Compositions and methods for treating coenzyme Q10 deficiency

Abstract

The present disclosure relates to compositions comprising coenzyme Q10 and a water soluble excipient, and methods for treating coenzyme Q10 deficiency in a subject, including oral administration of the composition. The composition can be in a solid or liquid dosage form, such as a ball, a granule, a tablet, a capsule, an oral solution and a soft capsule, and is used for oral administration. The composition may comprise coenzyme Q10 and a binder mixture coated on a tablet core, wherein the tablet core comprises a sugar, microcrystalline cellulose, or a mixture thereof. The composition is an immediate release formulation having high solubility in an aqueous medium.

Description

Invention Field

[0001] This invention broadly relates to compositions comprising coenzyme Q10 and water-soluble excipients, said excipients including polyethylene glycol (PEG), polysorbate, sodium docusate, poloxamer, organic acids, and hydroxypropyl methylcellulose (HPMC). This invention also broadly relates to methods for treating coenzyme Q10 deficiency in subjects using this invention.

[0002] This application claims the full rights and contents of Provisional Application No. 2023901172 filed in Australia on 20 April 2024, which is incorporated herein by reference. Background of the Invention

[0003] Ubiquinone, also known as coenzyme Q10 (abbreviated as CoQ10), is a fat-soluble benzoquinone that is insoluble in water. Coenzyme Q10 is involved in electron transport in mitochondria. Coenzyme Q10 is naturally found in most aerobic organisms, from bacteria to plants and animals. In mammals, coenzyme Q10 is present in every organ. Most foods also contain coenzyme Q10. The concentration of coenzyme Q10 in vegetable oils and meats is generally higher than in dairy products.

[0004] The solubility of coenzyme Q10 is 0.239 mg / mL, which means that more than 500 mL of water is needed to dissolve 150 mg of coenzyme Q10. However, it is difficult for a healthy person to keep 500 mL of water in their stomach for more than 10 minutes, because the water will pass through the digestive system from the stomach.

[0005] Coenzyme Q10 has a pKa of -4.7. For any drug to be absorbed, it must dissolve at the absorption site. Currently, various techniques are used to enhance the solubility of coenzyme Q10, including physical and chemical modifications to the drug, or other methods such as particle size reduction, crystal engineering, salt formation, solid dispersion, the use of surfactants, and complexation. Oral bioavailability depends on a variety of factors, including but not limited to water solubility, drug permeability, dissolution rate, first-pass metabolism, and presystemic metabolism. The most common causes of low oral bioavailability are poor drug solubility and low permeability. The term "soluble" can also be used to describe substances that form colloidal suspensions of extremely fine solid particles in a liquid.

[0006] There are various ubiquinone or coenzyme Q10 formulations available on the market, suitable for different routes of administration, but all formulations have the disadvantage of low solubility in aqueous media.

[0007] Coenzyme Q10 is insoluble in water and poorly absorbed orally. Therefore, high oral doses are usually required to achieve therapeutically effective plasma concentrations. This leads to excessively high concentrations of coenzyme Q10 in the digestive system, causing side effects. Poor absorption results in insufficient and unstable bioavailability and gastrointestinal mucosal toxicity.

[0008] The solubility of water-insoluble drugs is generally related to their particle size—as particles become smaller, the surface area to volume ratio increases. A larger surface area results in a stronger interaction with the solvent, thus increasing the drug's solubility in water.

[0009] Coenzyme Q10 is used to treat heart failure. A 2017 meta-analysis showed that daily intake of 30-100 mg of coenzyme Q10 reduced mortality by 31%. Exercise capacity was also improved. A 2018 meta-analysis concluded that preliminary evidence suggests oral coenzyme Q10 can reduce statin-related muscle symptoms, including muscle pain, muscle weakness, muscle cramps, and muscle fatigue.

[0010] Coenzyme Q10 has the chemical formula C59H90O4 and a molar mass of 863.4 g / mol. It is yellow or orange and solid at room temperature. Coenzyme Q10 is a component of the electron transport chain, participating in cellular aerobic respiration and producing energy in the form of ATP. 95% of the body's energy is produced in this way. Coenzyme Q10 exists in three redox states: completely oxidized (called ubiquinone or coenzyme Q10), semiquinone (also called ubiquitin-semiquinone), and completely reduced (called ubiquinol).

[0011] Coenzyme Q10 is generally well tolerated. However, excessive intake of coenzyme Q10 has been reported to cause some adverse reactions, primarily gastrointestinal ones. The most common side effects are gastrointestinal symptoms, including nausea, vomiting, loss of appetite, abdominal pain, rash, and headache.

[0012] Commercially available coenzyme Q10 supplements range in concentration from 5 to 600 mg per capsule, taken once or twice daily as needed. Different manufacturers offer different concentrations of coenzyme Q10, and the bioavailability of the formulations may also vary.

[0013] Coenzyme Q10 can also be used as a dietary supplement and can be prescribed or recommended by medical professionals for the prevention or treatment of heart failure symptoms.

[0014] There is a need for new coenzyme Q10 formulations with higher dissolution rates to reduce the dosage of coenzyme Q10, thereby reducing the risk or severity of side effects. Invention Overview

[0015] The present invention generally relates to compositions comprising coenzyme Q10 and water-soluble excipients, and methods for treating coenzyme Q10 deficiency.

[0016] On one hand, the present invention provides a composition comprising coenzyme Q10 and one or more water-soluble excipients selected from HPMC, PEG, sodium docusate, poloxamer, organic acids and polysorbates, wherein the composition has a coenzyme Q10 solubility greater than 60% in an aqueous medium.

[0017] In a preferred embodiment, the composition has a coenzyme Q10 solubility greater than 60%, 70%, 80%, or 90% in 1000 mL of aqueous medium at pH 4.5 and 0.5% Triton.

[0018] In a preferred embodiment, the composition is spherical and contains coenzyme Q10, a binder containing low molecular weight HPMC, and a core containing one or more excipients.

[0019] In a preferred embodiment, the molecular weight of HPMC is equal to or less than 26,000 g / mol.

[0020] In a preferred embodiment, the composition comprises a mixture of HPMC and coenzyme Q10 coated on the core surface, wherein the core comprises sugar, microcrystalline cellulose, or a mixture thereof.

[0021] In a preferred embodiment, the core comprises one or more of sugar, microcrystalline cellulose, lactose, starch, mannitol, sorbitol, fructose-1,6-diphosphate, and crospovidone, or a mixture thereof.

[0022] In a preferred embodiment, the composition comprises coenzyme Q10 and PEG 200 to 22000, wherein the composition is a liquid, granules, tablets or capsules.

[0023] In a preferred embodiment, the composition comprises 1 part by weight of coenzyme Q10 and 1 to 4 parts by weight of PEG1000 to 22000. Preferably, the composition further comprises a filler, a swelling agent, and a lubricating excipient.

[0024] In a preferred embodiment, the composition comprises 1 part coenzyme Q10 and 1 to 10 parts PEG 200 to 600 (parts by weight).

[0025] In a preferred embodiment, the composition is a granule, tablet, or capsule containing coenzyme Q10 and poloxamer. Preferably, the composition contains 1 part by weight of coenzyme Q10 and 1 to 4 parts by weight of poloxamer.

[0026] In a preferred embodiment, the composition comprises coenzyme Q10, PEG 1000 to 22000, and poloxamer, wherein the composition is in the form of granules, tablets, or capsules. Preferably, the composition comprises 1 part by weight of coenzyme Q10, 1 to 3 parts by weight of PEG 1000 to 22000, and 1 to 3 parts by weight of poloxamer. Preferably, the composition further comprises fillers, swelling agents, and lubricating excipients.

[0027] In a preferred embodiment, the composition comprises 1 part by weight of coenzyme Q10 and 0.5 to 3 parts by weight of sodium docusate. Preferably, the composition further comprises a filler, a swelling agent, and a lubricating agent.

[0028] In a preferred embodiment, the composition comprises 1 part by weight of coenzyme Q10, 1 to 3 parts by weight of PEG 1000 to 22000, 1 to 3 parts by weight of poloxamer and 0.5 to 1 part by weight of sodium docusate, and the formulation further comprises fillers, swelling agents and lubricating excipients.

[0029] In a preferred embodiment, the composition is spherical and comprises 1 part by weight of coenzyme Q10, 0.5 to 3 parts by weight of low molecular weight HPMC, and 1 part by weight of a core containing sugar, microcrystalline cellulose, or a mixture thereof.

[0030] In a preferred embodiment, the composition comprises 1 part by weight of coenzyme Q10, 2 parts by weight of HPMC and 1 part by weight of a core containing sugar, microcrystalline cellulose or a mixture thereof.

[0031] In a preferred embodiment, the composition is a granule or capsule containing coenzyme Q10 and low molecular weight HPMC, wherein the composition further contains one or more of lactose, microcrystalline cellulose and crospovidone, or a mixture thereof.

[0032] In a preferred embodiment, the composition is a liquid solution containing coenzyme Q10 and PEG 200 to 600. Preferably, the liquid solution is packaged in a bottle or soft capsule. Preferably, the composition contains 1 part coenzyme Q10 and 1 to 10 parts PEG 200 to 600.

[0033] In a preferred embodiment, the composition comprises coenzyme Q10 and ingredients selected from... 20. 40. 60 and A liquid solution of 80% polysorbate.

[0034] In a preferred embodiment, the composition comprises coenzyme Q10, PEG 200 to 600, and a mixture selected from [the group consisting of coenzyme Q10, PEG 200 to 600, and other ingredients]. 20. 40. 60 and A liquid solution of 80% polysorbate. Preferably, the liquid solution is contained in a bottle or soft capsule.

[0035] In a preferred embodiment, the composition comprises 1 part coenzyme Q10 by weight and 1 to 10 parts selected from... 20. 40. 60 and 80% polysorbate.

[0036] In a preferred embodiment, the composition comprises, by weight, 1 part coenzyme Q10 and 1 to 10 parts organic acids selected from malic acid, maleic acid, tartaric acid, succinic acid, citric acid and ascorbic acid.

[0037] On the other hand, the present invention provides a method for preparing a spherical coenzyme Q10 composition, the method comprising the following steps: a) Dissolve 1 part by weight of coenzyme Q10 in an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until coenzyme Q10 is completely dissolved. b) Dissolve 1 to 3 parts of low molecular weight HPMC in a solvent selected from ethanol, isopropanol or benzyl alcohol; c) Combine the solutions from step a) and step b) to form a solution containing coenzyme Q10 and HPMC; and d) Spray the coenzyme Q10 and HPMC solution from step c) onto the core in the fluidized bed, wherein the core contains sugar, microcrystalline cellulose or a mixture thereof to form spheres containing coenzyme Q10, HPMC and the core.

[0038] On the other hand, the present invention provides a method for producing a coenzyme Q10 composition, wherein the method includes the following steps: a) Dissolve 1 part by weight of coenzyme Q10 in an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until coenzyme Q10 is completely dissolved or dispersed. b) Add 1 to 3 parts of PEG 1000 to 22000, 1 to 3 parts by weight of poloxamer or 0.5 parts by weight of sodium docusate to the solution or dispersion of step a) until the PEG, poloxamer or sodium docusate are completely dissolved or dispersed. c) Place 1 part of lactose, microcrystalline cellulose, and crospovidone into a fluidized bed; d) Spray the solution or dispersion from step b) onto a fluidized bed to form a powder mixture; e) Spraying the PVP K30 solution into the fluidized bed of step d) to form particles; and f) Mix the granules from step e) with a lubricant (preferably magnesium stearate) and compress them into tablets or into capsules or granule bags.

[0039] On the other hand, the present invention provides compositions as described herein for providing cardiac nutrition to patients with heart disease.

[0040] On the other hand, the present invention provides the use of the compositions described herein in the preparation of medicaments for treating coenzyme Q10 deficiency or diseases associated with coenzyme Q10 deficiency (e.g., heart failure, cardiomyopathy, or myopathy), wherein the compositions are formulated for administration of 300 mg of coenzyme Q10 to a patient daily.

[0041] On the other hand, the present invention provides a method for treating coenzyme Q10 deficiency or diseases associated with coenzyme Q10 deficiency (e.g., heart failure, cardiomyopathy, or myopathy), comprising administering to a subject a composition of the present invention as described herein, wherein the composition is formulated for administering 300 mg of coenzyme Q10 to the patient daily. definition

[0042] To provide a more comprehensive understanding of the invention described herein, the following definitions are provided for the purposes of this disclosure.

[0043] The term “include” is an inclusive term that means to include, cover, encompass, or include the elements listed after the term, but does not exclude other elements not listed.

[0044] The term "mainly composed of" indicates that the list of elements may include additional components or excipients that do not substantially contribute to the implementation of the invention, other than the elements listed.

[0045] The term "composed of" is an exclusive term, meaning that it consists only of...

[0046] The term “therapeutic effective amount” or “effective amount” refers to an amount that, when administered to an animal to treat a disease, symptom, or condition, is sufficient to produce the desired therapeutic effect (e.g., to affect the treatment of the disease).

[0047] The terms “composition” and “formulation” are synonyms and are used interchangeably in this document.

[0048] The term "RPM" refers to revolutions per minute.

[0049] The terms “dissolution” and “dissociation” are synonyms and can be used interchangeably in this article.

[0050] The term "core" refers to a small sphere.

[0051] The term "PVP" refers to polyvinylpyrrolidone.

[0052] The term "HPMC" is an abbreviation for hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose), which is a mixed ether of methyl and hydroxypropyl groups.

[0053] Low molecular weight HPMC refers to HPMC with a molecular weight equal to or lower than 26,000 g / mol.

[0054] High molecular weight HPMC refers to HPMC with a molecular weight equal to or greater than 26,000 g / mol.

[0055] The term "PEG" refers to polyethylene glycol. PEG with a molecular weight of 200 to 400 g / mol can be in liquid form. PEG with a molecular weight of 600 g / mol can be in semi-liquid form. PEG with a molecular weight greater than 1,000 g / mol can be in solid form.

[0056] Polysorbates are surfactants, examples of which include 20. 40. 60 and 80. Invention Details

[0057] This invention will be described in conjunction with various specific and preferred embodiments and techniques. However, it should be understood that various changes and modifications can be made without departing from the spirit and scope of this invention.

[0058] This invention relates to compositions comprising coenzyme Q10 and one or more water-soluble excipients.

[0059] More specifically, embodiments of the present invention relate to compositions comprising coenzyme Q10 and one or more water-soluble excipients, such as hydroxypropyl methylcellulose (HPMC), preferably low molecular weight HPMC, PEG 1000 to 22,000, PEG 200 to 600, sodium docusate, poloxamer (e.g.) Polysorbates, for example 20. 40. 60 or 80. Fillers, expanders, and lubricating excipients. The present invention also relates to methods of treating coenzyme Q10 deficiency in subjects, including oral administration of such compositions.

[0060] In a preferred embodiment, the composition may be in the form of spheres, granules, capsules, tablets, soft capsules, or liquid. Preferably, the composition is an immediate-release formulation with high solubility in an aqueous medium.

[0061] In a preferred embodiment, the composition may be in the form of orally administered spheres. In a preferred embodiment, the spheres comprise a coating on the tablet core, wherein the coating comprises a mixture of coenzyme Q10 and HPMC (e.g., HPMC E5) covering the tablet core.

[0062] In a preferred embodiment, the composition may be in granular form, which may be filled into capsules or granule bags, or compressed into tablets for oral administration. Preferably, the granular composition comprises coenzyme Q10, PEG 1000 to 22,000, poloxamer, sodium docusate, low molecular weight HPMC with a molecular weight equal to or less than 26,000 g / mol, and one or more other excipients, such as fillers, swelling agents, and lubricating powders.

[0063] In a preferred embodiment, the composition comprises a mixture of coenzyme Q10 and a binder that coats a tablet core, wherein the tablet core comprises sugar, microcrystalline cellulose, or a mixture thereof. Preferably, the binder is low molecular weight (equal to or less than 26,000 g / mol) HPMC.

[0064] In another preferred embodiment, the formulation comprises coenzyme Q10, PEG with a molecular weight of 1000 to 22000 g / mol, and one or more other excipients, such as fillers, expanding agents, and lubricating powders. The formulation may be in the form of granules, tablets, or capsules.

[0065] In another preferred embodiment of the invention, the formulation comprises coenzyme Q10, PEG with a molecular weight of 1000 to 22000 g / mol, poloxamer, and one or more other excipients, such as fillers, swelling agents, and lubricating powders. The formulation is preferably in the form of granules, tablets, or capsules.

[0066] In another preferred embodiment of the invention, the formulation comprises coenzyme Q10, sodium docusate, and one or more other excipients, such as fillers, expanders, and lubricants, wherein the formulation is preferably in the form of granules, tablets, or capsules.

[0067] In another preferred embodiment of the invention, the formulation comprises coenzyme Q10, low molecular weight HPMC, and one or more other excipients, such as fillers, expanders, and lubricants, wherein the formulation is preferably in the form of granules and capsules.

[0068] In another preferred embodiment of the invention, the formulation comprises coenzyme Q10, HPMC, and poloxamer, wherein the formulation is preferably in the form of granules, tablets, or capsules.

[0069] In another preferred embodiment of the invention, the formulation comprises coenzyme Q10, poloxamer, and PEG 1000 to 22000, wherein the formulation is preferably in the form of granules, tablets, or capsules.

[0070] In another preferred embodiment of the invention, the formulation comprises coenzyme Q10, poloxamer, PEG 1000 to 22000 and HPMC, wherein the formulation may be in the form of granules, tablets or capsules.

[0071] In another preferred embodiment of the invention, the formulation comprises 1 part coenzyme Q10, 1 part poloxamer and 1 part PEG 1000 to 22000, wherein the formulation may be in the form of granules, tablets or capsules.

[0072] In another preferred embodiment of the present invention, the formulation comprises 1 part coenzyme Q10, 1 part PEG 1000-22000, 1 part crospovidone, and 1 part microcrystalline cellulose, and the formulation may be granules, tablets, or capsules.

[0073] In another preferred embodiment of the present invention, the formulation comprises 1 part coenzyme Q10, 2 parts PEG 1000-22000, 2 parts crospovidone and 2 parts microcrystalline cellulose, wherein the formulation may be granules, tablets or capsules.

[0074] In another preferred embodiment of the present invention, the formulation comprises 1 part coenzyme Q10, 10 parts PEG 1000-22000, 2 parts crospovidone and 3 parts microcrystalline cellulose, wherein the formulation may be granules, tablets or capsules.

[0075] In another preferred embodiment of the invention, the formulation comprises 1 part coenzyme Q10 and 1 to 10 parts PEG 200 to 600, wherein the formulation may be in liquid or soft capsule form.

[0076] In another preferred embodiment of the invention, the formulation comprises 1 part coenzyme Q10 and 1 to 10 parts polysorbate, for example... 20. 40. 60 and 80, wherein the formulation may be in the form of a liquid or a soft capsule.

[0077] In another preferred embodiment of the invention, the formulation comprises 1 part coenzyme Q10, 1 to 2 parts PEG 200 to 600 and 1 to 2 parts polysorbate, such as Tween 20, Tween 40, Tween 60 and Tween 80, wherein the formulation may be a liquid formulation or a soft capsule dosage form.

[0078] In another preferred embodiment of the present invention, the formulation comprises 1 part coenzyme Q10, 1 part poloxamer, 1 part crospovidone and 1 part microcrystalline cellulose, wherein the formulation may be in the form of granules, tablets or capsules.

[0079] In another preferred embodiment of the present invention, the formulation comprises 1 part coenzyme Q10, 2 parts poloxamer, 2 parts crospovidone and 2 parts microcrystalline cellulose, and the formulation may be granules, tablets or capsules.

[0080] In another preferred embodiment of the present invention, the formulation comprises 1 part coenzyme Q10, 0.5-1 part sodium docusate, 1 part crospovidone and 1 part microcrystalline cellulose, and the formulation may be granules, tablets or capsules.

[0081] In another preferred embodiment of the present invention, the formulation comprises 1 part coenzyme Q10, 1 part sodium docusate, 1 part PEG 1000-22000, 1 part crospovidone and 1 part microcrystalline cellulose, and the formulation may be granules, tablets or capsules.

[0082] The applicant unexpectedly discovered that compositions prepared according to the methods described herein exhibit a higher coenzyme Q10 dissolution rate in aqueous media, thereby enabling the achievement of therapeutic effects with a smaller dosage of coenzyme Q10. Therefore, an advantage of a particularly preferred embodiment of the present invention is that each unit dose of the composition can contain less coenzyme Q10 compared to currently available softgel compositions. This helps reduce the side effects associated with high levels of coenzyme Q10 in the digestive system while providing the same or better therapeutic efficacy. Currently, coenzyme Q10 is available in softgel form. Most commercially available coenzyme Q10 preparations are in softgel form containing vegetable oil and coenzyme Q10. The softgels of the present invention contain water-soluble excipients and do not contain oil-based excipients, thereby contributing to improved in vivo solubility.

[0083] CN 101703477 A describes the preparation of a coenzyme Q10 microsphere formulation and its production method. The coenzyme Q10 microspheres are made from coenzyme Q10 and pharmaceutical excipients, characterized in that the pharmaceutical excipients are excipients and binders, wherein the weight percentage content of coenzyme Q10 in the microsphere formulation is 2-80%, the weight percentage content of the excipients is 12-97%, and the weight percentage content of the binder is 1-8%. The microsphere formulation can be formulated as a sustained-release formulation or an enteric-coated formulation as needed. The preparation method of the coenzyme Q10 microspheres is as follows: (1) mixing coenzyme Q10 with excipients and grinding to micron powder level; (2) dissolving the binder in water, anhydrous ethanol, or aqueous ethanol; (3) forming microspheres using microsphere forming technology.

[0084] When preparing coenzyme Q10 compositions, domestic manufacturers traditionally classify the degree of pulverization of medicinal materials or extracts into coarse powder (oral administration, particle size 850μm±70μm, can pass through a 24-mesh sieve), medium powder (oral administration, particle size 250μm±9.9μm, can pass through a 65-mesh sieve), fine powder (for wound treatment, particle size 150μm±6.6μm, can pass through a 100-mesh sieve), even finer powder (for eye drops, particle size 125μm±5.8μm, can pass through a 120-mesh sieve), and ultrafine powder (particle size 75μm±4μm, can pass through a 200-mesh sieve).

[0085] The coenzyme Q10 composition of the present invention may be spherical, with an outer layer comprising a mixture of coenzyme Q10 and hydroxypropyl methylcellulose (HPMC). The sphere may contain a core comprising sugar, microcrystalline cellulose, or a mixture thereof. The outer layer comprising coenzyme Q10 and HPMC may be composed of multiple layers of coenzyme Q10 and HPMC. The coating process may be stopped when the sphere diameter reaches approximately 1 mm. The resulting coated spheres may be filled into capsules or granule bags. The composition described herein may also contain magnesium stearate as a lubricant.

[0086] The composition of the present invention is in the form of spheres containing 150 mg of coenzyme Q10, and its coenzyme Q10 dissolution rate can exceed 60%, 70%, 80%, 90% or 95% under the condition of 1000 mL of 0.5% Triton as the dissolution medium.

[0087] One embodiment of the present invention may contain 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of coenzyme Q10. Preferably, the content of coenzyme Q10 in the compositions described herein is a reduced dose relative to dosage forms in the prior art.

[0088] In one embodiment, the present invention provides a composition as described herein, wherein the composition has a coenzyme Q10 solubility of greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%, or greater than 85%, or greater than 90%, or greater than 95% in 1% Triton aqueous medium.

[0089] The compositions described herein may be used to treat coenzyme Q10 deficiency or diseases associated with coenzyme Q10 deficiency, such as heart failure, cardiomyopathy, or myopathy.

[0090] In one embodiment, the present invention provides an oral composition which may be in the form of spheres, granules, tablets, or capsules. The spheres or granules may be filled into capsules or granule bags, or the granules may be compressed into tablets. The spherical or pellet-shaped compositions of the present invention may contain coenzyme Q10, HPMC, and a core comprising sugar or microcrystalline cellulose. The outer layer of the spherical composition may contain coenzyme Q10 and HPMC, while the core contains sugar, starch, lactose, mannitol, sorbitol, fructose-1,6-bisphosphate, microcrystalline cellulose, or a mixture thereof. HPMC is an abbreviation for hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose), which is a mixed methyl and hydroxypropyl ether with a molecular weight equal to or less than about 26,000 g / mol. Preferably, the coenzyme Q10 spheres of the present invention are an immediate-release formulation.

[0091] In one embodiment, the method for producing coenzyme Q10 microspheres includes the following steps: a) Dissolve a certain amount of coenzyme Q10 in a ketone selected from acetone, butanone, or pentanone; b) Dissolve a certain amount of low molecular weight HPMC in an alcohol selected from ethanol, isopropanol, benzyl alcohol, or combinations thereof; c) The coenzyme Q10 ketone solution from step a) is mixed with the HPMC alcohol solution from step b) to form a solution containing coenzyme Q10 and HPMC, and sprayed into a fluidized bed containing a core, wherein the core contains one or more excipients, such as starch, lactose, sugar, mannitol, sorbitol, fructose-1,6-bisphosphate, microcrystalline cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose or mixtures thereof. d) Dry the microspheres or pellets containing the following substances: Coenzyme Q10 is mixed with HPMC, formed into spheres, pellets, or small spheres, and then filled into capsules or granule bags.

[0092] In one embodiment, the coenzyme Q10 microspheres of the present invention comprise about 1 part by weight of coenzyme Q10, about 0.5 to 3 parts by weight of low molecular weight HPMC, and about 0.5 to 2 parts by weight of a core, wherein the smaller the microsphere size, the less core is used. The core may comprise starch, lactose, sugar, mannitol, sorbitol, fructose-1,6-bisphosphate, microcrystalline cellulose, or mixtures thereof. Preferably, in 1000 mL of a 0.5% Triton aqueous solution buffered with sodium acetate to pH 4.5, and stirred at 75 RPM for 2 hours, the dissolution rate of coenzyme Q10 in the microspheres is greater than 60%, 80%, or 90%. For a fixed coenzyme Q10 content in the microspheres, a higher HPMC content results in a higher dissolution rate.

[0093] In one embodiment, the coenzyme Q10 composition of the present invention comprises a therapeutically effective amount of coenzyme Q10 and a binder comprising low molecular weight HPMC, wherein the amount of binder, by weight, can be 1 to 3 times that of the coenzyme Q10 in the composition. Preferably, the coenzyme Q10 microspheres are dissolved in 1000 mL of a 0.5% Triton aqueous solution buffered with sodium acetate to pH 4.5, stirred at 75 RPM for 2 hours, with the solution being in the range of 60% to 95%.

[0094] In one embodiment, the coenzyme Q10 microspheres of the present invention comprise 1 part by weight of coenzyme Q10, 0.5 parts by weight of HPMC, and about 0.5 parts by weight of a core, wherein the core comprises sugar, microcrystalline cellulose, or a mixture thereof. Preferably, the coenzyme Q10 microspheres of the present invention dissolve in more than 60% of their volume after stirring at 75 RPM for 2 hours in 1000 mL of a 0.5% Triton aqueous solution buffered with sodium acetate at pH 4.5.

[0095] In another embodiment, the coenzyme Q10 microspheres of the present invention comprise 1 part by weight of coenzyme Q10, 1 part by weight of HPMC, and about 0.5 parts by weight of a core, wherein the core comprises sugar, microcrystalline cellulose, or a mixture thereof. Preferably, the coenzyme Q10 microspheres of the present invention dissolve in more than 80% of their volume after stirring at 75 RPM for 2 hours in 1000 mL of a 0.5% Triton aqueous solution buffered with sodium acetate at pH 4.5.

[0096] In another embodiment, the coenzyme Q10 sphere of the present invention comprises 1 part by weight of coenzyme Q10, 1 part by weight of HPMC and about 1 part by weight of a core, wherein the core comprises sugar, microcrystalline cellulose or a mixture thereof.

[0097] In another embodiment, the coenzyme Q10 sphere of the present invention comprises 1 part by weight of coenzyme Q10, 1.5 parts by weight of HPMC and about 1 part by weight of a core, wherein the core comprises sugar, microcrystalline cellulose or a mixture thereof.

[0098] In another embodiment, the coenzyme Q10 microspheres of the present invention comprise 1 part by weight of coenzyme Q10, 2 parts by weight of HPMC and about 1 part by weight of a core, wherein the core comprises sugar, microcrystalline cellulose or a mixture thereof.

[0099] In another embodiment, the coenzyme Q10 microspheres of the present invention comprise 1 part by weight of coenzyme Q10, 3 parts by weight of HPMC and about 1 part by weight of a core, wherein the core comprises sugar, microcrystalline cellulose or a mixture thereof.

[0100] In another embodiment, the coenzyme Q10 microspheres of the present invention comprise 1 part by weight of coenzyme Q10, 2 parts by weight of HPMC and about 2 parts by weight of a core, wherein the core comprises sugar, microcrystalline cellulose or a mixture thereof.

[0101] In another embodiment, the coenzyme Q10 ball of the present invention comprises 1 part by weight of coenzyme Q10, 3 parts by weight of HPMC and about 2 parts by weight of core, wherein the core comprises sugar, microcrystalline cellulose or a mixture thereof.

[0102] In another embodiment, the coenzyme Q10 composition in particulate form of the present invention comprises coenzyme Q10, low molecular weight HPMC, filler, swelling agent, starch, lactose, sugar, mannitol, sorbitol, fructose-1,6-diphosphate, microcrystalline cellulose, crospovidone, or a mixture thereof.

[0103] In some embodiments, the core is a small sphere with a diameter of about 0.3 mm to about 1 mm, comprising sugar, starch, microcrystalline cellulose, lactose, mannitol, sorbitol, fructose-1,6-bisphosphate, crospovidone, and crospovidone sodium carboxymethyl cellulose.

[0104] In some embodiments, the reduced-dosage coenzyme Q10 composition of the present invention comprises a coenzyme Q10 coating located on the core, wherein the composition may be filled into capsules or granule bags.

[0105] In some embodiments, the reduced-dosage coenzyme Q10 composition of the present invention is in granule form, comprising coenzyme Q10 and a water-soluble excipient selected from one or more of low molecular weight HPMC, PEG 1000 to 22000, poloxamer, and sodium docusate, as well as a filler and a swelling agent selected from microcrystalline cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, or mixtures thereof. Preferably, the granules are filled into capsules or granule bags, or the granules are compressed into tablets.

[0106] In some embodiments, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 0.5 part low molecular weight HPMC, 1 to 3 parts PEG 100 to 22000, 1 to 2 parts poloxamer, 0.5 to 1 part sodium docusate, 10% microcrystalline cellulose, 1 part crospovidone and 1 part crospovidone sodium carboxymethyl cellulose, or a mixture thereof, wherein the formulation may be in the form of granules, tablets or capsules.

[0107] In some embodiments, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 1 to 2 parts PEG 1000 to 22000, 1 part poloxamer, 10% microcrystalline cellulose, 1 part crospovidone and 1 part crospovidone sodium carboxymethyl cellulose, or a mixture thereof, wherein the formulation may be in the form of granules, tablets or capsules.

[0108] In some embodiments, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 1 to 10 parts PEG 1000 to 22000, 10% microcrystalline cellulose, 1 part crospovidone and 1 part crospovidone sodium carboxymethyl cellulose, or a mixture thereof.

[0109] In some embodiments, the coenzyme Q10 composition of the present invention comprises coenzyme Q10, poloxamer, microcrystalline cellulose, crospovidone and crospovidone sodium carboxymethyl cellulose, or a mixture thereof.

[0110] In some embodiments, the coenzyme Q10 composition of the present invention comprises coenzyme Q10 and sodium docusate.

[0111] In some embodiments, the coenzyme Q10 composition of the present invention comprises coenzyme Q10 and PEG 200 to 600.

[0112] In some embodiments, the coenzyme Q10 composition of the present invention comprises coenzyme Q10 and a mixture selected from... 20. 40. 60 and 80% polysorbate, wherein the formulation may be in liquid or soft capsule form.

[0113] In some embodiments, the coenzyme Q10 composition of the present invention comprises coenzyme Q10 and 1,000 to 22,000 PEG.

[0114] In some embodiments, the composition of the present invention is spherical, comprising a core containing sugar, microcrystalline cellulose, or a mixture thereof, and an outer layer containing coenzyme Q10 and low molecular weight HPMC surrounding the core. Preferably, the diameter of the sphere is from about 0.3 mm to about 2 mm, or preferably, the diameter is from about 0.5 mm to 1.2 mm. Preferably, the sphere can be filled into a hard capsule or a spherical bag, wherein the composition is preferably an immediate-release product.

[0115] In some embodiments, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 1-2 parts poloxamer, 10% microcrystalline cellulose, 1 part crospovidone and 1 part crospovidone sodium carboxymethyl cellulose, or a mixture thereof.

[0116] In some embodiments, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 0.5-1 part sodium docusate, 10% microcrystalline cellulose, 1 part crospovidone and 1 part crospovidone sodium carboxymethyl cellulose, or a mixture thereof.

[0117] In some embodiments, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 0.5 to 1 part sodium docusate, 1 to 10 parts PEG 1000 to 22000, 10% microcrystalline cellulose, 1 part crospovidone, and 1 part crospovidone sodium carboxymethyl cellulose, or a mixture thereof. In some embodiments of the spheres of the present invention, the weight ratio of low molecular weight HPMC to coenzyme Q10 is 0.5:1 to 3:1. Preferably, this weight ratio is 1:1 to 2:1.

[0118] Hydroxypropyl methylcellulose (HPMC) is a water-soluble methylcellulose ether. In a preferred embodiment of the invention, HPMC has a low molecular weight. Preferably, HPMC is used as a binder. HPMC polymers have various viscosity grades, ranging from 4,000 to 100,000 mPas. The viscosity of the polymer affects the diffusion pathway. High molecular weight HPMC can be used as a matrix to control the release of hydrophilic and hydrophobic drugs and is a key excipient in sustained-release formulations. In sustained-release tablets, HPMC can act as a delaying agent. In a preferred embodiment of the invention, low molecular weight HPMC acts only as a binder.

[0119] In a preferred embodiment, the coenzyme Q10 composition of the present invention is prepared by the following method: a) Place 1 part by weight of coenzyme Q10 powder into a container and mix with about 6 parts of ketone selected from acetone, butanone or pentanone until the powder is completely dissolved; b) Place 0.5 to 3 parts of low molecular weight HPMC and about 1 to 18 parts of an alcohol selected from ethanol, isopropanol or benzyl alcohol into a container until the HPMC is completely dissolved. c) Place a core with a diameter of 0.4 mm to 1.0 mm into a fluidized bed, wherein the core contains sugar, microcrystalline cellulose or a mixture thereof; d) Mix the solutions from steps a) and b) together; e) Spray the solution from step d) onto a fluidized bed. The solution adheres to the surface of the core and dries, thus encapsulating the core and increasing its size. f) Fill the spheres obtained in step e) into capsules or granule bags.

[0120] In other embodiments, the coenzyme Q10 composition of the present invention can be prepared by the following method: a) Place 1 part by weight of coenzyme Q10 powder into a container containing about 3 to 6 parts of ketone (selected from acetone, butanone or pentanone) until the powder is completely dissolved. b) Dissolve or disperse 0.5 to 3 parts of low molecular weight HPMC in 1 to 18 parts of water; c) Mix the HPMC aqueous solution or mixture from step b) with the coenzyme Q10 ketone solution from step a) to form a suspension; d) Place one core sample with a diameter of 0.4 mm to 1.0 mm in a fluidized bed, wherein the core sample contains sugar, microcrystalline cellulose or a mixture thereof; e) Spray the suspension obtained in step c) onto a fluidized bed. The suspension adheres to the surface of the drug core and dries, thus encapsulating the drug core and increasing its size. f) Fill the spheres obtained in step e) into capsules or granule bags.

[0121] In another embodiment, the coenzyme Q10 composition of the present invention may be in granular form and may be prepared according to the following method: a) Place 1 part by weight of coenzyme Q10 powder into a container containing about 6 parts of a ketone selected from acetone, butanone or pentanone, until the powder is completely dissolved. b) Dissolve 0.5 to 3 parts of low molecular weight HPMC in about 3 to 18 parts of water; c) Place 1 to 3 parts of filler and expanding agent in a fluidized bed, wherein the filler and expanding agent include sugar, microcrystalline cellulose, lactose, crospovidone or a mixture thereof; d) Spray the mixture of solutions from a) and b) onto a fluidized bed; the mixture adheres to and dries with the filler and expanding agent to form particles and increase their size to approximately 24 mesh; e) Spraying PVPK30 aqueous solution onto a fluidized bed increases particle size; f) Mix the granules from step e) with magnesium stearate, and then fill them into capsules, granule bags, or compress them into tablets.

[0122] In another embodiment, the coenzyme Q10 composition of the present invention can be prepared according to the following method: a) Place 1 part by weight of coenzyme Q10 powder into a container containing about 6 parts of ketone (selected from acetone, butanone or pentanone) until the powder is completely dissolved. b) Dissolve 1 to 3 parts of PEG 1000 to 22000 in the solution from step a); c) Place 1 to 3 parts of filler and expanding agent into a fluidized bed, wherein the filler and expanding agent include microcrystalline cellulose, lactose, crospovidone or a mixture thereof; d) Spray the solution from step b) onto a fluidized bed; wherein the mixture adheres to and dries with the filler and expansion agent to form particles and increase their size until the particles reach approximately 24 mesh; e) Spraying PVPK30 aqueous solution onto a fluidized bed increases particle size; f) Mix the granules from step e) with magnesium stearate, and then fill them into capsules, granule bags, or compress them into tablets.

[0123] In one embodiment of the invention, the weight ratio of low molecular weight HPMC to coenzyme Q10 is 0.5:1. In another embodiment, the weight ratio of HPMC to coenzyme Q10 is 1:1. In another embodiment, the weight ratio of HPMC to coenzyme Q10 is 2:1. In yet another embodiment, the weight ratio of HPMC to coenzyme Q10 is 3:1. Preferably, the weight ratio of low molecular weight HPMC to coenzyme Q10 is between 1:1 and 2:1.

[0124] Preferably, the coenzyme Q10 composition of the present invention, after disintegration in aqueous solution in the form of capsules containing spheres, exhibits a dissolution rate significantly higher than that of prior art coenzyme Q10 soft capsules of the same strength. Preferably, compared to prior art soft capsules, this increases the absorption of coenzyme Q10 in the digestive system and reduces side effects caused by elevated coenzyme Q10 levels.

[0125] Coenzyme Q10 may have a variety of adverse reactions, which are uncommon and usually mild. These reactions may include decreased appetite, diarrhea, dizziness, indigestion, nausea, and vomiting. However, reducing the amount of coenzyme Q10 in the digestive system can reduce the frequency and / or severity of these side effects.

[0126] Coenzyme Q10 is available as a food supplement or medication, with single capsule doses of 30, 60, 100, 200, 300, 400, and 600 mg. Typically, the dose required to achieve a therapeutic plasma concentration >2.5 μg / mL is 200 mg twice daily with food. For patients with heart disease, the daily dose is 100 to 400 mg, while for neurodegenerative diseases, the maximum dose is 3000 mg. Coenzyme Q10 may also reduce statin-related muscle symptoms and heart failure mortality.

[0127] The coenzyme Q10 composition of the present invention may contain different amounts of coenzyme Q10, ranging from 20 mg to 600 mg. Preferably, the composition may be in the form of spheres, granules, tablets, capsules, liquids, or soft capsules.

[0128] In another embodiment, the composition of the present invention comprises 1 part by weight of coenzyme Q10, 0.5 to 3 parts by weight of low molecular weight HPMC and 0.5 to 1 part by weight of a core comprising sugar, microcrystalline cellulose or a mixture thereof.

[0129] In another embodiment, the spherical composition of the present invention comprises 20 to 150 mg of coenzyme Q10, 20 to 300 mg of low molecular weight HPMC, and 20 to 150 mg of a sugar core. Preferably, the spherical formulation is stirred at 75 RPM for 2 hours in 1000 mL of 0.5% Triton aqueous solution (pH 4.5, buffered with sodium acetate) to achieve a coenzyme Q10 dissolution rate of approximately 92.5%. In some embodiments, the spherical formulation may be filled into capsules or pill pouches.

[0130] In another embodiment, the composition of the present invention is a spherical formulation comprising 150 mg of coenzyme Q10, 150 mg of low molecular weight HPMC and 150 mg of a core comprising sugar, microcrystalline cellulose or a mixture thereof.

[0131] In another embodiment, the composition of the present invention is a spherical formulation comprising 120 mg coenzyme Q10, 240 mg low molecular weight HPMC, and 100 mg sugar core. Preferably, the microspheres are stirred in 1000 mL of 0.5% Triton aqueous solution (pH 4.5) at 75 RPM for 2 hours, resulting in a coenzyme Q10 solubility greater than 80%.

[0132] In another embodiment, the composition of the present invention is spherical, comprising 100 mg of coenzyme Q10, 200 mg of low molecular weight HPMC, and a core of 100 mg composed of a mixture of sugar and microcrystalline cellulose. Preferably, after stirring the spherical mixture in 1000 mL of a 0.5% Triton aqueous solution at pH 4.5 at 75 RPM for 2 hours, the coenzyme Q10 dissolution rate is greater than 80%.

[0133] In another embodiment, the composition of the present invention is spherical, comprising 100 mg of coenzyme Q10, 150 mg of low molecular weight HPMC, and a core of 100 mg composed of a mixture of sugar and microcrystalline cellulose. Preferably, the spherical formulation is stirred at 75 RPM for 2 hours in 1000 mL of a 0.5% Triton aqueous solution at pH 4.5, resulting in a coenzyme Q10 concentration greater than 80%.

[0134] In another embodiment, the composition of the present invention is a spherical formulation comprising 75 mg of coenzyme Q10, 75 to 150 mg of low molecular weight HPMC, and 50 to 100 mg of a core composed of a mixture of sugar and microcrystalline cellulose.

[0135] In another embodiment, the composition of the present invention is a spherical formulation comprising 45 mg of coenzyme Q10, 45 to 90 mg of low molecular weight HPMC, and 45 to 90 mg of a core composed of a mixture of sugar and microcrystalline cellulose.

[0136] In another embodiment, the composition of the present invention is in tablet form, comprising 45 mg coenzyme Q10, 45 to 135 mg PEG 1000 to 22000, 45 to 90 mg poloxamer, as well as crospovidone, crospovidone sodium carboxymethyl cellulose, lactose, and microcrystalline cellulose.

[0137] In another embodiment, the composition of the present invention is in tablet form, comprising 100 mg coenzyme Q10, 100 to 300 mg PEG 1000 to 22000, and 100 to 200 mg poloxamer. Preferably, the formulation further comprises crospovidone, crospovidone sodium carboxymethyl cellulose, lactose, and microcrystalline cellulose.

[0138] In one embodiment, the method for manufacturing the coenzyme Q10 composition of the present invention includes the following steps: a) Mix 1 part coenzyme Q10 with about 2 parts acetone by weight until the coenzyme Q10 is completely dissolved; b) Mix 0.5 to 3 parts of low molecular weight HPMC with 1.5 to 18 parts of ethanol; c) Mix the coenzyme Q10 acetone solution from step a) with the HPMC ethanol solution from step b). d) Place one part of a core containing sugar, microcrystalline cellulose or a mixture thereof in a fluidized bed; e) Spraying the solution from step c) onto a fluidized bed; wherein the solution adheres to and dries on the core surface, coating the core and increasing its size to form spheres; and f) Mix the resulting spheres with magnesium stearate and pack them into capsules or granule bags.

[0139] In one embodiment, the present invention provides a Q10 composition as described herein for providing cardiac nutrition to patients with heart disease.

[0140] In one embodiment, the present invention provides a method for treating coenzyme Q10 deficiency or a disease associated with coenzyme Q10 deficiency (e.g., heart failure, cardiomyopathy, or myopathy), the method comprising administering a Q10 composition as described herein to a patient, wherein less than 300 mg of coenzyme Q10 is administered to the patient once daily.

[0141] In one embodiment, the present invention provides the use of the Q10 composition as described herein for the treatment of coenzyme Q10 deficiency or diseases associated with coenzyme Q10 deficiency (e.g., heart failure, cardiomyopathy, or myopathy), wherein the composition is formulated for administration of 300 mg of coenzyme Q10 to a patient once daily.

[0142] In some embodiments, the compositions of the present invention are used to treat subjects with coenzyme Q10 deficiency, heart failure, myopathy, or cardiomyopathy at a dose of 5 mg to 600 mg daily. In some embodiments, the daily dose is 600 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 500 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 400 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 300 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 200 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 150 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 100 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 50 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 10 mg of coenzyme Q10 daily. In some embodiments, the daily dose is 5 mg of coenzyme Q10 daily.

[0143] In some embodiments, the coenzyme Q10 content in the composition of the present invention is 5 mg to 150 mg per capsule, and is used at a dose of 5 mg to 600 mg / day to treat patients with coenzyme Q10 deficiency, heart failure, myopathy, and cardiomyopathy. In some embodiments, the coenzyme Q10 content is 5 mg per capsule. In some embodiments, the coenzyme Q10 content is 10 mg per capsule. In some embodiments, the coenzyme Q10 content is 20 mg per capsule. In some embodiments, the coenzyme Q10 content is 50 mg per capsule. In some embodiments, the coenzyme Q10 content is 100 mg per capsule. In some embodiments, the coenzyme Q10 content is 120 mg per capsule. In some embodiments, the coenzyme Q10 content is 150 mg per capsule.

[0144] Preferably, the capsule comprises a sphere containing a core coated with coenzyme Q10 and HPMC, wherein the core contains sugar and microcrystalline cellulose, or a mixture thereof.

[0145] Coenzyme Q10 is a chemical substance that is insoluble in water and has low solubility in aqueous media. When testing the solubility of coenzyme Q10 in coenzyme Q10 soft capsules and APIs, the solubility of coenzyme Q10 in coenzyme Q10 APIs or coenzyme Q10 is approximately the same.

[0146] In some embodiments, the composition of the present invention is spherical, comprising water-insoluble coenzyme Q10 and low molecular weight water-soluble HPMC, both coated on the outside of a core comprising sugar, microcrystalline cellulose, or a mixture thereof. The composition may be in the form of spherical or hard capsules comprising said spherical shapes. Preferably, under the same dissolution conditions, said spherical or hard capsules comprising said spherical shapes have a higher coenzyme Q10 dissolution rate in an aqueous medium than coenzyme Q10 raw materials or coenzyme Q10 soft capsules.

[0147] In another embodiment, the composition of the present invention is in the form of granules, tablets, or capsules. The granules may contain water-insoluble coenzyme Q10 and low molecular weight water-soluble HPMC, wherein the granules further contain excipients such as microcrystalline cellulose, lactose, and crospovidone. The granules may be compressed into tablets or filled into hard capsules. Preferably, the granules or tablets of the present invention, under the same dissolution conditions, have a higher coenzyme Q10 dissolution rate in an aqueous medium than coenzyme Q10 raw materials or coenzyme Q10 soft capsules.

[0148] In another embodiment, the composition of the present invention is in the form of granules, tablets, or capsules. The granules may contain coenzyme Q10, PEG 1000 to 22000, poloxamer, sodium docusate, and HPMC. The granules may also contain one or more excipients, such as microcrystalline cellulose, lactose, crospovidone, and crospovidone carboxymethyl cellulose. The granules may be compressed into tablets or filled into hard capsules. Preferably, under the same dissolution conditions, the coenzyme Q10 dissolution rate of the granules or tablets of the present invention in an aqueous medium is higher than that of coenzyme Q10 raw materials or coenzyme Q10 soft capsules.

[0149] This invention relates to a convenient drug delivery system and its preparation method, preferably using common excipients, and is prepared at low cost through a simple method.

[0150] In one embodiment, a method for preparing a spherical coenzyme Q10 composition includes the following steps: a) Mix 1 part by weight of coenzyme Q10 with an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until the coenzyme Q10 is completely dissolved. b) Dissolve 0.5 to 3 parts of low molecular weight HPMC in 1.5 to 9 parts by weight of alcohol; c) Mix the coenzyme Q10 solution from step a) with the HPMC solution from step b) to form a solution; d) Place one part of a core containing sugar, microcrystalline cellulose or a mixture thereof in a fluidized bed; e) Spray the solution containing coenzyme Q10 and HPMC from step c) onto a fluidized bed containing drug cores to coat the cores and increase their particle size until spherical particles of the desired size are obtained; and f) Mix the spheres from step e) with magnesium stearate; and fill the resulting spheres into capsules or pill bags.

[0151] In another embodiment, the method for producing the granular dosage form composition of the present invention includes the following steps: a) Mix 1 part by weight of coenzyme Q10 with an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until the coenzyme Q10 is completely dissolved. b) Dissolve 1 to 3 parts of low molecular weight HPMC in 3 to 18 parts of an alcohol selected from ethanol, benzyl alcohol or isopropanol; c) Mix the solutions from steps a) and b) to form a solution containing HPMC and coenzyme Q10. d) will contain 1 One part microcrystalline cellulose, one part lactose and one part crospovidone filler and swelling agent are placed in a fluidized bed; e) Spray the solution containing coenzyme Q10 and HPMC from step c) onto a fluidized bed to form a powder mixture containing microcrystalline cellulose, lactose and crospovidone. f) Spray the powder mixture from step e) onto PVPK30 to form granules, and mix with magnesium stearate; g) Compress the granules obtained in step f) into tablets, or fill them into capsules or granule bags.

[0152] In another embodiment, a method for preparing the granular dosage form composition of the present invention includes the following steps: a) Mix 1 part by weight of coenzyme Q10 into an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until the coenzyme Q10 is completely dissolved. b) Mix 1 to 3 parts of low molecular weight HPMC with 3 to 18 parts of water to form a suspension; c) Mix the coenzyme Q10 solution from step a) and the HPMC suspension from step b) to form a suspension containing coenzyme Q10 and HPMC. d) Place one part of core material containing sugar, microcrystalline cellulose or a mixture thereof in a fluidized bed; e) Spray the suspension containing coenzyme Q10 and HPMC from step c) onto the fluidized bed; f) Fill the spheres obtained in step e) into capsules or granule bags.

[0153] The solid composition of the present invention can be produced by a wet granulation machine.

[0154] Preferably, compared with existing coenzyme Q10 soft capsules or tablets, the present invention has a higher coenzyme Q10 dissolution rate, which can reduce the amount of coenzyme Q10 required to treat heart disease, thereby reducing gastrointestinal side effects from excessive coenzyme Q10 in the gastrointestinal system. Preferably, the weight ratio of low molecular weight HPMC to coenzyme Q10 in the composition of the present invention is in the range of 0.5:1 to 3:1, or more preferably in the range of 1:1 to 2:1.

[0155] In some embodiments, the coenzyme Q10 composition of the present invention comprises 5 mg to 300 mg of coenzyme Q10, wherein the formulation is in spherical form, or in capsules or spherical bags containing said sphericals. Preferably, the coenzyme Q10 dissolution in the composition is greater than 80% when stirred at 75 rpm for 2 hours in 1000 mL of 0.5% Triton aqueous solution (pH 4.5).

[0156] In another embodiment, the coenzyme Q10 composition of the present invention is spherical, comprising 150 mg of coenzyme Q10, 150 mg to 300 mg of HPMC, and 100 to 150 mg of a core, wherein the core comprises sugar, microcrystalline cellulose, or a mixture thereof. Preferably, the composition is spherical, or in capsule form comprising said spherical shapes. Preferably, the coenzyme Q10 composition dissolves at more than 80% when stirred at 75 rpm for 2 hours in 1000 mL of 0.5% Triton aqueous solution at pH 4.5.

[0157] In another embodiment, the coenzyme Q10 composition of the present invention comprises 120 mg of coenzyme Q10 and 120 mg to 240 mg of HPMC, wherein the composition is in spherical form or in capsule form containing said sphericals. Preferably, the amount of coenzyme Q10 dissolved in the composition is greater than 80% when stirred at 75 RPM for 2 hours in 1000 mL of 0.5% Triton aqueous solution at pH 4.5.

[0158] In another embodiment, the coenzyme Q10 composition of the present invention comprises 50 mg of coenzyme Q10 and 50 mg to 150 mg of HPMC, wherein the composition is in spherical form or in capsule form containing said sphericals. Preferably, the coenzyme Q10 dissolution in the composition is greater than 80% after stirring at 75 RPM for 2 hours in 1000 mL of 0.5% Triton aqueous solution at pH 4.5.

[0159] In another embodiment, the coenzyme Q10 composition of the present invention comprises 30 mg of coenzyme Q10 and 60 mg to 90 mg of HPMC, wherein the composition is in the form of spheres or capsules containing said spheres. Preferably, the coenzyme Q10 dissolution in the composition is greater than 80% after stirring at 75 RPM for 2 hours in 1000 mL of 0.5% Triton aqueous solution at pH 4.5.

[0160] In another embodiment, the coenzyme Q10 composition of the present invention comprises 30 mg of coenzyme Q10, 30 mg to 90 mg of PEG1000 to 22000 and 30 to 60 mg of poloxamer, wherein the composition is in the form of granules, capsules or tablets.

[0161] In another embodiment, the coenzyme Q10 composition of the present invention comprises 30 mg to 150 mg of coenzyme Q10, 30 mg to 450 mg of PEG 1000 to 22000 and 30 to 450 mg of poloxamer, wherein the composition is in capsule or tablet form.

[0162] In another embodiment, the coenzyme Q10 composition of the present invention comprises 200 mg coenzyme Q10, 600 mg PEG 1000 to 22000, 200 mg poloxamer, 100 mg microcrystalline cellulose and 200 mg crospovidone, wherein the composition is in the form of granules or tablets.

[0163] In another embodiment, the coenzyme Q10 composition of the present invention comprises 150 mg coenzyme Q10, 300 mg PEG 1000 to 22000, 300 mg poloxamer, 100 mg microcrystalline cellulose and 150 mg crospovidone, wherein the composition is in the form of granules or tablets.

[0164] In another embodiment, the coenzyme Q10 composition of the present invention comprises 30 mg to 150 mg of coenzyme Q10, 30 mg to 300 mg of PEG 1000 to 22000, 30 mg to 300 mg of poloxamer, 30 mg to 75 mg of sodium docusate, 30 mg to 75 mg of HPMC, and 30 mg to 300 mg of an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, citric acid, or ascorbic acid, wherein the composition is in the form of granules, capsules, or tablets.

[0165] In another embodiment, the coenzyme Q10 composition of the present invention comprises 30 mg to 150 mg of coenzyme Q10, 30 mg to 300 mg of PEG 1000 to 22000, 30 to 300 mg of poloxamer, 30 to 150 mg of HPMC and 30 to 300 mg of an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, citric acid or ascorbic acid, wherein the composition is in the form of granules, capsules or tablets.

[0166] In another embodiment, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 1 to 3 parts PEG 1000 to 22000 and 1 to 3 parts poloxamer, wherein the composition is in capsule or tablet form.

[0167] In another embodiment, the coenzyme Q10 composition of the present invention comprises 30 mg to 150 mg of coenzyme Q10, 30 mg to 150 mg of PEG 1000 to 22000, 30 mg to 150 mg of poloxamer, 30 mg to 75 mg of sodium docusate, and 30 mg to 150 mg of an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, citric acid, or ascorbic acid, wherein the composition is in the form of granules, capsules, or tablets.

[0168] In another embodiment, the coenzyme Q10 composition of the present invention comprises 1 part coenzyme Q10, 1 to 3 parts low molecular weight HPMC, 1 to 3 parts PEG 1000 to 22000, 1 to 3 parts poloxamer, 1 part sodium docusate, and 1 to 3 parts an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, citric acid, or ascorbic acid, or a mixture thereof; wherein the composition is in the form of granules, capsules, or tablets.

[0169] In another embodiment, the coenzyme Q10 composition of the present invention comprises 30 mg to 150 mg of coenzyme Q10, 30 mg to 450 mg of PEG 1000 to 22000, 30 to 450 mg of poloxamer, 30 to 150 mg of sodium docusate, 30 to 150 mg of HPMC and 30 to 450 mg of an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, citric acid or ascorbic acid, wherein the composition is in the form of granules, capsules or tablets.

[0170] The compositions of the present invention may be liquid solutions or solid dosage forms comprising coenzyme Q10, water-soluble excipients (e.g., HPMC, PEG, sodium docusate, poloxamer, or pranoxam), and polysorbate, wherein the compositions have a high solubility of coenzyme Q10 of greater than 60% in an aqueous medium, and wherein the compositions may be used to treat coenzyme Q10 deficiency in subjects. The compositions may have a high solubility of coenzyme Q10 of greater than 70%, 80%, or 90% in a 0.5% Triton aqueous medium at pH 4.5.

[0171] The liquid composition of the present invention may be in the form of a soft capsule, comprising coenzyme Q10, PEG 200 to 600, and other ingredients selected from [the present invention]. 20. 40. 60 and Polysorbate 80 or a mixture thereof. This liquid solution can be bottled and taken orally.

[0172] The compositions of the present invention may be spherical, comprising coenzyme Q10, a core containing one or more excipients, and a binder comprising low molecular weight HPMC. Preferably, the molecular weight of HPMC is equal to or less than 26,000 g / mol.

[0173] The composition of the present invention may be spherical, comprising a mixture of HPMC and coenzyme Q10, coated on the surface of a tablet core, wherein the tablet core comprises sugar, microcrystalline cellulose or a mixture thereof.

[0174] The core of the composition may contain one or more of sugar, microcrystalline cellulose, lactose, starch, mannitol, sorbitol, fructose-1,6-diphosphate and crospovidone, or a mixture thereof.

[0175] The compositions of the present invention may comprise coenzyme Q10, PEG 1000 to 22000, poloxamer, and polysorbate, wherein the compositions may be in the form of granules, tablets, capsules, or liquids. The compositions of the present invention may comprise: a) 1 part coenzyme Q10, 10 parts PEG 1000 to 22000, wherein the composition may be in the form of granules, tablets or capsules, and also contains fillers, swelling agents and lubricants; b) 1 part coenzyme Q10, 2 parts PEG 1000 to 22000, wherein the composition may be in the form of granules, tablets or capsules, and also contains fillers, swelling agents and lubricants; c) 1 part coenzyme Q10, 3 parts PEG 1000 to 22000, wherein the composition may be in the form of granules, tablets or capsules, and also contains fillers, swelling agents and lubricants; d) 1 part coenzyme Q10, 1 part poloxamer, wherein the composition may also contain fillers, swelling agents and lubricants; e) 1 part coenzyme Q10, 2 parts poloxamer, wherein the composition may also contain fillers, swelling agents and lubricants; f) 1 part coenzyme Q10, 3 parts poloxamer, wherein the composition also contains fillers, swelling agents and lubricants; g) 1 part Coenzyme Q10, 1 part PEG 200-600, wherein the composition can be in a liquid form that can be filled into soft capsules; h) 1 part Coenzyme Q10, 2 parts PEG 200-600, wherein the composition can be in a liquid form that can be filled into soft capsules; i) 1 part Coenzyme Q10, 10 parts PEG 200-600, wherein the composition can be in a liquid form that can be filled into soft capsules; j) 1 part Coenzyme Q10, 1 part selected from... 20. 40. 60 and 80% of polysorbate, or a mixture thereof, the composition being in liquid form that can be filled into soft capsules; k) 1 part Coenzyme Q10, 2 parts selected from 20. 40. 60 and 80% of polysorbate, or a mixture thereof, the composition being in liquid form that can be filled into soft capsules; l) 1 part Coenzyme Q10, 10 parts selected from 20. 40. 60 and 80% polysorbate, or a mixture thereof, the composition being in liquid form that can be filled into soft capsules; m) 1 part coenzyme Q10, 0.5 to 1 part (by weight) sodium docusate, the composition being in the form of granules, tablets or capsules, and also containing fillers, expanders and lubricants; n) 1 part coenzyme Q10, 1 to 3 parts PEG 1000 to 22000, 1 to 3 parts poloxamer and 0.5 to 1 part (by weight) sodium docusate, the composition also contains fillers, swelling agents and lubricants; o) 1 part by weight of coenzyme Q10, 1 to 3 parts by weight of PEG 1000 to 22000, 0.5 to 1 part by weight of sodium docusate, and 0.5 to 1 part by weight of HPMC, wherein the composition may further contain fillers, swelling agents, and lubricants, and the composition is preferably in the form of granules, tablets, or capsules; or p) By weight, 1 part coenzyme Q10, 1 to 3 parts PEG 1000 to 22000, 1 to 3 parts poloxamer and 0.5 to 1 part sodium docusate, wherein the composition may further contain fillers, swelling agents and lubricants.

[0176] The composition of the present invention can be formed into a spherical shape and comprises, by weight: a) 1 part coenzyme Q10, 0.5 to 3 parts low molecular weight HPMC and 1 part core containing sugar, microcrystalline cellulose or a mixture thereof; b) 1 part coenzyme Q10, 1 part low molecular weight HPMC and 1 part core containing sugar, microcrystalline cellulose or a mixture thereof; c) 1 part coenzyme Q10, 2 parts low molecular weight HPMC and 1 part core containing sugar, microcrystalline cellulose or a mixture thereof; or d) 1 part coenzyme Q10, 3 parts low molecular weight HPMC and 1 core containing sugar, microcrystalline cellulose or a mixture thereof.

[0177] In a preferred embodiment, the composition of the present invention may be in the form of granules or capsules containing coenzyme Q10 and low molecular weight HPMC, wherein the composition further comprises lactose, microcrystalline cellulose, crospovidone, or a mixture thereof.

[0178] In a preferred embodiment, the composition of the present invention comprises coenzyme Q10 and PEG 200 to 600, preferably wherein the composition is in liquid or soft capsule form.

[0179] In a preferred embodiment, the composition of the present invention may comprise coenzyme Q10, PEG 200 to 600, and a mixture selected from [the group consisting of coenzyme Q10, PEG 200 to 600, and other ingredients]. 20. 40. 60 and A liquid solution of 80% polysorbate or a mixture thereof, wherein the composition may be in the form of soft capsules.

[0180] In a preferred embodiment, the composition of the present invention may comprise 1 part coenzyme Q10, 1 part PEG 200 to 600, and 1 part selected from [the following]. 20. 40. 60 and A liquid solution of polysorbate 80 or a mixture thereof, wherein the composition may be in the form of soft capsules.

[0181] In a preferred embodiment, the composition of the present invention may comprise 1 part coenzyme Q10, 2 parts PEG 200 to 600, and 1 to 2 parts selected from [the following is a list of ingredients]. 20. 40. 60 and A liquid solution of polysorbate 80 or a mixture thereof, wherein the liquid may be filled into soft capsules or bottles.

[0182] In a preferred embodiment, the composition of the present invention comprises 1 part by weight of coenzyme Q10 and 1 to 10 parts selected from […]. 20. 40. 60 and 80% polysorbate, wherein the composition may be in the form of soft capsules.

[0183] In one embodiment, a method for preparing a spherical coenzyme Q10 composition includes the following steps: a) Dissolve 1 part by weight of coenzyme Q10 in an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until coenzyme Q10 is completely dissolved. b) Dissolve 1 to 3 parts of low molecular weight HPMC in a solvent selected from ethanol, isopropanol or benzyl alcohol; c) Mix the solution from step a) with the solution from step b) to form a solution containing coenzyme Q10 and HPMC; and d) Spray the coenzyme Q10 and HPMC solution from step c) onto the core in a fluidized bed, wherein the core contains sugar, microcrystalline cellulose, or a mixture thereof to form spheres.

[0184] In one embodiment, a method for preparing a coenzyme Q10 composition includes the following steps: a) Dissolve 1 part by weight of coenzyme Q10 in an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform. b) Add 1 to 3 parts of PEG 1000 to 22000, 1 to 3 parts of poloxamer, or 0.5 parts by weight of sodium docusate to the solution in step a) until the PEG, poloxamer, or sodium docusate are completely dissolved or dispersed. c) Add 1 part each of lactose, microcrystalline cellulose and crospovidone to the fluidized bed; d) Spray the mixture containing coenzyme Q10 from step b) onto the tablet cores on the fluidized bed to form a powder mixture; e) Spray the PVP K30 solution into the fluidized bed of step d) to form particles; f) Mix the granules from step e) with a lubricant (e.g., magnesium stearate) and compress them into tablets or fill them into capsules or granule bags.

[0185] The compositions of this invention can be used to provide cardiac nutrition for patients with heart disease.

[0186] In another embodiment, the present invention provides the use of the compositions of the present invention in the preparation of a medicament for treating coenzyme Q10 deficiency or diseases associated with coenzyme Q10 deficiency (e.g., heart failure, cardiomyopathy, or myopathy), wherein the compositions are formulated for administration of 300 mg of coenzyme Q10 to a patient once daily. General manufacturing methods

[0187] The following embodiments illustrate a method for preparing a composition containing coenzyme Q10 according to the present invention.

[0188] In one embodiment, the composition of the present invention comprises coenzyme Q10, low molecular weight HPMC, and a core comprising sugar, microcrystalline cellulose, or a mixture thereof. Coenzyme Q10 and HPMC are mixed together as a coating layer on the core surface. Preferably, the weight ratio of HPMC to coenzyme Q10 is in the range of about 0.5:1 to 3:1.

[0189] Preferably, compared with existing coenzyme Q10 soft capsules, the spherical or capsule-containing coenzyme Q10 composition of the present invention has a higher coenzyme Q10 solubility in aqueous media or digestive systems, thereby increasing absorption in the human body after ingestion.

[0190] In one embodiment, the coenzyme Q10 composition of the present invention is in granular form, comprising coenzyme Q10, PEG 1000 to 22000, poloxamer, and low molecular weight HPMC, as well as fillers and swelling agents comprising microcrystalline cellulose, lactose, crospovidone, and crospovidone sodium carboxymethyl cellulose. A solution containing HPMC and coenzyme Q10 is mixed with microcrystalline cellulose, lactose, and crospovidone in a fluidized bed. The composition of the present invention may be in the form of granules, tablets, or capsules containing said granules.

[0191] The formulations of the present invention can be prepared by a variety of methods known to those skilled in the art. General methods for preparing spheres

[0192] The following examples illustrate methods for preparing the compositions of the present invention (including the sphere and capsule forms of the present invention).

[0193] In one embodiment, the spherical coenzyme Q10 composition of the present invention is prepared by the following method: a) Dissolve 1 part by weight of coenzyme Q10 raw material in 2 to 6 parts by weight of organic solvent, wherein the organic solvent is selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane and trichloromethane. b) Dissolve 1 to 3 parts of HPMC in 2 to 18 parts by weight of an alcohol selected from ethanol, benzyl alcohol and isopropanol, or disperse it in a large amount of water. c) Place one part of a core containing sugar, microcrystalline cellulose or a mixture thereof in a fluidized bed; d) Mix the solution from step a) with the solution or suspension from step b) and spray it onto a fluidized bed containing the drug core; e) Mix the spheres obtained in step d) with magnesium stearate; and f) Fill the spheres obtained in step e) into capsules or core bags. General methods for manufacturing granules using HPMC

[0194] The following examples illustrate methods for manufacturing the compositions of the present invention, including in the form of granules, tablets, and capsules according to the present invention. a) Dissolve 1 part by weight of coenzyme Q10 raw material in 2 to 6 parts by weight of an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or trichloromethane until completely dissolved. b) Dissolve 1 to 3 parts of HPMC in 2 to 18 parts by weight of an alcohol (selected from ethanol, isopropanol or benzyl alcohol) until completely dissolved; c) Mix the coenzyme Q10 solution from step a) with the HPMC solution from step b); d) Place 1 part of croscarmellose sodium, 1 part of croscarmellose and 1 part of microcrystalline cellulose in a fluidized bed; e) Spray the solution containing coenzyme Q10 and HPMC from step c) onto a fluidized bed to form granular powder; f) Mix the particles from step e) with magnesium stearate; g) Fill the granules obtained in step f) into capsules, compress them into tablets, or pack them into granule bags. General method for preparing particles containing PEG 10000 to 22000, poloxamer, and sodium docusate.

[0195] The following examples illustrate methods for preparing the compositions of the present invention (including granules and tablets). a) Dissolve 1 part by weight of coenzyme Q10 raw material in 2 to 6 parts by weight of an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or trichloromethane until completely dissolved; b) Dissolve 1 to 3 parts of PEG 1000 to 22000, 1 to 3 parts of poloxamer and 1 part of sodium docusate in 3 to 10 parts of an alcohol selected from ethanol, isopropanol or benzyl alcohol until completely dissolved; c) Mix the coenzyme Q10 solution from step a) with the solution obtained in step b); d) Place 1 part croscarmellose sodium, 1 part croscarmellose and 1 part microcrystalline cellulose in a fluidized bed; e) Spray the solution from step c) onto a fluidized bed to form granular powder; f) Spray an 8% PVPK30 solution onto a fluidized bed to bind the powder together and obtain granules; g) Mix the particles from step f) with magnesium stearate; h) The granules obtained in step g) are encapsulated, compressed into tablets, or packaged into granule bags. General method for preparing particles containing PEG and poloxamer

[0196] The following examples illustrate methods for preparing the compositions of the present invention, including granules, tablets, and capsules. a) Dissolve 1 part by weight of coenzyme Q10 raw material in 2 to 6 parts by weight of an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or trichloromethane until completely dissolved. b) Dissolve 1 to 3 parts of PEG 1000 to 22000 and 1 to 2 parts of poloxamer in 3 to 12 parts of an alcohol selected from ethanol, isopropanol or benzyl alcohol until completely dissolved. c) Mix the coenzyme Q10 solution from step a) with the PEG / poloxam solution from step b); d) Place 1 to 2 parts of croscarmellose sodium and 1 to 2 parts of croscarmellose in a fluidized bed; e) Spray the solution containing coenzyme Q10, poloxamer and PEG 1000 to 22000 from step c) onto a fluidized bed to form granular powder; f) Spray an 8% PVPK30 solution onto a fluidized bed to bind the powder together and obtain granules; g) Mix the particles from step f) with magnesium stearate; h) The granules obtained in step g) are encapsulated, compressed into tablets, or packaged into granule bags. General methods for treating coenzyme Q10 deficiency

[0197] One embodiment of the present invention relates to administering the compositions of the present invention disclosed herein to treat coenzyme Q10 deficiency or diseases associated with coenzyme Q10 deficiency, including, for example, heart failure, cardiomyopathy, or myopathy.

[0198] In some embodiments, when used to treat coenzyme Q10 deficiency, the coenzyme Q10 content in the composition of the present invention is about 5 mg to 150 mg per tablet. In some embodiments, when used to treat heart failure, cardiomyopathy, or myopathy, the dose of coenzyme Q10 in the composition of the present invention is about 5 mg to 150 mg daily. Example

[0199] The present invention will now be illustrated by the following examples, which should not be construed as limiting the invention in any way, and are merely examples of the various formulations described herein.

[0200] Dissolution testing was performed on capsules containing 150 mg of coenzyme Q10. After stirring at 75 rpm for 2 hours in 1000 mL of 0.5% Triton (surfactant) aqueous solution, the dissolved amount was 26 mg, accounting for 17.3%.

[0201] Another existing technology composition, BLACKMORES 150 mg Coenzyme Q10 soft capsules, was also tested for dissolution. In 1000 mL of 0.5% Triton solution (buffered with sodium acetate to pH 4.5), with stirring at 75 rpm for 2 hours, the dissolved amount (batch number 31185) was 14 mg, or 9.3%. After stirring for 3 hours, the dissolved amount was approximately 26 mg, indicating that the soft capsules did not improve the dissolution of Coenzyme Q10.

[0202] Further solubility tests were performed using BLACKMORES 150mg Coenzyme Q10 soft capsules (batch number 31185), and the following results were obtained by stirring at 75 RPM in 1000 mL of 0.5% Triton aqueous solution with different buffering conditions:

[0203] Dissolution tests were also conducted on 150mg (30mg x 5) Coenzyme Q10 soft capsules (batch number 20211105) produced by Dongying Zouning Biotechnology Co., Ltd. The capsules were dissolved in 1000mL of 0.5% Triton aqueous solution (buffered with 0.1% Tween 80) at 75RPM for 2 hours, and the dissolution rate was 0.2%.

[0204] A representative dissolution method that can be used according to the present invention is as follows: the composition containing 150 mg of coenzyme Q10 microspheres is stirred at 75 RPM for 2 hours in 1000 mL of 0.5% Triton solution (buffered with sodium acetate to pH 4.5) to achieve a dissolution of 145 mg. Example 1: Preparation of Coenzyme Q10 spheres and their dissolution in 1000 mL of 0.5% Triton aqueous solution (pH 4.5, buffered with sodium acetate).

[0205] Prepare coenzyme Q10 capsules containing 150 mg of coenzyme Q10 using the following method: a) Dissolve 1500g of coenzyme Q10 raw material in 3000g of acetone; b) Dissolve 1500g HPMC(E5) in 4950g ethanol; c) Mix the solution from step a) and the solution from step b) to form a solution; d) Place 3000g of sucrose cores (0.5mm to 0.71mm in diameter) in a fluidized bed; e) Spray the mixture from step c) onto a fluidized bed; f) Cool the material on the fluidized bed to a temperature below 35°C to obtain spherical or granular products; g) Fill the spheres or granules from step f) into capsules or granule bags.

[0206] The composition with batch number 220824 had the highest coenzyme Q10 dissolution rate, but the number of spheres was too large to fill into capsules. However, the spheres could be filled into granule bags.

[0207] The following five examples use a similar production method as described above, but with different reagent ratios, resulting in different dissolution amounts, as shown below: Example 2: Preparation of Coenzyme Q10 granules and 90mg tablets using fluidized bed granulation: Batch number S221130 reagents ]]> ​ Content of each reagent (mg) Content of each reagent (g) Cross-linked polyvinylpyrrolidone 120 720 lactose 30 180 microcrystalline cellulose 60 360 Coenzyme Q10 90 540 HPMC 180 1080 PVPK30 10 60 magnesium stearate 4.9 29.4 talcum powder 3.6 21.6

[0208] Coenzyme Q10 granules and 90mg tablets are prepared according to the following steps: a) Dissolve 540g of coenzyme Q10 raw material in 1080g of acetone; b) Disperse 1080g of HPMC in 7200g of water; c) Mix the solution from step a) and the mixture from step b) together to form a mixture; d) Place 180g lactose, 720g crospovidone and 360g microcrystalline cellulose in a fluidized bed; e) Spray the mixture containing coenzyme Q10 and HPMC from step c) onto the fluidized bed; f) Spraying an 8% PVPK30 solution onto a fluidized bed yields granules; g) Mix the granules from step f) with magnesium stearate; compress the resulting granules into tablets, wherein the tablets contain 90 mg of coenzyme Q10.

[0209] Dissolution tests were conducted on Coenzyme Q10 granules and tablets (each containing 90 mg of Coenzyme Q10) in 1000 mL of 0.5% Triton aqueous solution (pH 4.5, buffered with sodium acetate) with stirring at 75 RPM. The results are as follows:

[0210] The dissolution rate of tablets is lower than that of the granules of this invention. The dissolution rate of both coenzyme Q10 granules and tablets is lower than that of the coenzyme Q10 microspheres of this invention. Example 3: Formulation of 45 mg Coenzyme Q10 granules and tablets

[0211] A dissolution test was conducted on coenzyme Q10 tablets and granules (each tablet containing 45 mg of coenzyme Q10) in 1000 mL of 0.5% Triton aqueous solution with stirring at 75 RPM. The following results were obtained: Example 4: Formulations of granules and tablets containing 45 mg Coenzyme Q10 and 90 mg PEG 6000

[0212] The following results were obtained from a dissolution test of coenzyme Q10 tablets and granules (each tablet containing 45 mg of coenzyme Q10) in 1000 mL of 0.5% Triton aqueous solution with stirring at 75 RPM: Example 5: Coenzyme Q10 tablet formulation and dissolution in 1000 mL of 0.5% Triton and 0.1% Tween 80 aqueous solution

[0213] Prepare coenzyme Q10 tablets containing 30 mg of coenzyme Q10 using the following method: a) Dissolve 300g of coenzyme Q10 raw material, 900g of sorbitol, 120g of lecithin and 900g of malic acid in 7800g of acetone; b) Place 300g of crospovidone, 300g of crospovidone sodium carboxymethyl cellulose and 300g of sodium dodecyl sulfate in a fluidized bed; c) Spray the solution from step a) onto the fluidized bed; d) A 3% PVPK30 solution is sprayed onto a fluidized bed to form particles; e) Mix the granules from step d) with magnesium stearate and talc. Compress the resulting granules into tablets, wherein each tablet contains 30 mg of coenzyme Q10.

[0214] Coenzyme Q10 granules and tablets (each containing 30 mg of coenzyme Q10) were placed in 1000 mL of 0.5% Triton X-100 and 0.1% Tween 80 aqueous solution and stirred at 75 rpm for dissolution testing. The results are as follows: Example 6: Formulation of Coenzyme Q10 capsules and dissolution in 1000 mL of 0.5% Triton aqueous solution

[0215] Prepare coenzyme Q10 capsules containing 150mg of coenzyme Q10. The method is as follows: a) Dissolve 1500g of coenzyme Q10 raw material and 1500g of citric acid in 39000g of acetone; b) Dissolve hydroxypropyl methylcellulose (E5) in 5000g of ethanol; c) Mix the solution from step a) with the solution from step b); d) Place 700g lactose, 600g microcrystalline cellulose and 700g sorbitol in a fluidized bed; e) Spray the mixture from step c) onto a fluidized bed; f) Spray a 2.4% PVPK30 solution onto a fluidized bed to form particles. g) Cool the material on the fluidized bed to a temperature below 35°C to obtain spherical or granular products; h) Mix the spherical or granular product from g) with magnesium stearate and talc; pass the resulting granules through a 24-mesh sieve and then fill them into capsules.

[0216] Coenzyme Q10 capsules (each containing 150 mg of coenzyme Q10) were placed in 1000 mL of 0.5% Triton aqueous solution and stirred at 75 rpm for dissolution testing. The results are as follows:

Claims

1. A composition comprising coenzyme Q10 and one or more water-soluble excipients, The excipients are selected from hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), sodium docusate, poloxamer, organic acids, and polysorbate, wherein... The solubility of coenzyme Q10 in the aqueous medium in the composition is greater than 60%.

2. The composition according to claim 1, wherein, Coenzyme Q10 in the composition The solubility in 1000 mL of a 0.5% Triton aqueous solution with pH 4.5 is greater than 60%, 70%, 80%, or 90%.

3. The composition according to claim 1, wherein, The composition is spherical. The sphere comprises coenzyme Q10, a binder comprising low molecular weight HPMC, and a core comprising one or more excipients.

4. The composition according to any one of claims 1 to 3, wherein the molecular weight of the HPMC is equal to or less than 26,000 g / mol.

5. The composition according to any one of claims 2 or 3, wherein the composition comprises a mixture of HPMC and coenzyme Q10 coated on the surface of a core material, wherein the core material comprises sugar, microcrystalline cellulose, or a mixture thereof.

6. The composition according to any one of claims 1 to 5, wherein the core material comprises one or more of sugar, microcrystalline cellulose, lactose, starch, mannitol, sorbitol, fructose 1,6-bisphosphate and crospovidone, or a mixture thereof.

7. The composition of claim 1, wherein the composition comprises coenzyme Q10 and PEG 200 to 22000, wherein the composition is a liquid, granules, tablets or capsules.

8. The composition according to any one of claims 1 or 7, wherein the composition comprises 1 part coenzyme Q10 and 1 to 4 parts (by weight) PEG 1000 to 22000.

9. The composition according to claim 8, further comprising a filler, an expander, and a lubricating excipient.

10. The composition according to any one of claims 1 or 7, wherein the composition comprises 1 part coenzyme Q10 and 1 to 10 parts (by weight) PEG 200 to 600.

11. The composition according to any one of claims 1 or 7, wherein the composition comprises 1 part (part by weight) of coenzyme Q10 and 1 to 10 parts of an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, citric acid and ascorbic acid.

12. The composition of claim 1, wherein the composition is granules, tablets or capsules, comprising coenzyme Q10 and poloxamer.

13. The composition of claim 12, wherein the composition comprises 1 part coenzyme Q10 and 1 to 4 parts poloxamer.

14. The composition of claim 1, wherein the composition comprises coenzyme Q10, PEG 1000 to 22000 and poloxamer, wherein the composition is in the form of granules, tablets or capsules.

15. The composition of claim 14, wherein the composition comprises 1 part coenzyme Q10, 1 to 3 parts PEG 1000 to 22000 and 1 to 3 parts poloxamer (by weight).

16. The composition of claim 15, further comprising a filler, an expander, and a lubricating agent.

17. The composition of claim 1, wherein the composition comprises 1 part coenzyme Q10 and 0.5 to 3 parts docusate sodium (by weight).

18. The composition of claim 1, wherein the composition comprises 1 part coenzyme Q10, 1 to 3 parts PEG 1000 to 22000, 1 to 3 parts poloxamer and 0.5 to 1 part sodium docusate (by weight), and the composition further comprises a filler, a swelling agent and a lubricating agent.

19. The composition of claim 1, wherein the composition is spherical and comprises, by weight, 1 part coenzyme Q10, 0.5 to 3 parts low molecular weight hydroxypropyl methylcellulose (HPMC), and 0.5 to 1 part a core material comprising sugar, microcrystalline cellulose, or a mixture thereof.

20. The composition of claim 1, wherein the composition is a granule or capsule comprising coenzyme Q10 and low molecular weight hydroxypropyl methylcellulose (HPMC), wherein, The composition also contains one or more of lactose, sugar, microcrystalline cellulose and / or crospovidone, or a mixture thereof.

21. A method for preparing a spherical coenzyme Q10 composition, the method comprising the following steps: a) Dissolve 1 part by weight of coenzyme Q10 in an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until the coenzyme Q10 is completely dissolved. b) Dissolve 0.5 to 3 parts by weight of low molecular weight hydroxypropyl methylcellulose (HPMC) in a solvent selected from ethanol, isopropanol or benzyl alcohol; c) Mix the solution from step a) with the solution from step b) to form a solution containing coenzyme Q10 and HPMC; as well as d) Spray the coenzyme Q10 and HPMC solution from step c) onto the core material of the fluidized bed, wherein the core material contains sugar, microcrystalline cellulose or a mixture thereof, to form spheres containing coenzyme Q10, HPMC and the core material.

22. A method for preparing a coenzyme Q10 composition, the method comprising the following steps: a) Dissolve 1 part by weight of coenzyme Q10 in an organic solvent selected from acetone, butanone, pentanone, ethanol, isopropanol, benzyl alcohol, dichloromethane or chloroform until coenzyme Q10 is completely dissolved or dispersed. b) Add 1 to 3 parts of PEG 1000 to 22000, 1 to 3 parts of poloxamer, or 0.5 to 1 part of sodium docusate (by weight) to the solution or dispersion of step a) until the PEG, poloxamer, or sodium docusate are completely dissolved or dispersed. c) Place 1 part lactose, 1 part sugar, 1 part microcrystalline cellulose and 1 part crospovidone in a fluidized bed; d) Spray the solution or dispersion from step b) onto a fluidized bed to form a powdered mixture; e) Spraying the PVP K30 solution onto the fluidized bed of step d) to form particles; and f) Mix the granules from step e) with a lubricant (preferably magnesium stearate) and compress the granules into tablets or into capsules or granule bags.

23. The composition according to any one of claims 1 to 20, for providing cardiac nutrition to patients with heart disease.

24. The composition according to any one of claims 1 to 20, for manufacturing a medicament for treating coenzyme Q10 deficiency or diseases associated with coenzyme Q10 deficiency, such as heart failure, cardiomyopathy, or myopathy, wherein, This composition is formulated for daily administration of 300 mg of coenzyme Q10 to patients.

25. A method of treating coenzyme Q10 deficiency or a disease associated with coenzyme Q10 deficiency, such as heart failure, cardiomyopathy, or myopathy, comprising administering to a subject the composition of any one of claims 1 to 20, wherein the composition is formulated for administering 300 mg of coenzyme Q10 to the patient daily.

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