volume by about 0 to about 20 times, about 1 to about 19 times, about 2 to about 18 times, about 3 to about 17 times, about 4 to about 16 times, about 5 to about 15 times, about 6 to about 14 times, about 7 to about 13 times, about 8 to about 12 times, about 9 to about 11 times, about 10 to about 12 times, about 10 to about 13 times, about 10 to about 14 times, about 10 to about 15 times, about 10 to about 16 times, about 10 to about 17 times, about 10 to about 18 times, about 10 to about 19 times, about 10 to about 20 times, or any single value or subrange thereof. When the release-modifying coating is placed in a medium containing water (e.g., an acidic medium with pH ≥ 3.0, a buffered salt medium, or the gastrointestinal tract), the acid-swellable coating film-forming agent absorbs water and expands in volume to the aforementioned range, causing the release-modifying coating to rupture. Cracks and pores are formed on the release-modifying coating, and water in the medium enters the interior of the release-modifying coating through the cracks and pores, causing the capsule shell to dissolve and rupture. This allows the contents to be continuously released into the medium through the ruptured capsule shell and release-modifying coating until the capsule shell and release-modifying coating disintegrate and the contents are completely released into the medium.

[0139] In some embodiments, the modulated coating comprises a water-insoluble film-forming agent and alginate. In some embodiments, the modulated coating comprises a water-insoluble film-forming agent and sodium alginate.

[0140] In some embodiments, the mass ratio of the water-insoluble coating film-forming agent to sodium alginate is about (60-95):(5-40), about (62-93):(7-37), about (65-90):(10-35), about (67-88):(12-33), about (70-86):(14-30), about (72-85):(15-28), about (73-83):(17-27), about (75-80):(20-25), about (78-80):(20-22), about (80-82):(18-20), about (82-85):(15-18), about (85-90):(10-15), about (88-90):(10-12), about (73-82):(18-27), or any single value or subrange thereof.

[0141] In some embodiments, the mass fraction of the water-insoluble coating film-forming agent may include about 73% to about 82%, about 70% to about 85%, about 65% to about 90%, or any single value or subrange thereof, based on the total mass of the water-insoluble coating film-forming agent and sodium alginate.

[0142] In some embodiments, the mass fraction of sodium alginate may include about 20% to about 25%, about 18% to about 28%, about 18% to about 30%, about 15% to about 30%, about 10% to about 35%, or any single value or subrange thereof, based on the total mass of the water-insoluble coating film-forming agent and sodium alginate.

[0143] In some embodiments, the water-insoluble coating film-forming agent may be mixed with other excipients, exemplary excipients including plasticizers and / or emulsifiers.

[0144] In some embodiments, the water-insoluble coating film-forming agent may be mixed with a solvent, with water being an exemplary solvent.

[0145] In some embodiments, the mass fraction of the water-insoluble film-forming agent may include about 70% to about 99%, about 75% to about 95%, about 75% to about 90%, about 80% to about 90%, about 70% to about 85%, or any single value or subrange thereof, based on the total mass of the water-insoluble film-forming agent and other excipients in the coating.

[0146] In some embodiments, the modulated coating comprises ethyl cellulose and sodium alginate.

[0147] In some embodiments, the emulsifier mixed with ethyl cellulose may include at least one selected from fatty acid polyglycerides, medium-chain triglycerides, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, propylene glycol monoesters or diesters of fats and fatty acids, sodium lauryl sulfate, and sorbitan monostearate. In some embodiments, the emulsifier mixed with ethyl cellulose preferably includes medium-chain triglycerides. In some embodiments, the mass fraction of the emulsifier may include, based on the total mass of ethyl cellulose and other excipients in the coating, about 0.1% to about 15%, about 0.2% to about 13%, about 0.3% to about 12%, about 0.4% to about 10%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 5%, about 0.6% to about 4.8%, about 0.7% to about 4.5%, about 0.8% to about 4%, about 0.9% to about 3.8%, about 1% to about 3.5%, about 1.2% to about 3.3%, about 1.5% to about 3%, about 1.8% to about 2.8%, about 2% to about 5%, about 2.2% to about 5%, about 2.5% to about 5%, or any single value or subrange thereof.

[0148] In some embodiments, the plasticizer mixed with ethyl cellulose may include at least one selected from alkyl carboxylate, polypropylene glycol, oleic acid, castor oil, coconut oil, dibutyl sebate, polyethylene glycol, propylene glycol, glycerin, triacetin, acetyl triethyl citrate, triethyl citrate, tributyl citrate, and acetyl tributyl citrate. In some embodiments, the plasticizer mixed with ethyl cellulose preferably includes oleic acid. In some embodiments, the mass fraction of the plasticizer, based on the total mass of ethyl cellulose and other excipients in the coating, may include about 0.1% to about 15%, about 0.2% to about 13%, about 0.3% to about 12%, about 0.4% to about 10%, about 0.5% to about 8%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.7% to about 4.5%, about 1% to about 4%, about 1.1% to about 3.8%, about 1.2% to about 3.5%, about 1.3% to about 3.3%, about 1.4% to about 3%, about 1.5% to about 2.8%, about 1.6% to about 2.5%, about 1.7% to about 2.2%, about 1.8% to about 2%, about 1.9% to about 3%, about 2% to about 4%, or any single value or subrange thereof.

[0149] In some embodiments, the mass fraction of ethyl cellulose may include about 65% to about 90%, about 68% to about 88%, about 70% to about 85%, about 72% to about 85%, about 75% to about 85%, about 78% to about 85%, or any single value or subrange thereof, based on the total mass of the modulating coating.

[0150] In some embodiments, the acid-swellable coating film-forming agent may include sodium alginate.

[0151] In some embodiments, the mass fraction of sodium alginate, based on the total mass of the release coating, may include about 10% to about 30%, about 12% to about 28%, about 14% to about 25%, about 15% to about 23%, about 16% to about 23%, about 18% to about 22%, about 10% to about 20%, about 10% to about 18%, or any single value or subrange thereof. In some embodiments, the mass fraction of sodium alginate, based on the total mass of the release coating, preferably includes about 14% to about 28%, more preferably about 18% to about 22%.

[0152] In some embodiments, the mass ratio of ethyl cellulose to sodium alginate may include about (60-95):(5-40), about (63-93):(7-37), about (65-90):(10-35), about (67-88):(12-33), about (70-86):(14-30), about (70-85):(15-30), about (72-85):(15-28), about (73-83):(17 -27), about (70-80):(20-30), about (75-80):(20-25), about (77-80):(20-23), about (80-82):(18-20), about (82-85):(15-18), about (85-90):(10-15), about (88-90):(10-12), about (73-82):(18-27), or any single value or subrange thereof.

[0153] In some embodiments, the mass fraction of ethyl cellulose may include about 73% to about 82%, about 70% to about 85%, about 65% to about 90%, or any single value or subrange thereof, based on the total mass of ethyl cellulose and sodium alginate.

[0154] In some embodiments, the mass fraction of sodium alginate may include about 20% to about 25%, about 18% to about 28%, about 18% to about 30%, about 15% to about 30%, about 10% to about 35%, or any single value or subrange thereof, based on the total mass of ethyl cellulose and sodium alginate.

[0155] In some embodiments, the modulated coating comprises ethyl acrylate-methyl methacrylate copolymer and sodium alginate.

[0156] In some embodiments, the emulsifier mixed with the ethyl acrylate-methyl methacrylate copolymer may include at least one of fatty acid polyglycerides, medium-chain triglycerides, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, propylene glycol monoesters or diesters of fats and fatty acids, sodium lauryl sulfate, and sorbitan monostearate. In some embodiments, the emulsifier mixed with the ethyl acrylate-methyl methacrylate copolymer preferably includes medium-chain triglycerides. In some embodiments, the mass fraction of the emulsifier may include, based on the total mass of the ethyl acrylate-methyl methacrylate copolymer and other excipients in the coating, about 0.1% to about 15%, about 0.2% to about 13%, about 0.3% to about 12%, about 0.4% to about 10%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 5%, about 0.6% to about 4.8%, about 0.7% to about 4.5%, about 0.8% to about 4%, about 0.9% to about 3.8%, about 1% to about 3.5%, about 1.2% to about 3.3%, about 1.5% to about 3%, about 1.8% to about 2.8%, about 2% to about 5%, about 2.2% to about 5%, about 2.5% to about 5%, or any single value or subrange thereof.

[0157] In some embodiments, the plasticizer blended with the ethyl acrylate-methyl methacrylate copolymer may include at least one of alkyl carboxylate, polypropylene glycol, oleic acid, castor oil, coconut oil, dibutyl sebate, polyethylene glycol, propylene glycol, glycerin, triacetin, acetyl triethyl citrate, triethyl citrate, tributyl citrate, and acetyl tributyl citrate. In some embodiments, the plasticizer blended with the ethyl acrylate-methyl methacrylate copolymer preferably includes oleic acid. In some embodiments, the mass fraction of the plasticizer, based on the total mass of the ethyl acrylate-methyl methacrylate copolymer and other excipients in the coating, may include about 0.1% to about 15%, about 0.2% to about 13%, about 0.3% to about 12%, about 0.4% to about 10%, about 0.5% to about 8%, about 0.5% to about 6%, about 0.5% to about 5%, about 0.7% to about 4.5%, about 1% to about 4%, about 1.1% to about 3.8%, about 1.2% to about 3.5%, about 1.3% to about 3.3%, about 1.4% to about 3%, about 1.5% to about 2.8%, about 1.6% to about 2.5%, about 1.7% to about 2.2%, about 1.8% to about 2%, about 1.9% to about 3%, about 2% to about 4%, or any single value or subrange thereof.

[0158] In some embodiments, the mass fraction of the ethyl acrylate-methyl methacrylate copolymer may include about 65% to about 90%, about 68% to about 88%, about 65% to about 75%, about 70% to about 85%, about 72% to about 85%, about 75% to about 85%, about 78% to about 85%, or any single value or subrange thereof, based on the total mass of the modulated coating.

[0159] In some embodiments, the acid-swellable coating film-forming agent may include sodium alginate.

[0160] In some embodiments, the mass fraction of sodium alginate, based on the total mass of the release coating, may include about 20% to about 25%, about 18% to about 28%, about 18% to about 30%, about 15% to about 30%, about 10% to about 35%, or any single value or subrange thereof. In some embodiments, the mass fraction of sodium alginate, based on the total mass of the release coating, preferably includes about 14% to about 28%, more preferably about 18% to about 22%.

[0161] In some embodiments, the mass ratio of ethyl acrylate-methyl methacrylate copolymer to sodium alginate may include about (60-95):(5-40), about (60-90):(10-40), about (60-85):(15-40), about (60-80):(20-40), about (63-93):(7-37), about (65-90):(10-35), about (65-80):(20-35), about (65-75):(25-35), or about (67-88):(12-33). ), about (70-86):(14-30), about (72-85):(15-28), about (73-83):(17-27), about (75-80):(20-25), about (77-80):(20-23), about (80-82):(18-20), about (82-85):(15-18), about (85-90):(10-15), about (88-90):(10-12), about (73-82):(18-27), or any single value or subrange thereof.

[0162] In some embodiments, the mass fraction of the ethyl acrylate-methyl methacrylate copolymer may include about 75% to about 80%, about 73% to about 82%, about 70% to about 85%, about 65% to about 90%, or any single value or subrange thereof, based on the total mass of the ethyl acrylate-methyl methacrylate copolymer and sodium alginate.

[0163] In some embodiments, based on the total mass of the ethyl acrylate-methyl methacrylate copolymer and sodium alginate, the mass fraction of sodium alginate may include about 20% to about 25%, about 18% to about 28%, about 18% to about 30%, about 15% to about 30%, about 10% to about 35%, or any single value or subrange thereof. Further information regarding sodium alginate can be found in other parts of this disclosure.

[0164] The weight gain of the release coating in this disclosure refers to the percentage of the mass of the release coating to the mass of the capsule, wherein the capsule does not contain a coating and comprises contents and a capsule shell encapsulating the contents. In some embodiments, the weight gain of the release coating may include about 1% to about 10%. In some embodiments, the weight gain of the release coating may include about 2% to about 9%. In some embodiments, the weight gain of the release coating may include about 3% to about 8%. In some embodiments, the weight gain of the release coating may include about 3% to about 7%. In some embodiments, the weight gain of the release coating may include about 4% to about 7%. In some embodiments, the weight gain of the release coating may include about 3% to about 7%. In some embodiments, the weight gain of the release coating may include about 3.25% to about 6.15%. In some embodiments, the weight gain of the release coating may include about 3.5% to about 6%. In some embodiments, the weight gain of the release coating may include about 4% to about 5.5%. In some embodiments, the weight gain of the release coating may include about 4.5% to about 5%. In some embodiments, the weight gain of the modulated coating may include about 1% to about 10%, such as about 1%, about 2%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.15%, about 6.5%, about 7%, about 8%, about 9%, or about 10%.

[0165] In some embodiments, the modulated-release coating formulations (also referred to as "modulated-release coated pharmaceutical compositions" or "modulated-release pharmaceutical compositions") or other coated formulations of this disclosure are prepared by a method comprising the following steps: (a) adding the pharmaceutical product to be coated (e.g., a capsule containing contents) into a coating machine, setting the rotation speed of the coating pan, turning on the exhaust, intake, and heating, setting the intake temperature, and preheating the material; and (b) adjusting the rotation speed of the coating pan to keep the material in a free-rolling state, adjusting the spray flow rate, spray gun distance, spray pressure, and hot air blower frequency, spraying the coating liquid to coat the pharmaceutical product, controlling the coating weight gain or thickness as needed, and obtaining a pharmaceutical product with a coated outer surface.

[0166] In some embodiments, the coating solution may be formulated from a coating film-forming agent and a solvent. In some embodiments, the solvent may include water.

[0167] In some embodiments, the coating solution can be prepared directly from a water-insoluble coating film-forming agent and an acid-swellable coating film-forming agent without the need for additional solvents.

[0168] In some embodiments, the modulated-release pharmaceutical composition of this disclosure may also be a capsule formulation comprising: a capsule shell and contents, the contents being encapsulated by the capsule shell, the outer surface of the capsule shell being coated with a modulated-release coating. In some embodiments, the contents of this disclosure may include EPA-FFA with a purity of about 95% or higher. In some embodiments, the contents of this disclosure may include self-emulsifying contents. Further details regarding high-purity EPA-FFA, self-emulsifying contents, capsule shells, and modulated-release coatings can be found in the descriptions in other parts of this disclosure.

[0169] Based on the characteristics of EPA-FFA, this disclosure considers the use of self-emulsification technology to prepare a self-emulsifying drug delivery system (SEDDS). The preparation of SEDDS systems is well-known in the art. Emulsifiers with a hydrophilic-lipophilic balance (HLB) value between 11 and 15 (which may include two or more emulsifiers, with the one enhancing the emulsification effect referred to as a co-emulsifier) ​​prepared into SEDDS exhibit better emulsification effects. In application, nonionic surfactants with lower toxicity are often chosen as emulsifiers. In self-emulsifying formulations, the role of co-emulsifiers is mainly to increase the fluidity of the oil-water interface film, reduce the surface tension of the oil and water, and regulate the emulsifier. Emulsifiers with an HLB value <15 can be selected as co-emulsifiers. Three main principles are followed when selecting a self-emulsifying formulation: (1) the types of excipients selected should be as simple and effective as possible; (2) the selected emulsifiers and co-emulsifiers should have low toxicity and hemolytic activity; (3) when emulsification capabilities are similar, the number of excipient types should be minimized. Generally, those skilled in the art are capable of selecting suitable self-emulsifying formulations, including emulsifiers and co-emulsifiers. The evaluation method for emulsifiers and co-emulsifiers can be as follows: take 20 ml of the mixed solution and inject it into 10 ml of water (37 degrees Celsius), shake it slightly, observe the self-emulsification phenomenon, and let it stand for a period of time to observe the emulsification phenomenon. The evaluation is based on the self-emulsification effect known in the art, such as the solution being a milky white liquid without turbidity or oil-water separation.

[0170] In some embodiments, this disclosure also provides a self-emulsifying pharmaceutical composition. In some embodiments, the self-emulsifying pharmaceutical composition may include self-emulsifying contents and a capsule shell.

[0171] In some embodiments, the capsule shell may encapsulate self-emulsifying contents. Further details regarding the capsule shell can be found in the remainder of this disclosure.

[0172] In some embodiments, the self-emulsifying contents of this disclosure may include high-purity EPA-FFA and pharmaceutically acceptable excipients. In some embodiments, the mass fraction of high-purity EPA-FFA may be about 60% and above, about 65% and above, about 70% and above, about 72% and above, about 75% and above, about 78% and above, about 80% and above, about 82% and above, about 85% and above, about 88% and above, about 90% and above, about 92% and above, about 95% and above, about 98% and above, or about 99% and above. In some embodiments, based on the total mass of the self-emulsifying contents, the mass fraction of the excipients may not exceed about 40%, about 38%, about 35%, about 33%, about 30%, about 28%, about 25%, about 23%, about 20%, about 18%, about 15%, about 12%, about 10%, about 8%, about 5%, or about 2%.

[0173] In some embodiments, pharmaceutically acceptable excipients in the self-emulsifying contents may include emulsifiers. In some embodiments, the mass fraction of the emulsifier, based on the total mass of the self-emulsifying contents, may include about 1% to about 40%, about 2% to about 37%, about 5% to about 35%, about 8% to about 33%, about 10% to about 30%, about 11% to about 29%, about 12% to about 28%, about 13% to about 27%, about 14% to about 26%, about 15% to about 25%, about 16% to about 26%, about 17% to about 27%, about 18% to about 28%, about 19% to about 29%, about 20% to about 30%, or any single value or subrange thereof.

[0174] The range of emulsifiers that can be selected is well known in the art. In some embodiments, the emulsifier may include surfactant-based emulsifiers and / or hydrophilic polymeric emulsifiers.

[0175] In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 0-40. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 0-20. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 0.5-18. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 1-16. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 3-14. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 4-12. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 4-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 5-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 6-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 8-10. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 10-12. In some embodiments, the emulsifier may include an emulsifier with a hydrophilic-lipophilic balance (HLB) value of about 12-14. In some embodiments, the emulsifier may include an emulsifier with an HLB value between 11 and 15. In some embodiments, the emulsifier may include an emulsifier with an HLB value between 12 and 14. In some embodiments, the emulsifier may include an emulsifier with an HLB value between 13 and 15.

[0176] In some embodiments, the emulsifier may include, but is not limited to, at least one of polyoxyethylene fatty alcohol ethers, polyoxyethylene-polyoxypropylene copolymers, gum arabic, tragacanth gum, Bletilla striata gum, apricot gum, pectin, peach gum, sodium alginate, agar, casein, sodium cholate, cholesterol, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene dehydrated sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, sucrose fatty acid ester, lecithin, glycerol fatty acid ester, glyceryl mono- and di-stearate esters, glycerol, propylene glycol, poloxamer 188, poloxamer 407, sodium oleate, Tween 20, Tween 80, and 15-hydroxystearic acid polyethylene glycol ester.

[0177] In some embodiments, the emulsifier may be any one or a combination of lecithin, glyceryl mono- and glyceryl distearate, poloxamer 188, poloxamer 407, sodium oleate, Tween 20, Tween 80, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, glyceryl monooleate, PEG-15-hydroxystearic acid, PEG-15-hydroxystearic acid, glycerol, propylene glycol, etc.

[0178] In some embodiments, the emulsifier may include polyoxyethylene (40) hydrogenated castor oil and lecithin. In some embodiments, the emulsifier may include lecithin and polyoxyethylene (35) castor oil. In some embodiments, the emulsifier preferably includes polyoxyethylene (35) castor oil and egg yolk lecithin. In some embodiments, the emulsifier preferably includes polyoxyethylene (35) castor oil and soybean lecithin.

[0179] In some embodiments, the mass fraction of polyoxyethylene (35) castor oil may include about 1% to about 40%, about 3% to about 38%, about 5% to about 35%, about 7% to about 32%, about 10% to about 30%, about 15% to about 30%, about 17% to about 28%, about 20% to about 30%, about 20% to about 28%, about 20% to about 25%, about 22% to about 25%, about 22% to about 23%, or any single value or subrange thereof, based on the total mass of the self-emulsifying contents.

[0180] In some embodiments, the mass fraction of egg yolk lecithin, based on the total mass of the self-emulsifying contents, may include about 0 to about 20%, about 1 to about 18%, about 2 to about 15%, about 3 to about 12%, about 4 to about 10%, about 5 to about 8%, about 0.5% to about 5%, about 0.5% to about 3%, about 1% to about 2%, or any single value or subrange thereof.

[0181] Self-emulsifying contents can be prepared by the following steps: weigh EPA-FFA and emulsifier, mix them in a mixing tank, purge with nitrogen, heat to 55-65°C, turn on stirring, and stir until dissolved and clear to obtain self-emulsifying contents.

[0182] In some embodiments, this disclosure also provides a modulated-release pharmaceutical composition. In some embodiments, the modulated-release pharmaceutical composition of this disclosure may include self-emulsifying contents, a capsule shell, and a modulated-release coating, wherein the capsule shell encapsulates the self-emulsifying contents, and the modulated-release coating is coated on the outer surface of the capsule shell. In some embodiments, the self-emulsifying contents may include high-purity EPA-FFA and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients may include emulsifiers. Further details regarding high-purity EPA-FFA, pharmaceutically acceptable excipients, and modulated-release coatings can be found in the descriptions in other parts of this disclosure.

[0183] In some embodiments, the self-emulsifying contents of this disclosure may further include antioxidants. Exemplary antioxidants may include, but are not limited to, any one or a combination of citric acid, ascorbic acid, astaxanthin, ferulic acid, paeonol, paeonol ester of ferulic acid, acetylated paeonol ester of acetylferulic acid, tea polyphenols, α-tocopherol, tocopherol, quercetin, rosmarinic acid, etc. In some embodiments, based on the total mass of the self-emulsifying contents, the self-emulsifying contents of this disclosure may include one or more antioxidants in a mass fraction of about 0.01% to about 0.1%, about 0.025% to about 0.05%, about 0.05% to about 0.5%, about 0.1% to about 0.4%, or about 0.2% to about 0.3%. In some embodiments, the self-emulsifying contents of this disclosure may not include antioxidants.

[0184] In some embodiments, the self-emulsifying pharmaceutical compositions and / or modulated-release pharmaceutical compositions of this disclosure can be used as therapeutic agents for diseases in animals (particularly mammals), such as therapeutic agents for dyslipidemia, hypertriglyceridemia, and cardiovascular diseases such as myocardial infarction, stroke, coronary revascularization, and angina pectoris, or therapeutic agents for lowering triglyceride levels in the blood above normal. In some embodiments, the self-emulsifying pharmaceutical compositions and / or modulated-release pharmaceutical compositions of this disclosure can be used in combination with statins as therapeutic agents for cardiovascular diseases in animals (particularly mammals). In some embodiments, exemplary mammals may include humans, livestock (such as cattle, horses, and pigs), and companion animals (such as dogs, cats, rabbits, rats, and mice). In some embodiments, mammals are preferably humans. In some embodiments, the self-emulsifying pharmaceutical compositions and / or modulated-release pharmaceutical compositions of this disclosure are preferably used as therapeutic agents for hypertriglyceridemia in humans.

[0185] In some embodiments, this disclosure relates to the use of the release coating in the preparation of formulations for releasing contents comprising EPA-FFA of a purity of about 95% or higher at pH ≥ 3.5. In some embodiments, this disclosure relates to a method of releasing, at pH ≥ 3.5, the contents comprising EPA-FFA of a purity of about 95% or higher, comprising coating the outermost layer of the formulation with the release coating. In some embodiments, this disclosure relates to the release coating for releasing, at pH ≥ 3.5, the contents comprising a formulation comprising EPA-FFA of a purity of about 95% or higher. In some embodiments, the release coating comprises a release polymer and an acid-swellable coating film-forming agent. In some embodiments, the release polymer comprises at least one of a water-poorly soluble coating film-forming agent and an enteric coating film-forming agent. In some embodiments, the release polymer comprises a water-poorly soluble coating film-forming agent. In some embodiments, the water-poorly soluble coating film-forming agent comprises at least one of ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, and cellulose acetate. In some embodiments, the acid-swellable coating film-forming agent includes at least one of alginate and pectin. In some embodiments, the acid-swellable coating film-forming agent includes at least one of sodium alginate, potassium alginate, ammonium alginate, and pectin.

[0186] This disclosure does not impose any particular limitation on the preparation method of high-purity EPA-FFA. In some embodiments, high-purity EPA-FFA can be prepared according to any of the following routes: (1) using ester-type fish oil as raw material, hydrolyzing and purifying it to obtain free fatty acids; or (2) using extracted crude triglycerides as raw material, refining and purifying them to obtain ester-type fish oil, and then hydrolyzing and purifying it to obtain free fatty acids.

[0187] The exemplary preparation method of high-purity EPA-FFA provided in this article is as follows:

[0188] (1) Preparation of fish oil compositions in the form of ethyl esters (also known as "ethyl ester type fish oil")

[0189] Fish oil compositions in the form of ethyl esters with different fatty acid ratios can be prepared using preparation methods well known in the art.

[0190] An exemplary preparation method includes the following steps: extracting crude triglyceride oil from fish (anchovy, tuna, sardines, mackerel, and herring), and then obtaining refined fish oil through degumming, deacidification, and decolorization; converting the triglyceride-type fish oil into ethyl ester-type fish oil; and then preparing ethyl ester-type fish oil using one or more methods selected from urea inclusion, silver ion complexation, thin-film evaporation, molecular distillation, preparative chromatography, or distillation separation. In some embodiments, ethyl ester-type fish oil can be purchased directly, and then the ethyl ester-type fish oil product can be prepared using one or more methods selected from urea inclusion, silver ion complexation, thin-film evaporation, molecular distillation, or preparative chromatography or distillation separation.

[0191] (2) Preparation of high-purity EPA (or "high-purity EPA-FFA") in free acid form Where R represents: R = EPA chain CH3(CH3CH=CH)5(CH2)3-, and EtOH is ethanol (Ethanol).

[0192] EPA-FFA compositions can be prepared from EPA-EE compositions using saponification reactions known in the art. An exemplary preparation method is as follows:

[0193] Weigh a certain amount of EPA-EE and add it to the reaction vessel. Weigh 0.5 times the weight of EPA-EE and dissolve it in an appropriate amount of purified water. Add an appropriate amount of ethanol to obtain a sodium hydroxide-ethanol solution. Add the above sodium hydroxide-ethanol solution dropwise to the reaction vessel containing EPA-EE and stir continuously. React at 50-60℃ for 4 hours. Add n-heptane to the reaction solution and add 0.5 times the weight of EPA-EE in dilute hydrochloric acid. Stir and react for 1 hour. Allow to stand and separate. Wash the n-heptane layer with purified water until the lower aqueous layer is neutral. Add an appropriate amount of activated carbon to the n-heptane layer, stir for 30 minutes, filter, and concentrate the filtrate under reduced pressure until solvent-free to obtain the EPA-FFA composition.

[0194] After obtaining the EPA-FFA composition, this paper uses gas chromatography to detect the fatty acid composition and content.

[0195] Detection of EPA-FFA and other fatty acids: Refer to the General Rules of the United States Pharmacopeia. <401> The "Omega-3 Fatty Acids Determination and Profile" procedure involves methylating the sample before detecting the content of EPA-FFA and other fatty acids.

[0196] As used herein, “about” means any value within ±10% of the range; for example, “about 10” includes 9 to 11. Unless otherwise stated herein, the listing of numerical ranges is intended only as a shorthand method for individually referring to each individual value falling within that range, and incorporating each individual value into the specification is equivalent to listing it separately herein. All methods described herein may be performed in any suitable order unless otherwise stated herein or clearly contradicted by the context.

[0197] The use of any and all instances or exemplary language provided herein is intended to illustrate certain materials and methods only and does not limit the scope. The language in this specification should not be construed as indicating that any unclaimed element is necessary for practicing the disclosed materials and methods.

[0198] As shown in this disclosure and claims, unless the context clearly indicates otherwise, the words "a," "an," "an," and / or "the" do not specifically refer to the singular and may also include the plural. Generally, the terms "comprising" and "including" only indicate the inclusion of expressly identified steps and elements, which do not constitute an exclusive list; the method or composition may also include other steps or elements. Examples

[0199] Specific embodiments of this disclosure will now be described with reference to the following examples. It should be understood that these examples are disclosed by way of illustration only and should not be construed as limiting the scope of this disclosure in any way. Example 1: Comparative Study of Pharmaceutical Compositions of Different Formulation Types

[0200] API (Active Pharmaceutical Ingredient): EPA-FFA (purity 98.4%).

[0201] Preparation process: Weigh EPA-EE (from Sichuan Guowei Pharmaceutical Co., Ltd.) and add it to the reaction vessel. Weigh 0.5 times the weight of EPA-EE and dissolve it in purified water, then add ethanol to obtain a sodium hydroxide-ethanol solution. Add the above sodium hydroxide-ethanol solution dropwise to the reaction vessel containing EPA-EE, and stir continuously for 4 hours at 50-60℃. Add n-heptane to the reaction solution, then add 0.5 times the weight of EPA-EE in dilute hydrochloric acid and stir for 1 hour. Allow to stand and separate; wash the n-heptane layer with purified water until the lower aqueous layer is neutral. Add activated carbon to the n-heptane layer, stir for 30 minutes, filter, and concentrate the filtrate under reduced pressure until solvent-free to obtain an EPA-FFA composition with a purity of 98.4%.

[0202] The above APIs were used for emulsifier screening. The types and amounts of the optimized emulsifiers are shown in Table 3: Table 3 Types of Emulsifiers As can be seen, all the emulsifiers in the table above can achieve the purpose of self-emulsification of EPA-FFA.

[0203] From the emulsifiers mentioned above, select the exemplary emulsifiers shown in Table 4 below, and formulate self-emulsifying contents according to the indicated prescriptions: Table 4 Self-emulsifying Content Prescriptions

[0204] Preparation process of self-emulsifying contents:

[0205] Weigh out EPA-FFA, polyoxyethylene (35) castor oil, and egg yolk lecithin according to the prescription dosage in Table 4, mix them in a mixing tank, purge with nitrogen for protection, heat to 55-65℃, turn on stirring (the liquid surface will swirl, without splashing), stir until dissolved and clear, and obtain the self-emulsified contents.

[0206] Non-self-emulsifying contents (conventional gastric coagulation) prescriptions: Table 5 Non-self-emulsifying contents prescriptions

[0207] Soft capsule shell prescription: Table 6 Soft capsule shell prescription

[0208] Soft capsule manufacturing process:

[0209] Gelatinizing: Weigh the capsule shell gelatin, glycerin, and purified water according to Table 6. Add the weighed glycerin and purified water to the gelatinizing tank and start stirring (20-30 rpm). Once the mixture reaches 60-70℃, stop stirring, add the gelatin, and then start stirring again (20-30 rpm) for 30-60 minutes, until no obvious particles are visible. After the gel is dissolved, evacuate the vacuum until no obvious air bubbles remain inside the solution. The viscosity of the solution (measured at 60℃) should be controlled within the range of 15000-25000 mPa·s.

[0210] Shot pressing, washing, and drying: Adjust the temperature of the capsule container (55-65℃), the spray nozzle temperature (35-45℃), the main machine speed (1-3 rpm), and the refrigeration system temperature below 20℃. Add the contents (including the self-emulsifying and non-self-emulsifying contents prepared above) to the hopper, maintain a micro-nitrogen flow, and adjust the filling amount according to the dosage of the contents. Control the thickness of the capsule shell (0.7-0.9 mm) during pressing. The pressed soft capsules are conveyed to a rotary drum for pre-drying, washing, and drying to obtain soft capsules containing the contents (referred to as "self-emulsifying gastric-soluble capsules" and "conventional gastric-soluble capsules," respectively).

[0211] Studies were conducted on soft capsules prepared using the above-mentioned content formulation and process, soft capsule shell formulation and process, and different coating formulations. The effects of time-dependent coating, pH 5.5 enteric coating, pH 6.0 enteric coating and the release-modifying coating form of this disclosure on the pharmacokinetic properties of the active ingredient were compared.

[0212] 1. Time-dependent coating

[0213] The formulation design of time-dependent coatings involves using a mixture of non-pH-dependent sustained-release materials and porogens to prepare the coating, thereby achieving the purpose of delayed release.

[0214] 1.1 Delay coating of the marketed drug Epanova

[0215] Referring to the excipient composition of the extended-release coating formulation of the marketed drug Epanova, a corresponding coating formulation dosage was proposed and examined. The coating formulation is shown in Table 7. Table 7 Epanova Coating Formulation Table 8 Release characteristics of Epanova coated formulation

[0216] Results Analysis: Epanova's coating formulation shows that the coating film, using a large amount of talc, has a certain degree of permeability. The coating film swells after absorbing water, causing it to rupture at the soft capsule seam, releasing the contents. Because the coating thickness is uneven at the soft capsule seam, this coating method makes product quality difficult to control, and it is difficult to delay release to 30 minutes, failing to meet the requirements for delayed-release coating.

[0217] 1.2 Homemade Delay Coating

[0218] For the development of time-dependent coating formulations, the inventors have repeatedly used non-pH-dependent sustained-release materials (such as ethyl cellulose aqueous dispersions) mixed with pore-forming agents (such as hydroxypropyl methylcellulose (HPMC)) to prepare coatings in order to achieve delayed release.

[0219] The recipes for homemade time-delay coatings are shown in Table 9: Table 9 Recipes for Homemade Time-Delay Coatings

[0220] Preparation of delayed coating solution: According to the prescription dosage in Table 9, take EC aqueous dispersion, add TEC and stir to mix to obtain solution 1. Take the prescription dosage of talc, yellow iron oxide, and titanium dioxide, add to purified water at 80℃, stir to disperse, add HPMC, stir to disperse and cool to obtain solution 2. Mix solution 1 and solution 2, and pass through an 80-mesh sieve to obtain the coating solution.

[0221] Delayed coating process: Capsules encapsulated with EPA-FFA (conventional gastric-coated capsules) are added to a coating machine. The coating pan speed is set to 2-4 rpm, and the exhaust, intake, and heating modules of the coating pan are turned on. The intake air temperature is set to 45-70℃, preheating the material temperature to 30-45℃. The coating pan speed is set to 3-8 rpm, maintaining free tumbling of the material. The spray flow rate (15-60 g / min), spray gun distance (20cm-30cm), spray pressure (0.2-0.4 MPa), and hot air fan frequency (25-40 Hz) are adjusted. The coating liquid is sprayed in for coating. During the coating process, the material temperature is controlled at 30-45℃, and the coating weight gain is controlled within the range of approximately 2.45%-8.32%, resulting in a drug composition coated with a delayed coating (referred to as "self-made delayed-coated formulation").

[0222] 2. pH 5.5 enteric coating

[0223] Referring to commercially available fish oil enteric-coated products, the coating is prepared using a combination of Eutetech L30D-55 and NE30D. Since the coating prepared by these two materials begins to dissolve in a buffer salt medium at pH 5.5, it is called pH 5.5 enteric coating.

[0224] The pH 5.5-dependent enteric coating formulations are shown in Table 10: Table 10 pH 5.5 Enteric Coating Formulations

[0225] Preparation of pH 5.5 enteric coating solution: Dissolve polysorbate 80 (Tween 80) in purified water according to the dosage specified in Table 10. Add NE30D while stirring, and stir until homogeneous to obtain solution 1. Dissolve GMS in purified water at 80℃ according to the dosage specified in Table 10. Add TEC and the remaining Tween 80 while stirring, and emulsify by high-speed shearing until homogeneous. Cool to obtain solution 2. Add the prescribed amount of L30D-55 to solution 1 while stirring, mix until homogeneous, then add to solution 2, mix until homogeneous, and pass through an 80-100 mesh sieve to obtain the coating solution.

[0226] pH5.5 enteric coating process: The capsules (conventional gastric-coated capsules) encapsulated with EPA-FFA are coated according to the aforementioned self-made delayed coating preparation process, and the coating weight gain is controlled within the range of about 5.33% to about 9.02% to obtain a pharmaceutical composition coated with pH5.5 enteric coating (referred to as "pH5.5 enteric coating formulation").

[0227] 3. pH 6.0 enteric coating

[0228] The basic material selected for the pH 6.0 formulation is Eutrich L100, which begins to dissolve in a pH 6.0 buffer salt medium and can be used as a pH 6.0 coating polymer. Eutrich L100 is a powdered solid that is soluble in organic solvents or prepared as an aqueous dispersion for coating.

[0229] The pH 6.0 enteric coating formulation is shown in Table 11: Table 11 pH 6.0 Enteric Coating Formulation

[0230] Preparation of pH 6.0 enteric coating solution: Take the dosage of Eucerin L100 and TEC according to the prescription in Table 11, add 95% ethanol, stir to dissolve, and obtain the coating solution.

[0231] pH 6.0 enteric coating process: The capsules (conventional gastric-coated capsules) encapsulated with EPA-FFA are coated according to the aforementioned self-made delayed coating preparation process, and the coating weight gain is controlled within the range of about 3.79% to about 5.65% to obtain a pharmaceutical composition coated with pH 6.0 enteric coating (referred to as "pH 6.0 enteric coating formulation").

[0232] 4. Adjusting the coating

[0233] 4.1 Release Coating 1

[0234] The coating method uses a combination of ethyl cellulose (EC) and sodium alginate, which has the characteristic of releasing at low pH values ​​(pH≥3.5).

[0235] The formulation of the modulating coating 1 is shown in Table 12: Table 12 Formulation of Modulating Coating 1

[0236] Preparation of the coating solution: Weigh purified water, sodium alginate, and ethyl cellulose aqueous dispersion (type B) (purchased from Shanghai Carrefour Coating Technology Co., Ltd.) according to the dosage specified in Table 12. Add sodium alginate (purchased from JRS Pharma GmbH & Co. KG, sold by Beijing Fengli Jingqiu Pharmaceutical Co., Ltd.) to the purified water while stirring. Stir for approximately 60-90 minutes until the solution becomes clear. Add ethyl cellulose aqueous dispersion (type B) while stirring and stir for 30 minutes to obtain the coating solution.

[0237] Adjusted-release coating process: The capsules containing the self-emulsifying contents (self-emulsifying gastric-soluble capsules) are coated according to the aforementioned coating process, and the coating weight gain is controlled within the range of about 3.25% to about 6.15% to obtain a pharmaceutical composition coated with adjusted-release coating 1 (referred to as "adjusted-release coating 1 formulation").

[0238] 4.2 Adjustment Coating 2

[0239] The coating method uses a combination of NM30D and sodium alginate, which has the characteristic of releasing at low pH values ​​(pH≥3.5).

[0240] The formulations for the modulating coating 2 are shown in Table 13: Table 13 Formulations for the Modulating Coating 2

[0241] Preparation of the coating solution: Weigh purified water, sodium alginate, and NM30D (produced by Evonik Operations GmbH, sold by Shanghai Changwei Pharmaceutical Excipients Technology Co., Ltd.) according to the dosage specified in Table 13. Add sodium alginate (produced by JRS Pharma GmbH & Co. KG, sold by Beijing Fengli Jingqiu Pharmaceutical Co., Ltd.) to the purified water while stirring. Stir for approximately 60-90 minutes until the solution becomes clear. Add NM30D while stirring and stir for 30 minutes to obtain the coating solution.

[0242] Adjusted-release coating process: The capsules containing the self-emulsifying contents (self-emulsifying gastric-soluble capsules) are coated according to the aforementioned coating process, and the coating weight gain is controlled within the range of about 3.25% to about 6.15% to obtain a pharmaceutical composition coated with adjusted-release coating 2 (referred to as "adjusted-release coating 2 formulation").

[0243] Disintegration time was investigated for soft capsule formulations coated with the four different coatings (self-made delayed-release coating, pH 5.5 enteric coating, pH 6.0 enteric coating, and modified-release coating), as well as uncoated conventional gastric-coated EPA-FFA soft capsules and self-emulsifying gastric-coated EPA-FFA soft capsules. The disintegration time investigation method is as follows:

[0244] Disintegration time test in pH 6.8 medium: The method for determining the disintegration time is described in the General Chapter 0921 Disintegration Time Test Method of the Pharmacopoeia of the People's Republic of China: 2020 Edition, Part IV. Take 6 test capsules and test them in the apparatus and method specified in General Chapter 0921 Capsules of the Pharmacopoeia of the People's Republic of China: 2020 Edition, Part IV. First, test them in hydrochloric acid solution (9→1000) without baffles for 2 hours. The capsule shells of each capsule should not have cracks or disintegration. Then, remove the basket, wash it with a small amount of water, add baffles to each tube, and test it again in artificial intestinal fluid (using pH 6.8 phosphate buffer instead) as described above. All capsules should disintegrate within 1 hour. If one capsule does not disintegrate completely, take another 6 capsules for retesting. All capsules should meet the requirements.

[0245] Disintegration time test in pH 4.5 medium: Refer to the General Rules of the Pharmacopoeia of the People's Republic of China (2020 Edition, Part IV), and perform the disintegration time test method 0921. Take 6 test tablets and, according to the apparatus and method described above, first test in hydrochloric acid solution (9→1000) without baffles for 2 hours. Each tablet's capsule shell should not show cracks or disintegration. Then, remove the basket, wash with a small amount of water, add baffles to each tube, and test in pH 4.5 acetate-sodium acetate buffer solution. All tablets should disintegrate within 1 hour. If one tablet does not completely disintegrate, take another 6 tablets for retesting; all should meet the requirements.

[0246] Disintegration time test in pH 3.5 medium: Refer to the General Rules of the Pharmacopoeia of the People's Republic of China (2020 Edition, Part IV), 0921 Disintegration Time Test Method for disintegration time determination. Take 6 test tablets and, according to the apparatus and method described above, first test in hydrochloric acid solution (9→1000) without baffles for 2 hours. Each tablet's capsule shell should not show cracks or disintegration. Then, remove the basket, wash with a small amount of water, add baffles to each tube, and test again in pH 3.5 phosphate-potassium dihydrogen phosphate buffer. If one tablet does not completely disintegrate, take another 6 tablets for retesting; all should meet the requirements.

[0247] Disintegration time test in pH 1.2 medium: Disintegration time was determined according to the General Rules 0921 Disintegration Time Test Method in the Pharmacopoeia of the People's Republic of China (2020 Edition, Part IV). Six capsules were taken and tested in hydrochloric acid solution (9→1000) without a baffle for 2 hours using the apparatus and method specified in General Rules 0921 (Capsules) of the Pharmacopoeia of the People's Republic of China (2020 Edition, Part IV). No cracks or disintegration were observed in the capsule shell of each capsule.

[0248] Disintegration time test in aqueous medium: Refer to the General Chapter 0921 Disintegration Time Test Method in the *Pharmacopoeia of the People's Republic of China: 2020 Edition, Part IV*. Take 6 test capsules and test them in an aqueous medium according to the apparatus and method specified in General Chapter 0921 (Capsules) of the *Pharmacopoeia of the People's Republic of China: 2020 Edition, Part IV*, with a baffle added to each tube. If one capsule fails to disintegrate, take another 6 capsules for retesting; all should meet the requirements.

[0249] The results of the release characteristics study of different drug compositions are shown in Table 14: Table 14 Release characteristics of different drug compositions

[0250] Experimental results, as shown in Table 14, indicate that the modulated-release coating formulations (modulated-release coating group 1 and modulated-release coating group 2) containing self-emulsifying contents (active ingredient EPA-FFA) are insoluble at pH 1.2 but disintegrate rapidly above pH 3.5. Compared to conventional enteric-coated formulations (e.g., self-made delayed-release coating group, pH 5.5 enteric-coated group, and pH 6.0 enteric-coated group), the modulated-release coating formulations achieve release at relatively lower pH levels (pH ≥ 3.5). Therefore, packaging the contents into modulated-release coating formulations, because this specific modulated-release coating can disintegrate within 1 hour in buffered salt media at pH ≥ 3.5, allows the modulated-release coating formulation to be released below the pylorus or in the upper intestinal tract (e.g., the duodenum), thereby significantly reducing intestinal side effects such as diarrhea and abdominal pain.

[0251] Comparative pharmacokinetic studies of different drug compositions

[0252] The pharmacokinetic studies of the six drug compositions shown in Table 14 above were conducted in beagle dogs under both fasting and feeding conditions:

[0253] I. Pharmacokinetic Experiments of Drugs Administered on an Empty Stomach 1. Animals: Beagle dogs, male, approximately 9 - 11 kg, 6 in number; purchased from Chengdu Dashuo Laboratory Animal Co., Ltd., license number: SCXK (Chuan) 2024 - 0031. 2. Grouping and dosing regimens (the specification refers to the dosage of API): (1) Conventional gastric - soluble group: Administered conventional gastric - soluble capsules, prescriptions are shown in Table 14, Table 5, and Table 6; 1 capsule per animal (specification: 1 g / capsule), once a day, single - dose administration. (2) pH5.5 enteric - coated group: Administered pH5.5 enteric - coated preparations, prescriptions are shown in Table 14, Table 5, Table 6, and Table 10; 1 capsule per animal (specification: 1 g / capsule), once a day, single - dose administration. (3) Self - made extended - release coated group: Administered self - made extended - release coated preparations, prescriptions are shown in Table 14, Table 5, Table 6, and Table 9; 1 capsule per animal (specification: 1 g / capsule), once a day, single - dose administration. (4) pH6.0 enteric - coated group: Administered pH6.0 enteric - coated preparations, prescriptions are shown in Table 14, Table 5, Table 6, and Table 11; 1 capsule per animal (specification: 1 g / capsule), once a day, single - dose administration. (5) Self - emulsifying gastric - soluble group: Administered self - emulsifying gastric - soluble capsules, prescriptions are shown in Table 14, Table 4, and Table 6; 1 capsule per animal (specification: 1 g / capsule), once a day, single - dose administration. (6) Sustained - release coated group 1: Administered sustained - release coated 1 preparations, prescriptions are shown in Table 14, Table 4, Table 6, and Table 12; 1 capsule per animal (specification: 1 g / capsule), once a day, single - dose administration. 3. Experimental methods: After 5 days of adaptive feeding of Beagle dogs, without grouping, each research preparation was successively administered once according to the above - mentioned dosing regimens. The wash - out period between each preparation was 7 days. All animals were fasted overnight before drug administration (the fasting time should be no less than 12 hours), and then the corresponding number of preparations was orally administered. After drug administration, fasting continued for 4 hours, and then each animal was fed 200 g of dog food. Thereafter, each dog was allowed to eat freely, and water was not restricted throughout the process. Whole blood (about 0.5 mL) was collected from the cephalic vein of the forelimb or the saphenous vein of the hindlimb (non - drug - administration site) of all animals for sample analysis. Blood samples were collected from each group of animals at - 24±2 h, - 12±1 h before drug administration, and at 0 h before drug administration, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h, and 48 h after drug administration on the day of drug administration. All blood samples were anticoagulated with K2 - EDTA and then added to centrifuge tubes for centrifugation. After centrifugation, they were stored at - 60°C or below. The concentration of total EPA acid in Beagle dog plasma was detected by the validated LC - MS / MS method. The main pharmacokinetic parameters, such as T max 、C max 、AUC last 、CV, etc., were calculated using WinNonlin according to the non - compartmental model method (NCA). Among them, T max is the peak - time, indicating the time required from drug administration to reaching the peak concentration; C max is the maximum plasma drug concentration, indicating the highest plasma concentration reached after drug administration; AUClast AUC is the area under the plasma concentration-time curve at 48 hours after drug administration, indicating the bioavailability of the drug; CV is the coefficient of variation. The main pharmacokinetic parameters of each group of preparations were averaged according to the results of 6 beagle dogs for result comparison.

[0254] II. Pharmacokinetic Experiments after Feeding 1. Animals: Beagle dogs, male, about 9 - 11 kg, 6; purchased from Chengdu Dashuo Laboratory Animal Co., Ltd., license number: SCXK (Chuan) 2024 - 0031. 2. Grouping and dosing regimens: (1) Conventional gastric-soluble group: Given conventional gastric-soluble capsules, the prescriptions are shown in Tables 14, 5 and 6; 1 capsule per animal (specification: 1 g / capsule), once a day, single-dose administration. (2) pH 5.5 enteric-coated group: Given pH 5.5 enteric-coated preparations, the prescriptions are shown in Tables 14, 5, 6 and 10; 1 capsule per animal (specification: 1 g / capsule), once a day, single-dose administration. (3) Self-made delayed-release coated group: Given self-made delayed-release coated preparations, the prescriptions are shown in Tables 14, 5, 6 and 9; 1 capsule per animal (specification: 1 g / capsule), once a day, single-dose administration. (4) pH 6.0 enteric-coated group: Given pH 6.0 enteric-coated preparations, the prescriptions are shown in Tables 14, 5, 6 and 11; 1 capsule per animal (specification: 1 g / capsule), once a day, single-dose administration. (5) Self-emulsifying gastric-soluble group: Given self-emulsifying gastric-soluble capsules, the prescriptions are shown in Tables 14, 4 and 6; 1 capsule per animal (specification: 1 g / capsule), once a day, single-dose administration. (6) Modified-release coated group: Given modified-release coated preparation 1, the prescriptions are shown in Tables 14, 4, 6 and 12; 1 capsule per animal (specification: 1 g / capsule), once a day, single-dose administration. 3. Experimental method: After 5 days of adaptive feeding of beagle dogs, without grouping, each research preparation was sequentially given a single dose according to the above dosing regimens, and the washout period between each preparation was 7 days. All animals were fed 50 g of dog food before drug administration. Each dog was orally given the corresponding number of preparations 30 minutes after finishing eating. The animals were fasted for 4 hours after drug administration, and then each animal was fed 150 g of dog food, and then each dog was allowed to eat freely and water was not restricted throughout the process. Whole blood (about 0.5 mL) was collected from the cephalic vein of the forelimb or the saphenous vein of the hindlimb (non-drug administration site) of all animals for sample analysis. Blood samples were collected from each group of animals at -24 ± 2 h, -12 ± 1 h before drug administration, and at 0 h before drug administration and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h and 48 h after drug administration on the day of drug administration. All samples were anticoagulated with K2-EDTA and then added to centrifuge tubes for centrifugation, and then stored at -60 °C or below after centrifugation. The concentration of total EPA acid in beagle dog plasma was detected by the validated LC-MS / MS method. The main pharmacokinetic parameters were calculated using WinNonlin according to the non-compartmental model method (NCA), for example, T max 、C max 、AUC lastCV, etc. The principal metabolic kinetic parameters of each formulation were compared by averaging the results from six beagle dogs.

[0255] Experimental results

[0256] The pharmacokinetic data of fasted and fed beagle dogs are shown in Table 15. Table 15: Pharmacokinetic Results of Fasted and Fed Beagle Dogs

[0257] Analysis of Pharmacokinetic Results of Beagle Dog Experiments

[0258] When taken on an empty stomach, compared to conventional gastric-coated EPA-FFA capsules, the pH 5.5 enteric-coated formulation and the self-made delayed-release coating formulation of EPA-FFA showed significantly higher coefficients of variation and lower bioavailability. The pH 6.0 enteric-coated formulation of EPA-FFA exhibited a substantial decrease in bioavailability. Note: Compared to conventional gastric-coated EPA-FFA formulations, the active ingredient EPA-FFA is not suitable for formulation into conventional pH 5.5 and pH 6.0 enteric-coated and delayed-release coating formulations.

[0259] On an empty stomach, the coefficient of variation for self-emulsifying gastric-soluble capsules of EPA-FFA was significantly higher than that for conventional gastric-soluble capsules of EPA-FFA. Note: Compared to conventional gastric-soluble capsules of EPA-FFA, the active ingredient EPA-FFA is not suitable for formulation into self-emulsifying gastric-soluble capsules.

[0260] Surprisingly, when taken on an empty stomach, the coefficient of variation of EPA-FFA significantly decreased while maintaining high bioavailability compared to conventional gastric-coated capsules, pH 5.5 enteric-coated formulations, pH 6.0 enteric-coated formulations, homemade delayed-release coating formulations, and self-emulsifying gastric-coated capsules, as well as the modulated-release coating formulation. Furthermore, it reduced gastric side effects such as hiccups and nausea. This indicates that when preparing the active ingredient of high-purity EPA-FFA into a publicly disclosed modulated-release formulation, the self-emulsifying contents and modulated-release coating can have a synergistic effect, significantly reducing the coefficient of variation while maintaining high bioavailability.

[0261] After feeding, the bioavailability of the pH 6.0 enteric-coated formulation was significantly lower than that of EPA-FFA's conventional gastric-coated capsules. This may be because, in postprandial conditions, the enteric-coated formulation is released in the lower part of the intestine, leading to incomplete absorption of the active ingredient. Furthermore, compared to EPA-FFA's pH 5.5 enteric-coated formulation, EPA-FFA's self-made delayed-release coating formulation, EPA-FFA's pH 6.0 enteric-coated formulation, and EPA-FFA's self-emulsifying gastric-coated capsules, EPA-FFA's self-emulsifying controlled-release coating formulation showed a lower coefficient of variation while maintaining higher bioavailability.

[0262] Furthermore, by comparing the pharmacokinetic data before (fasting) and after (feeding), it was found that the self-emulsifying modulated-release coating formulation disclosed herein can maintain high bioavailability before and after meals, with low inter-individual coefficient of variation, and no significant difference between the results before and after meals, indicating minimal influence of food.

[0263] In summary, for the active ingredient EPA-FFA, the self-emulsification of the contents and the release-modulating coating have a synergistic effect, simultaneously reducing the coefficient of variation, improving bioavailability, and reducing the influence of food. Example 2: Comparative Study of Efficacy

[0264] 1. Preparation method of contents (1) EPA-EE Purchase commercially available Vascepa soft capsules and take their contents for experimentation. (2) EPA-FFA Use the self-emulsifying gastric-soluble capsules prepared in Example 1 and take their contents for experimentation, that is, the self-emulsifying contents in Table 4 of Example 1.

[0265] The efficacy of the above-mentioned drug composition in rats:

[0266] I. Materials and Methods 1. Animals: Sprague-Dawley (SD) rats, male (250 - 300 g), 10 rats in each group. Purchased from Sichuan Vital River Laboratory Animal Technology Co., Ltd., license number: SCXK(Sichuan)2023 - 0040. 2. Grouping and dosing regimens (dosing amounts are calculated based on the amount of API): (1) Blank control group: Intragastric administration of MCT (medium-chain triglyceride), once a day, dosing volume is 5 mL / kg. (2) Model control group: Intragastric administration of MCT, once a day, dosing volume is 5 mL / kg. (3) Ethyl ester - 1000 group: Administered the content of Vascepa soft capsules (stock solution), dosing amount: 1000 mg / kg; administered the stock solution, once a day by intragastric administration. (4) Free acid - 250 group: Administered the self-emulsifying content of Example 1, dosing amount: 250 mg / kg; administered once a day by intragastric administration. (5) Free acid - 500 group: Administered the self-emulsifying content of Example 1, dosing amount: 500 mg / kg; administered once a day by intragastric administration. (6) Free acid - 750 group: Administered the self-emulsifying content of Example 1, dosing amount: 750 mg / kg; administered once a day by intragastric administration. 3. Experimental method: After 5 days of adaptive feeding in a SPF-class animal house (experimental animal use license number: SYXK(Sichuan)2018 - 212), SD rats were randomly divided into two groups, the blank control group and the model group. The drinking water for rats in the blank control group was the drinking water for experimental animals, while rats in the model group were given experimental animal drinking water containing 25 wt% fructose. All animals were allowed to freely eat and drink for two weeks. After two weeks of feeding, blood was collected to detect the TG level. According to the TG levels of the animals, model group animals with a significant difference (p < 0.05) from the mean TG of the blank control group were randomly divided into the model control group, free acid - 250, free acid - 500, free acid - 750, and ethyl ester - 1000 groups, with 10 rats in each group. The blank control group and the model control group were intragastrically administered MCT, once a day, dosing volume is 5 mL / kg. Each dosing group was intragastrically administered according to the above dosing regimen, once a day, for 2 consecutive weeks. During the dosing period, the drinking water for the blank control group was the drinking water for experimental animals, while the model control group and each dosing group continued to be given experimental animal drinking water containing 25% fructose, and all animals were allowed to freely eat. Before dosing, 7 days after dosing, and at the end of 2 weeks of dosing, blood was collected from each group of rats to detect the TG level, and the change rate of the TG level after dosing compared to the TG level before dosing was calculated for each individual animal group and statistically analyzed.

[0267] II. Experimental Results

[0268] The experimental results at 7 days and 14 days of dosing are as follows. The baseline is the TG index of rats before starting dosing: Table 16 Change rate of TG compared to baseline at 7 days and 14 days of dosing (%)

[0269] Experimental results showed that, compared with the model control group, the free acid-250 group, free acid-500 group, and free acid-750 group significantly reduced plasma TG levels, and the reduction in TG increased with increasing dose. The free acid-500 group (administered with a dose of 500 mg / kg of the self-emulsified contents) achieved similar efficacy to ethyl acetate-1000, successfully achieving a reduced dosage.

[0270] The basic concepts have been described above. Obviously, for those skilled in the art, the detailed disclosure above is merely illustrative and does not constitute a limitation of the present invention. Without inventive effort, those skilled in the art may make various modifications, improvements, and corrections to the present invention. Such modifications, improvements, and corrections still fall within the spirit and scope of the exemplary embodiments described herein. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by the context.

[0271] The use of any and all instances or exemplary language provided herein is intended solely to illustrate certain materials, products, and methods, and does not constitute a limitation on the scope. The language in this specification should not be construed as indicating that any unclaimed element is necessary for practicing the disclosed materials, products, and methods.

[0272] Furthermore, this specification uses specific terms to describe embodiments thereof. For example, "in some embodiments," "in multiple embodiments," "one embodiment," "an embodiment," and / or "some embodiments" refer to a particular feature, structure, or characteristic associated with at least one embodiment of this specification. Therefore, it should be emphasized and noted that the repeated use of "in some embodiments," "in multiple embodiments," "one embodiment," "an embodiment," and / or "some embodiments" in different locations within this specification does not necessarily refer to the same embodiment. Moreover, certain features, structures, or characteristics in one or more embodiments of this specification can be appropriately combined.

[0273] While the foregoing disclosure has discussed some inventive embodiments that are currently considered useful through various examples, it should be understood that such details are for illustrative purposes only, and the claims are not limited to the disclosed embodiments. Rather, the claims are intended to cover all modifications and equivalent combinations that conform to the substance and scope of the embodiments described herein.

[0274] Similarly, it should be noted that, in order to simplify the descriptions disclosed herein and thus aid in the understanding of one or more embodiments of the invention, multiple features may sometimes be grouped into a single embodiment in the foregoing description of the embodiments. However, this method of disclosure does not imply that the subject matter of this specification requires more features than those mentioned in the claims.

[0275] For each patent, patent application, patent application publication, and other material, such as articles, books, specifications, publications, and documents, referenced in this specification, the entire contents of which are incorporated herein by reference. This excludes historical documents that are inconsistent with or conflict with this specification, as well as documents that limit the broadest scope of the claims in this specification (currently or subsequently appended to this specification). It should be noted that in the event of any inconsistency or conflict between the descriptions, definitions, and / or terminology used in the supplementary materials to this specification and the content of this specification, the descriptions, definitions, and / or terminology used in this specification shall prevail.

[0276] Finally, it should be understood that the embodiments described in this specification are merely illustrative of the principles of the embodiments described herein. Other variations may also fall within the scope of this specification. Therefore, alternative configurations of the embodiments in this specification are intended to be exemplified rather than limited, and are considered consistent with the teachings of this specification. Accordingly, the embodiments in this specification are not limited to those explicitly described and illustrated herein.

[0277] For purposes of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or contents of these documents.

Claims

A self-emulsifying pharmaceutical composition, the pharmaceutical composition comprising: EPA-FFA with purity of about 95% and above and an emulsifier. The pharmaceutical composition of claim 1, wherein, The mass fraction of the emulsifier is about 1% to about 40% based on the total mass of the pharmaceutical composition. The pharmaceutical composition of claim 1 or 2, wherein, The emulsifier comprises one or more of emulsifiers with HLB value of 1-16, preferably comprises one or more of lecithin, poloxamer, tween, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, glycerol monostearate, glycerol distearate, 15-hydroxystearic acid polyethylene glycol ester, sodium oleate, glycerol monooleate, caprylocaproyl macrogolglycerides, glycerol, propylene glycol. A modified release pharmaceutical composition, the pharmaceutical composition comprising: a capsule shell for encapsulating the self-emulsifying pharmaceutical composition of any one of claims 1-3; a modified release coating coated on the outer surface of the capsule shell. The pharmaceutical composition of claim 4, wherein, The modified release coating comprises a modified release polymer and an acid-swellable coating film former, the modified release polymer comprising at least one of a water-insoluble coating film former, an enteric coating film former. The pharmaceutical composition of claim 5, wherein, The water-insoluble coating film former comprises at least one of ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, cellulose acetate; and / or The enteric coating film former comprises at least one of cellulose acetate phthalate, acrylic resin, hydroxypropyl methyl cellulose acetate succinate; and / or The acid-swellable coating film former comprises at least one of sodium alginate, potassium alginate, ammonium alginate, and pectin. The pharmaceutical composition of any one of claims 4-6, wherein, The modified release coating comprises a water-insoluble coating film former and sodium alginate. The pharmaceutical composition of claim 7, wherein, The mass ratio of the water-insoluble coating film former to sodium alginate is about (60-95):(5-40). The pharmaceutical composition of any one of claims 4-8, wherein, The capsule shell comprises gelatin and a plasticizer; Preferably, the mass fraction of the gelatin comprises about 50% to about 80% based on the total mass of the capsule shell; The mass fraction of the plasticizer comprises about 20% to about 50% based on the total mass of the capsule shell; Preferably, the plasticizer is a polyol plasticizer. The pharmaceutical composition of any one of claims 4-9, wherein, The pharmaceutical composition further comprises the self-emulsifying pharmaceutical composition of any one of claims 1-3. A modified release pharmaceutical composition, the pharmaceutical composition comprising: a modified release coating, the modified release coating disintegrates in a buffer salt medium with pH≥3.5 in 1h. The pharmaceutical composition of claim 11, wherein, The modified release coating disintegrates in a buffer salt medium with pH=4.5 in 1h. The pharmaceutical composition of claim 11 or 12, wherein, The pharmaceutical composition further comprises: a capsule shell, the modified release coating coated on the outer surface of the capsule shell; a content, the content encapsulated by the capsule shell. The pharmaceutical composition of claim 13, wherein, The content comprises EPA-FFA with purity of about 95% and above. The self-emulsifying pharmaceutical composition of any one of claims 1-3, or the modified release pharmaceutical composition of any one of claims 4-14, for use in the treatment and / or prevention of dyslipidemia, hypertriglyceridemia, or cardiovascular diseases, or reducing the content of triglyceride in blood above the normal level; Preferably, the cardiovascular diseases are myocardial infarction, stroke, coronary revascularization, or angina pectoris.

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