TW202000191A - Sustained release formulations of BEMPEDOIC ACID - Google Patents

Abstract

Herein disclosed are sustained-release bempedoic acid compositions with improved bioavailability and pharmacokinetic characteristics, kits comprising said compositions, and methods of use thereof. Also described are methods of delivering bempedoic acid.

Description

BEMPEDOIC 　ACID sustained release formulation

Bempedoic acid (ETC-1002) acts as a prodrug in vivo, which is converted into active substance (ETC) by endogenous liver acyl-coenzyme (CoA) synthase (ACS) activity in vivo -1002-CoA). A specific ACS isozyme, that is, an extremely long-chain acyl-CoA synthetase (ACSVL1), is required to form an active substance. Once activated, ETC-1002-CoA directly inhibits ATP-citrate lyase (ACL), and mediates the effect on lipid metabolism via this effect. In traditional formulations, part of the leukoderma in the dosage form is activated, and the remaining unactivated portion of the administered dose is removed. To some extent, this is due to the low solubility and high permeability of many biopharmaceutical classification systems ("BCS") class II active pharmaceutical ingredients ("API") (such as tannin). Therefore, there is a need in the industry to increase the exposure of active drugs to the liver without increasing the dosage of dodecanoic acid administered to patients.

The present inventors have discovered that the sustained release of dominoic acid provides increased activation efficiency to the active substance and improves the exposure of the activated drug in the liver.

Aspects of the present disclosure include pharmaceutical formulations, which include the following components: (i) 50%-70% leukoderma acid, (ii) filler, (iii) diluent or solubilizer, and (iv ) Adhesive, wherein the formulation is formulated for sustained release of tannin. In some aspects, the filler is selected from the group consisting of, for example, microcrystalline cellulose, sodium carboxymethyl cellulose, and a combination of microcrystalline cellulose and sodium carboxymethyl cellulose. In some aspects, the diluent or solubilizer is selected from the group consisting of, for example, sodium lauryl sulfate and sodium starch glycolate. In some aspects, the binder is, for example, hydroxypropyl methyl cellulose (HMPC). In some aspects, the formulation is formulated as a solid. In some aspects, the formulation is formulated for oral administration.

In some aspects, any of the formulations described above contains pleurotropin dispersed in a polymeric matrix. In some aspects, any of the formulations described above is a formulation that exhibits a drug release profile corresponding to the following pattern: where (for example) after 2 hours, no more than 30% of the total mass of leukoderma Release into the individual. In some aspects, any of the formulations described above exhibits a drug release curve corresponding to the following pattern: where (for example) after 4 hours, the release of no more than 75% of the total mass acid. In some aspects, any of the formulations described above is a formulation that exhibits a drug release curve corresponding to the following pattern: where (for example) after 8 hours, no more than 90% of the total mass of Bianpi Duoyi is released acid. In some aspects, any of the formulations set forth above is a formulation that provides a therapeutically effective concentration of leukolide at a time of, for example, a 24-hour period when administered to a human subject.

In some aspects, in any of the formulations described above, the filler component is (for example) microcrystalline cellulose or sodium carboxymethyl cellulose or sodium carboxymethyl cellulose and microcrystalline cellulose combination. In some aspects, the amount of filler component in the formulation is 5%-50% w/w. In some aspects, the binder component is about 0.1%-1.5% w/w. In some aspects, the formulations described above include, for example, 50%-70% w/w of flavonoid dodecanoic acid, 30%-45% w/w of filler component, 1%-5 % w/w diluent or solubilizer component and 0.1%-1.5% w/w adhesive component. In some aspects, the formulations described above include, for example, 55%-65% w/w of flavonoid dodecanoic acid, 30%-45% w/w of the filler component, 1%-5 % w/w diluent or solubilizer component and 0.1%-1.5% w/w adhesive component. In some aspects, the formulations described above include, for example, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg or 220 mg of flavonoid dodecanoic acid.

In some aspects, the formulation set forth above dissolves at a zero-order release rate for at least (for example) 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In some aspects, the formulation set forth above includes dermatine and polymer matrix, and has a hardness of, for example, 2-30 kg. In some aspects, the formulation set forth above is shaped as a sphere or has a thickness to diameter ratio that effectively allows erosion when dissolution is tested.

In some aspects, when administered to a human individual, any of the formulations described above provides a therapeutically effective concentration of leukolide in a 24-hour period. In some aspects, the formulation when administered to a human individual provides a maximum plasma concentration of dombydoic acid that does not exceed (for example) 50 µg/mL, 60 µg/mL, 70 µg/mL, or 80 µg/mL ( C _max ). In some aspects, the formulation provides, after administration to a human individual, a maximum plasma concentration ( _Cmax ) of leukodermic acid in the range of 45 µg/mL to 60 µg/mL for (e.g.) 20 hours, 21 hours, 22 hours, 23 hours or 24 hours.

In some aspects, any of the formulations described above is formulated as, for example, gelatin capsules or lozenges. In some aspects, the gelatin capsule contains, for example, a powdered excipient.

In some aspects, the present disclosure encompasses a method of administering a leukoderma multi-acid formulation to a human individual in need thereof, wherein the formulation comprises a dermo-derma multi-acid acid and a polymer matrix, and wherein the administration is such that The maximum plasma concentration ( _Cmax ) of pidoyi acid does not exceed about (for example) 60 µg/mL, and the plasma concentration after administration is in the range of about 45-57 µg/mL for 24 hours. In a related aspect, the formulation is one of the formulations described above.

In some aspects, the present disclosure encompasses a method of treating an individual's cardiovascular disease or reducing the risk of cardiovascular disease, the method comprising administering an effective amount of a pharmaceutical formulation to a human individual in need thereof, wherein the formulation includes edema The components of dodecanoic acid and the polymer, and the dissolution of the formulation exhibits a drug release curve corresponding to the following pattern: for example, after 2 hours, do not release more than 30% of the flaky dodecanoic acid; after 4 hours, release Do not exceed 75% of the scalp dodecanoic acid; after 8 hours, release no more than 90% of the scalp dodecanoic acid. In some aspects, when administered to an individual, the method provides a therapeutically effective concentration of leukolide in a 24-hour period to treat cardiovascular disease or reduce the risk of cardiovascular disease. In another related aspect, the formulation administered does not release more than 95% of leukotopic acid after 8 hours. In a related aspect, the formulation administered is one of the formulations described above.

In some aspects of the method described above, the polymer is hydroxypropyl methyl cellulose (HPMC). In certain other aspects, the leukoderma in the formulation administered is (for example) about 30-80% by weight, and the polymer is hydroxypropyl methylcellulose (HPMC) and is (for example) About 15-35% by weight.

In certain aspects of any of the methods described above, when administered to a human individual with, for example, hypercholesterolemia, mixed dyslipidemia, type 2 diabetes, obesity, chronic liver disease, or kidney disease, This method reduces total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). In certain other aspects of any of the methods described above, the method reduces the level of very low density lipoprotein (VLDL) in the individual to below the level of the control individual receiving placebo. In certain other aspects of any of the methods described above, the method reduces the size of the VLDL particles in the individual below the size of the control individual receiving placebo. In some other aspects of any of the methods described above, this method reduces the ratio of lipoprotein element B (ApoB) to lipoprotein element A-1 (ApoA1) in the individual to be lower than the control receiving placebo The ratio of individuals. In certain other aspects of any of the methods described above, the method reduces the level of low density lipoprotein cholesterol (LDL-C) in the individual. In some other aspects of any of the methods described above, this method reduces the LDL-C content by at least 5%, 10%, 15% or 20%. In some other aspects of any of the methods described above, this method reduces the LDL-C content by 5%-40% relative to the original untreated or placebo-treated individual. In certain other aspects of any of the methods described above, this method is at least as effective as an equivalent dose of immediate-release dombyid acid formulation to reduce the LDL-C content in an individual. In certain other aspects of any of the methods described above, the method is at least as effective as a higher dose of immediate-release dominoic acid formulation to reduce LDL-C content in an individual, wherein the higher dose It is 180 mg/day.

In addition, the sustained release compositions set forth herein provide an effective means of systemic delivery of dominoic acid. Therefore, lower doses and/or less frequent administration (relative to known dombynoic acid formulations) are required to produce the same effect. In this way, undesirable side effects can be reduced, minimized or eliminated.

In one aspect, the present disclosure provides a pharmaceutical composition comprising a solid dosage form, the solid dosage form comprising blepharonic acid and a polymer matrix. In one aspect, the disclosure provides solid dosage forms that are capsules or lozenges.

In one aspect, the present disclosure provides a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: dermatophyllic acid and a polymeric matrix. In one aspect, the edible polyphenolic acid is dispersed in the polymer matrix.

In one aspect, the present disclosure provides a zero-order sustained-release composition that includes pleurotropin and a polymer matrix. In one aspect, the zero-order sustained-release composition contains leukolide, dispersed in a polymeric matrix.

In one aspect, the present disclosure provides a pharmaceutical composition comprising a solid dosage form, wherein the physical properties of the solid dosage form are such that it exhibits a certain dissolution curve when testing dissolution using a United States Pharmacopeia (USP) device.

In one aspect, the present disclosure provides a method of treating or reducing the risk of cardiovascular disease in an individual, which is implemented by administering the compositions disclosed herein, which in some embodiments may be sustained release The formulation or in other embodiments may be an immediate release formulation. In one aspect, the present disclosure provides a method of treating an individual's metabolic syndrome by administering the composition disclosed herein. In one aspect, the present disclosure provides a method of treating non-alcoholic fatty liver disease (NAFLD) in an individual, which is implemented by administering the composition disclosed herein. In one aspect, the present disclosure provides a method of treating non-alcoholic steatohepatitis (NASH) in an individual, which is implemented by administering the composition disclosed herein.

In some aspects, the present disclosure encompasses a method of inhibiting ATP-citrate lyase (ACL) in an individual, wherein the method comprises administering to the individual a pharmaceutical dosage form of any of the formulations above.

In some aspects, the present disclosure encompasses a method of treating an individual's metabolic syndrome, wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

In some aspects, the present disclosure encompasses a method of treating an individual's metabolic syndrome, wherein the individual is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes, or any combination thereof, and Wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

In some aspects, the present disclosure encompasses a method of treating an individual's metabolic syndrome, wherein the individual has hypercholesterolemia, and wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

In some aspects, the present disclosure encompasses a method of treating an individual's metabolic syndrome, wherein the metabolic syndrome is non-alcoholic fatty liver disease (NAFLD), and wherein the method includes administering an effective amount of any of the above formulations The pharmaceutical dosage form.

In some aspects, the present disclosure encompasses a method of treating an individual's metabolic syndrome, wherein the metabolic syndrome is non-alcoholic steatohepatitis (NASH), and wherein the method comprises administering an effective amount of any of the above formulations The pharmaceutical dosage form.

In addition, the sustained release compositions set forth herein provide an effective means of systemic delivery of dominoic acid. Therefore, lower doses and/or less frequent administration (relative to known dombynoic acid formulations) are required to produce the same effect. In this way, undesirable side effects can be reduced, minimized or eliminated.

In one aspect, the present disclosure provides a pharmaceutical composition comprising a solid dosage form, the solid dosage form comprising blepharonic acid and a polymer matrix. In one aspect, the disclosure provides solid dosage forms that are capsules or lozenges.

In one aspect, the present disclosure provides a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: dermatophyllic acid and a polymeric matrix. In one aspect, the edible polyphenolic acid is dispersed in the polymer matrix.

In one aspect, the present disclosure provides a zero-order sustained-release composition that includes pleurotropin and a polymer matrix. In one aspect, the zero-order sustained-release composition contains leukolide, dispersed in a polymeric matrix.

In one aspect, the present disclosure provides a pharmaceutical composition comprising a solid dosage form, wherein the physical properties of the solid dosage form allow it to exhibit a certain dissolution curve when tested for dissolution using a United States Pharmacopeia (USP) device.

In one aspect, the present disclosure provides a method of treating or reducing the risk of cardiovascular disease in an individual, which is implemented by administering the compositions disclosed herein, which in some embodiments may be sustained release The formulation or in other embodiments may be an immediate release formulation. In one aspect, the present disclosure provides a method of treating an individual's metabolic syndrome by administering the composition disclosed herein. In one aspect, the present disclosure provides a method of treating non-alcoholic fatty liver disease (NAFLD) in an individual, which is implemented by administering the composition disclosed herein. In one aspect, the present disclosure provides a method of treating non-alcoholic steatohepatitis (NASH) in an individual, which is implemented by administering the composition disclosed herein.

In another aspect, the present disclosure provides a method of administering bilobatran acid or a method of delivering bilobatran acid, which methods are disclosed by administering above and are described in more detail below To implement.

Cross-reference of related applications

This application claims the priority rights of US Provisional Application No. 62/710,417 filed on February 16, 2018 and US Provisional Application No. 62/774,083 filed on November 30, 2018. These temporary applications Each case is incorporated by reference in its entirety. Advantages and utility

In one aspect, the present disclosure provides compositions and methods for the sustained release of flavonoid acid formulations.

The present disclosure includes a sustained-release composition that includes dombyid acid and a polymer matrix. The present disclosure covers the various components that form a sustained release formulation that includes dermatoxylin and polymer materials. For example, the present disclosure includes formulations for parenteral use, such as filled or unfilled lozenges or caplets. In the case of unfilled caplet tablets, the polymer may have sufficient porosity to allow fluid to enter one or more caplet cavity and be driven to release by osmotic pressure. An example of this technology is the sustained release caplet pump invented by Alza Corp, such as, for example, U.S. Patent Nos. 3,760,984, 3,845,770, 4,008,719, 4,036,227, 4,093,708, 4,111,202, and No. 4,449,983, No. 4,455,143, No. 4,576,604, No. 4,673,405, No. 4,732,915 and No. 4,777,049.

The sustained release technology of the present disclosure includes delayed release and extended release formulations. These systems improve the temporary delivery of drug delivery by allowing the active ingredient to be released to the therapeutic content of the active drug over an extended period of time by intermittent administration (an example of delayed release) or by controlled or sustained administration (an example of extended release) . Delayed release lozenges or caplets can be configured for repeated action, and enteric coating so that timed release can be achieved by slowly diffusing the active through the barrier coating. These extended-release formulations can be lozenges, which are filled with materials, polymers that normally degrade in a controlled manner in vivo.

These compositions improve the bioavailability of the activated form of dominoic acid and effectively extend the half-life of the administered drug. These compositions can be used to treat or reduce the risk of cardiovascular disease and other related comorbidities.

The disclosed method of sustained-release dominoic acid composition has many advantages. These tannin-derived multi-acid compositions not only maximize conversion to the active part and optimize pharmacokinetic properties, such as increasing the amount of the activated form of the drug in the liver, etc. The composition can be used to reduce the daily dose. The sustained-release dermatoxyl acid composition disclosed herein provides a therapeutically effective amount of dermatophyl acid over a longer period of time (compared to the immediate-release formulation) and the concentration is within the therapeutic window for a longer period of time. definition

Unless otherwise specified, the terms used in the patent application scope and specification are defined as described below. The practice of the present invention includes the use of conventional techniques of medicinal chemistry well known to those skilled in the art.

The term "cardiovascular disease" refers to diseases of the heart and circulatory system. These diseases are usually associated with abnormal lipoproteinemia and/or abnormal lipids. Cardiovascular diseases that can be prevented or treated using the composition of the present invention include (but are not limited to) atherosclerosis; atherosclerosis; stroke; ischemia; endothelial dysfunction, specifically those dysfunctions that affect blood vessel elasticity; surrounding Vascular diseases; coronary heart disease; myocardial infarction; cerebral infarction and restenosis.

In general, the term "sustained release" refers to a rate that is designed to be at a predetermined (but not necessarily constant) rate with minimal side effects over a specific period of time (eg, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, etc.) Release the drug to maintain the dosage form of the desired drug concentration range. This can be achieved through a variety of formulations, as exemplified by the sustained release formulations of Lepidotropin as described herein.

The term "abnormal dyslipidemia" refers to a condition that results in or manifests in abnormal levels of circulating lipids. If the blood lipid content is too high, the composition of the present invention is administered to the patient to restore the normal content. The normal content of lipids is reported in medical papers known to those skilled in the art. For example, the recommended blood levels of LDL, HDL, free triglycerides and other parameters related to lipid metabolism can be found in the American Heart Association and the National Cholesterol Education Program of the American Heart, Lung, and Blood Institute Cholesterol Education Program of the National Heart, Lung and Blood Institute). At present, the recommended content of HDL cholesterol in blood is higher than 35 mg/dL; the recommended content of LDL cholesterol in blood is lower than 130 mg/dL; the recommended ratio of LDL:HDL cholesterol in blood is lower than 5:1, ideally 3.5:1 ; And the recommended content of free triglycerides in the blood is less than 200 mg/dL.

The term "metabolic syndrome" refers to a group of conditions that occur together (increased blood pressure, hyperglycemia, excess body fat around the waist, and abnormal cholesterol or triglyceride levels), thereby increasing the risk of heart disease, stroke, and diabetes. These pathologies are the co-occurrence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia and hypertension.

The term "non-alcoholic fatty liver disease (NAFLD)" refers to a condition in which excess fat is stored in the liver. This fat accumulation is not caused by the use of large amounts of alcohol. Non-alcoholic fatty liver disease (NAFLD) is characterized by or diagnosed as follows: after excluding secondary causes of fat accumulation in the liver (such as heavy drinking, certain medications, and other medical conditions), on imaging or in liver tissue The existence of fat in the liver (fatty liver). NAFLD is further histologically classified as non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).

The term "simple fatty liver or non-alcoholic fatty liver (NAFL)" refers to a form of NAFLD in which there is fat in the liver but with little or no inflammation or liver cell damage. NAFL is characterized by fatty liver, and there is no evidence of liver cell damage in the form of hepatocyte swelling.

The term "non-alcoholic steatohepatitis (NASH)" refers to a form of NAFLD in which patients suffer from hepatitis (inflammation of the liver) and liver cell damage in addition to having fat in the liver. Inflammation and liver cell damage can cause liver fibrosis or scarring. NASH is characterized by the presence of fatty liver and inflammation (bloating) of hepatocytes with or without fibrosis.

The term "individual" refers to any mammal including humans, and therefore includes mammals, such as veterinarians and other animals of research interest, which include (but are not limited to): apes, cows, horses, dogs, cats, and rodents . The term "individual" is used interchangeably with the term "patient".

The term "mammal" as used herein includes both human and non-human mammals, such as non-human primates, dogs, cats, rodents, cattle, horses, and pigs.

The term "administering (administration)" drugs and/or therapies to individuals (and the grammatical equivalent of this phrase) refers to the direct or indirect administration of both, which can be administered to individuals by medical professionals, Self-administration and/or indirect administration may be the act of prescribing or inducing prescribing drugs and/or therapies to the individual.

The term "treating or treatment of" a condition or disease refers to taking steps to alleviate the symptoms of the condition or disease, or otherwise obtain some beneficial or desired results for the individual, including clinical results. Any beneficial or desired clinical outcome may include, but is not limited to, alleviating or improving one or more cancer symptoms or conditional survival and reducing tumor burden or tumor volume; reducing the degree of disease; delaying or slowing tumor progression or disease progression; improving, Relieve or stabilize tumors and/or disease states; or other beneficial outcomes.

The term "improvement" refers to any therapeutically beneficial outcome in the treatment of a disease state (eg, a disease state of the cardiovascular system), including prevention, mitigation of its severity, or progression or remission.

The term "in situ" or "in vitro" refers to a process that occurs in living cells that grow separately from living organisms, such as growth in tissue culture.

The term "in vivo" refers to processes that occur in living organisms.

The term "sufficient amount" means an amount sufficient to produce the desired effect.

。The term "lepidic acid" or "ETC-1002" refers to 8-hydroxy-2,2,14,14 tetramethyl pentadecanedioic acid:

.

。The term "activated erythropoietin" or "activated ETC-1002" refers to (9R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purine -9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydro-2-furanyl)-3,5,9,26-tetrahydroxy-8,8,20,20,32,32- Hexamethyl-10,14,19-trioxo-2,4,6-trioxa-18-thia-11,15-diaza-3,5-diphosphacosatriane- 33-acid 3,5-dioxide:

.

The term "zero-order release rate" refers to a substantially constant release rate, so that the drug is dissolved in the used environmental fluid at a substantially constant rate. The zero-order release rate can vary from its average release rate by up to about 25% and preferably does not exceed about 10%.

The term "therapeutically effective concentration" or "therapeutically effective amount" means an amount of a drug that is effective in improving symptoms of a disease, for example, an amount that treats at least one symptom of cardiovascular disease, or means reducing the individual's cardiovascular in a statistically significant way The amount of medicine at risk of disease.

The term "phosphate buffer" means any buffer solution containing disodium hydrogen phosphate and sodium chloride. Some of these buffer solutions contain potassium cations or potassium cations instead of sodium cations. In any case, those skilled in the art are familiar with compatible inorganic compounds and organic compounds that can be added to these solutions (commercially available or otherwise prepared in the laboratory by standard methods), as minor modifications can be made as needed /Addition (for example, the addition of relatively small amounts of Ca ²⁺ , Fe ^3+, and/or ethylenediaminetetraacetic acid (ETDA)), as long as the ability of the solution to maintain a reasonably constant pH does not change. Those skilled in the art can refer to, for example, Conover, WJ Chem. Educ., 1998, 75 (2), 153, which is incorporated herein by reference in its entirety.

The term " _Cmax " refers to the observed total maximum plasma concentration of an analyte (eg, drug or prodrug).

其中C_i 係相應取樣時間點t_i 時之血漿藥物濃度，且n係直至且包括最後可量化濃度之時間點數。 終末半衰期(T_1/2 )係使用以下方程式來計算：

其中λ係終末消除速率常數。 自時間0至無窮大之血漿濃度-時間曲線下面積係根據以下方程式來計算：

其中C_最後 係最後可量測之濃度。The pharmacokinetic parameters described in this article include: the area under the plasma concentration-time curve (AUC _0-t and AUC _{0- ∞} , the unit of both is the amount * time/volume); AUCτ, ss; the maximum plasma concentration (C _maximum); maximum plasma concentration (T _max); and terminal elimination half-life (T _1/2). The maximum concentration time (T _max) was determined as the time corresponding to _{the maximum} of C. The area under the plasma concentration-time curve (AUC _0-t ) up to the time corresponding to the last measurable concentration is calculated by numerical integration using the following linear trapezoidal rule:

Where C _i is the plasma drug concentration at the corresponding sampling time point t _i , and n is the number of time points up to and including the last quantifiable concentration. The terminal half-life (T _1/2 ) is calculated using the following equation:

Where λ is the final elimination rate constant. The area under the plasma concentration-time curve from time 0 to infinity is calculated according to the following equation:

Wherein the concentration of the final measuring system can _last C.

The term "T _max" means an analyte (eg, a drug or prodrug thereof) of the plasma concentration time to reach maximum plasma concentrations.

The term "AUCτ, ss" refers to the area under the concentration-time curve during the dosing interval at steady state, where the unit is defined as quantity*time/volume.

The term "therapeutic window" refers to the dose range of a drug/API that triggers a therapeutic response in a patient without causing any significant adverse effects. Generally, the therapeutic window is the ratio of the minimum effective concentration (MEC) to the minimum toxic concentration (MTC).

The term "polycellulose" means a polymer prepared from cellulose having a weight average molecular weight of 500 Da to 5,000,000 Da, which is optionally cross-linked and includes derivatives of cellulose. Such derivatives include "functionalized" cellulose polymers resulting from the reaction or crosslinking of cellulose polymers with one or more organic functional groups. The functional group is pendant, and although it can change the chemical and physical properties of the cellulose polymer, it does not fundamentally change (1) the core structure of the sugar repeating chemical motif, or (2) the sugar The position of the valence link (ie, the number of carbons connected to each sugar via an O-glycoside linkage) and how the sugar is covalently linked (α/β). Those skilled in the art are familiar with these functional groups and methods for preparing these derivatives. Those skilled in the art can refer to Handbook of Polymers for Pharmaceutical Technologies: Biodegradable Polymers, Volume 3, Vijay Kumar Thakur and Manju Kumari Thakur, Wiley, 2015, which are incorporated by reference in their entirety.

其中Mi係鏈之分子量且Ni係該分子量之鏈數。The term "weight average molecular weight" refers to Mw or the molecular weight that takes into account the molecular weight of the chain when determining the contribution to the average molecular weight. Mw is determined by an analytical method that is sensitive to the molecular size of the polymer chain rather than just the chain count. Analysis techniques such as dynamic light scattering provide Mw. Mw is calculated by:

Where Mi is the molecular weight of the chain and Ni is the number of chains of that molecular weight.

It must be noted that unless the context clearly indicates otherwise, the singular forms "a" and "the" as used in this specification and the accompanying patent application include plural indicators. Pharmaceutical composition

Disclosed herein is a sustained release pharmaceutical dosage form comprising a solid oral dosage form. In some embodiments, the solid oral dosage form comprises dermatophyllic acid and a polymer matrix. In some embodiments, the solid oral dosage form comprises leukodermic acid dispersed within the polymeric material.

In some aspects, the present disclosure provides a sustained-release pharmaceutical dosage form comprising a solid oral dosage form containing dominoic acid and a polymer matrix, wherein the polymer is hydroxypropyl methylcellulose (HPMC). In some aspects, the solid oral dosage form includes leukodermic acid dispersed within HPMC. In some aspects, the leukodermic acid is not dispersed in the polymer. In some aspects, leukoderma is not dispersed in HPMC.

In one aspect, the present disclosure provides a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: dermatophyllic acid and a polymeric matrix, and wherein the solid oral dosage form is administered to an individual Within a period of 12 hours, within a period of 14 hours, within a period of 16 hours, within a period of 18 hours, within a period of 20 hours, within a period of 22 hours, within a period of 24 hours, in Provide a therapeutically effective concentration of pleurotropin in a 36-hour period or a 48-hour period.

In one aspect, the present disclosure provides a solid oral dosage form that is a gelatin capsule. In one aspect, the solid oral dosage form is a hard shell capsule containing rounded powder particles. In one aspect, the solid oral dosage form is a soft shell capsule. In one aspect, the solid oral dosage form further comprises gelatin capsules of powder excipients. In one aspect, the solid oral dosage form is a gelatin capsule of excipient further contained in the suspension. In one aspect, the solid oral dosage form is a gelatin capsule further comprising one or more plasticizers (such as glycerin or sorbitol). In one aspect, the solid oral dosage form further comprises one or more of the following gelatin capsules: colorant, preservative, disintegrant, lubricant, and surface treatment agent.

In one aspect, the present disclosure provides solid oral dosage forms that are lozenges. In one aspect, the present disclosure provides solid oral dosage forms that are diamond shaped lozenges.

In one aspect, the present disclosure provides a solid oral dosage form that is a gelatin capsule. In one aspect, the present disclosure provides a solid oral dosage form that is a capsule, which contains a solid composition comprising pipidolic acid and one or more excipients. Trichidonic acid-structure and synthesis

The structure of edible dodecanoic acid (also known as ETC-1002 or 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid):

ETC-1002 and the process for synthesizing ETC-1002 are disclosed in the issued US Patent No. 7,335,799. Details of this process can be found in published US Patent Publication No. US2005/0043278A1, paragraphs [0247]-[0343] of the specification, which are incorporated herein by reference in their entirety.

As used herein, the term "lepidic acid" also covers the pharmaceutically acceptable salts of the compound. Such pharmaceutically acceptable salts include (but are not limited to) hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, citric acid, tartaric acid, methanesulfonic acid, fumaric acid, malic acid, maleic acid and mandelic acid, Mucic acid salt, N-oxide, sulfate, acetate, monohydrogen phosphate, dihydrogen phosphate, acetate trihydrate, bis(heptafluorobutyrate), bis(methylaminoformate) , Bis(pentafluoropropionate), bis(pyridine-3-carboxylate), bis(trifluoroacetate), hydrogen tartrate, hydrochloride and sulfate pentahydrate, benzenesulfonate, benzyl alcohol Salt, bicarbonate, hydrogen tartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, ethanedisulfonate, Estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, ethanolyl p-aminophenyl arsenate (glycollylarsanilate), hexyl m-benzene Diphenolate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate , Mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, pamoate, embonate, pantothenic acid Salt, phosphate/hydrogen phosphate, polygalacturonate, salicylate, stearate, hypoacetate, succinate, sulfate, tannate, tartrate, tea chlorate (teoclate) , Triethyl iodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum salt, calcium salt, lithium salt , Magnesium salt, potassium salt, sodium propionate and zinc salt and the like. Polymer matrix hydrophilic and hydrophobic components

According to the present disclosure, the main component of the matrix of the sustained release formulation may be a hydrophilic polymer. Hydrophilic polymers are extremely suitable for oral controlled drug delivery because they can reproduce desirable drug characteristics and are cost effective. However, pleurotropin is hydrophobic, and the absorption process in the body depends to some extent on the lipophilic nature of the dosage form. Therefore, the desired release curve can be obtained by incorporating both hydrophilic and hydrophobic components and/or excipients in the dosage form, the exact nature of which is derived on a case-by-case basis.

The matrix of the sustained-release pharmaceutical composition includes a polymer as a main component. Both synthetic and natural polymers and/or derivatives and/or combinations thereof can be used in compositions within the scope of this disclosure.

The polysaccharide can be used as a polymer in the oral sustained release formulation of the present disclosure. Such formulations may include cellulose (polymer) derivatives such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl cellulose and Methyl cellulose (MC). Each cellulose derivative has different grades and has different properties in terms of molecular weight, viscosity, solubility, hydration, etc. Therefore, different polymers and their different derivatives can be used to formulate the dissolution controlled and diffusion controlled release systems of the present disclosure. Polymers with diffusion control are usually water-insoluble, but some are water-soluble. Common polymers used in diffusion control systems (storage and monolithic systems) include cellulose (e.g. ethyl cellulose), collagen, nylon, poly(alkyl cyanoacrylate), polyethylene, Poly(ethylene-co-vinyl acetate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl ethyl methacrylate), poly(methyl methacrylate), polyurethane and silicon rubber.

In addition to dissolution release kinetics, polymer glass transition temperature (Tg) is also an extremely important polymer property. Tg affects properties such as fluidity, compressibility, flexibility, permeability, etc.

Plasticizers can be incorporated into the polymer blends of this disclosure as appropriate. Examples of plasticizers are glycerin, glyceryl triacetate (triacetin), poly(ethylene glycol) (PEG) and propylene glycol. Plasticizers are also commonly used in film coatings to help polymers achieve the desired film quality. Because plasticizers reduce the rigidity of polymer molecules, they can be used to increase the rate of diffusion of pleurotropin through the dosage form. Synthetic / natural polymers and derivatives

The so-called "natural polymer" is a polymer substance found and extractable in nature. These polymers are usually water-soluble materials. Examples of natural polymers include polysaccharides (such as cellulose), polynucleotides (such as RNA or DNA), and polyamides (such as proteins).

Synthetic polymers are derived from petroleum and are made by scientists and engineers. Examples of synthetic polymers include (poly)vinyl, acrylate, nylon, polyethylene, polyester, and Teflon.

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a synthetic polymer and is selected from the group consisting of: poly(vinyl alcohol) (PVA), poly(acrylic acid), poly(ethylene oxide) Alkane) (PEO), poloxamer, pluronic and polymethacrylate.

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a combination of two synthetic polymers and the two polymers are selected from the group consisting of: Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611 and Aqualon.

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is selected from the group consisting of: hydroxypropyl methyl cellulose (HPMC), HPC (hydroxypropyl cellulose), hydroxyethyl fiber (HEC), EC (ethyl cellulose), MC (methyl cellulose), sodium alginate, sodium carboxymethyl cellulose, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, micro Crystalline cellulose and Aqualon. In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a combination of two polymers and the two polymers are selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose (HEC), EC (ethyl cellulose), MC (methyl cellulose), sodium alginate, sodium carboxymethyl cellulose, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose and Aqualon. In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a combination of three polymers and the three polymers are selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), HPC ( (Hydroxypropyl cellulose), hydroxyethyl cellulose (HEC), EC (ethyl cellulose), MC (methyl cellulose), sodium alginate, sodium carboxymethyl cellulose, Carbopol, Eudragit, Avicel PH- 101, HPMC 606, Avicel CL-611, microcrystalline cellulose and Aqualon.

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a combination of four or more synthetic polymers selected from any of the polymers listed herein.

In any of the aspects set forth herein, the present disclosure provides a polymer matrix, wherein the polymer is a synthetic polymer and the matrix includes a plasticizer. In some aspects, the plasticizer may be one or more of the plasticizers listed herein. Plasticizers are well known in the industry, and therefore those skilled in the art can refer to the reference text disclosed herein and select any of the plasticizers listed therein. Examples of plasticizers include, but are not limited to: glycerin, glyceryl triacetate (triacetin), poly(ethylene glycol) (PEG), propylene glycol, and combinations thereof.

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is selected from the group consisting of polycellulose, microcrystalline cellulose, polyvinyl acetate, polyvinylpyrrolidone, polyacrylate , PH-insensitive ammonium polymers and their mixtures.

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is selected from the group consisting of: (poly)cellulose (eg ethyl cellulose), collagen, nylon, poly(cyanoacrylate) Ester), polyethylene, poly(ethylene-co-vinyl acetate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl ethyl methacrylate), poly(methyl methacrylate), poly Urethane and silicone rubber.

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is microcrystalline cellulose. In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a mixture of microcrystalline cellulose and polycellulose. In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a mixture of microcrystalline cellulose and hydroxypropyl methyl cellulose (HPMC). In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is hydroxypropyl methyl cellulose (HPMC). In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is polycellulose. Porosity and permeability

API ingot making and solid granulation have effects on dosage form density, porosity and hardness, disintegration and particle size. An increase in solid density and hardness will result in a decrease in permeability and solvent penetration.

其中ε係基質之孔隙度，T係彎曲度，C₀ 係基質中每單位體積存在之藥物總量，Cα係在時間t時藥物於釋放介質中之溶解度，M係每單位面積之藥物釋放量且Ds係藥物於釋放介質中之擴散係數。In some aspects, the present disclosure provides a polymer matrix that is not porous but amorphous. In some aspects, the present disclosure provides a polymer matrix with relatively low porosity. The porosity can be calculated by:

Where ε is the porosity of the matrix, T is the curvature, C ₀ is the total amount of drug present per unit volume in the matrix, Cα is the solubility of the drug in the release medium at time t, and M is the amount of drug released per unit area And Ds is the diffusion coefficient of the drug in the release medium.

In some aspects, the present disclosure provides a polymer matrix with an average particle size of 10-200 μm. In some aspects, the present disclosure provides a polymer matrix with an average particle size of 20-180 μm. In some aspects, the present disclosure provides a polymer matrix with an average particle size of 20-150 μm. In some aspects, the present disclosure provides a polymer matrix having an average particle size of 40-100 μm.

In some aspects, the present disclosure provides a polymer matrix having the following average pore size: 10-200 nm, 20-180 nm, 20-150 nm, or 40-100 nm. Synthesis example

In some aspects, the present disclosure provides a polymer matrix, wherein the polymer is a derivative of a synthetic or natural polymer. Those skilled in the art can use organic synthesis techniques to synthesize monomer compounds, as long as the reactive organic functional groups of the monomers are not simultaneously (thermally) polymerized. Another way for those skilled in the art to prepare derivatives of synthetic polymers is to polymerize (in a controlled polymerization) the desired polymer (ie, the starting material), or in the case of natural polymers, from sources such as Sigma Aldrich, Companies such as TCI Chemicals, Strem, etc. obtain the desired commercially available natural polymer starting materials, and then perform one or more organic synthesis reactions on the polymer to functionalize it with the desired pendant groups. The reaction can be initiated using the potentially reactive organic functional groups of the polymer, that is, those that are nucleophilic or electrophilic in nature. Those skilled in the art should be careful not to react the functional groups of each monomer unit covalently linked to the polymer, because the reaction of these groups will degrade the polymer and reduce the average molecular weight of the polymer chain. However, in the case of natural polymers, this chain scission usually occurs, and those skilled in the art will try to alleviate these severe reaction conditions.

An example of the first method uses acrylate polymers. The acrylate monomer can be functionalized by means of a carboxylic acid ester via an esterification or amidation reaction with a desired nucleophilic functional group that becomes a pendant group. For example, acrylic acid can be functionalized with 3000 Da polyethylene glycol via Steglich esterification reaction conditions. The resulting ethylene glycol acrylate can be polymerized with AIBN "azoisobutyronitrile" under thermal conditions in a controlled manner (optionally with another monomer compound (such as methyl methacrylate) to produce a copolymer) to prepare Desired polymers of Tg and other physical properties.

Another example of a synthetic polymer derivative is applicable to natural polymers, and includes preparing the derivative by functionalizing the natural polymer with organic functional groups. For example, natural polymer cellulose can react with propylene oxide and methyl chloride via hydroxyl functional groups in the presence of sodium hydroxide reagent. The product formed is a cellulose polymer (polycellulose), which has a (methyl and isopropyl) ether functional group which is a certain percentage of the previous hydroxyl functional groups. In some aspects, the percentage of ether functional groups is 0.1%-50%, preferably 0.1%-45%, preferably 0.1%-30%, preferably 0.1%-15%, preferably 0.1% -10%, preferably 0.1%-9%, preferably 0.1%-8%, preferably 0.1%-7%, preferably 0.1%-6%, preferably 0.1%-5%, more It is preferably 0.1%-4%, preferably 0.1%-3%, preferably 0.1%-2%, preferably 0.1%-1% or more preferably 0.1%-0.5%.

These derivatization reactions and preparations are well known to those skilled in the art. Those skilled in the art can use textbooks such as the following for reference: Biodegradable Polymers in Pharmacy and Medicine. Classification, Chemical Structure, Principles of Biodegradation and Use, Jan Gajdziok Roman Goněc David Vetchý, Verlag, 2016; Cellulose and Cellulose Derivatives: Synthesis , Modification and Applications, Ibrahim H. Mondal, Nova Science Publishers Incorp., 2015 and Biomedical Polymers: Synthesis and Processing, Vinod B. Damodaran, Divya Bhatnagar, N. Sanjeeva Murthy, Springer, 2016, these textbooks are cited in full text The way is incorporated into this article. Excipients are used as components of solid dosage forms

During the manufacturing process of the solid dosage form, when mixed with various excipients, the dissolution rate of the pure drug can be changed.

Those skilled in the art can commercially purchase certain compounds and materials for use as excipients, or more precisely, derivatize known compounds and starting materials. These synthetic methods (and methods for formulating solid dosage forms using these excipients) are well known in the industry, and refer to the main text references in this article and Handbook of Pharmaceutical Excipients, 4th Edition, Rowe RC, Sheskey PJ, Weller PJ Editor, London, UK: AphA and the Pharmaceutical Press, 2003, which is incorporated by reference in its entirety.

In some aspects, the present disclosure provides a solid dosage form comprising pipidolic acid and a polymer matrix, wherein the solid dosage form further comprises a surfactant. In some aspects, the present disclosure provides a solid dosage form comprising pipidolic acid and a polymer matrix, wherein the solid dosage form further comprises an anionic surfactant. In some aspects, the present disclosure provides a solid dosage form comprising pipidolic acid and a polymer matrix, wherein the solid dosage form further comprises an anionic surfactant, wherein the anionic surfactant is sodium lauryl sulfate.

In some aspects, the present disclosure provides a solid dosage form comprising dombyid acid and a polymer matrix, wherein the solid dosage form further comprises microcrystalline cellulose and sodium lauryl sulfate.

For other suitable compounds used as excipients for the solid oral dosage forms disclosed herein, see also the main textbooks mentioned herein, such as Remington, The Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co. 21st edition. Types of excipients

Excipients can be added to meet certain medical functions, such as diluents (fillers), dyes, binders, granulating agents, disintegrating agents, and lubricants.

In some aspects, the present disclosure provides a solid dosage form comprising pipidolic acid and a polymer matrix, wherein the solid dosage form further comprises a binder, filler, diluent, dye, granulating agent, disintegrating agent, lubricating agent Agent or any combination thereof.

In some aspects, the present disclosure provides a solid dosage form comprising the following: leukodermic acid, polymer matrix and binder, filler, diluent, dye, granulating agent, disintegrant, lubricant, or any One combination. In some aspects, the present disclosure provides a solid dosage form that includes the following: leukoderma, a polymer matrix, and a binder and lubricant. In some aspects, the present disclosure provides a solid dosage form that includes the following: dodecanoic acid, a polymer matrix, and a binder and lubricant, wherein the lubricant is a surfactant. In some aspects, the present disclosure provides a solid dosage form comprising the following: leukodermic acid, a polymer matrix, and a binder and lubricant, wherein the lubricant is sodium lauryl sulfate. Solid dosage form

The pharmaceutical dosage form may include various solid forms, for example, the medicine may be a pill, such as a lozenge, a lozenge-like lozenge or lozenge-like buccal dosage form (eg sublingual or oral disintegrating gum), a pill or lozenge lozenge, Film etc.

In general, sustained-release solid oral dosage forms can be divided into three basic categories: matrix-based lozenges/pills, multiparticulate solids, and osmotic solid dosage forms. The present disclosure provides a sustained-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises dermatine dodecanoic acid and a polymer. In some aspects, the polymer system is in the form of a polymer matrix. In other aspects, the polymer is a pure dry powder. The solid oral dosage form disclosed in the present invention can be formulated into any of the above mentioned dosage forms.

In one aspect, the present disclosure provides a solid oral dosage form that includes dombyid acid and a polymer matrix.

In one aspect, the present disclosure provides a solid oral dosage form, wherein the solid dosage form is a lozenge.

In one aspect, the present disclosure provides a solid oral dosage form, wherein the solid dosage form is a gelatin capsule. In one aspect, the present disclosure provides a solid oral dosage form, wherein the solid dosage form further comprises gelatin capsules of powder excipients.

In one aspect, the present disclosure provides a solid oral dosage form, wherein the dosage form is not diffusion controlled but dissolution controlled. Properties of the formulation

In some aspects, the present disclosure provides a solid dosage form comprising pipidolic acid, wherein the dosage form provides sustained release of pipidolic acid over a period of at least 2-8 hours after oral administration, or produces a certain amount The release curve of dominoic acid, for example, after oral administration of dominoic acid, the _maximum C for at least 1 hour for dermal multi-acid (or its metabolite, activated dermal multi-acid) Platform period. Weight range and composition amount

In one aspect, the present disclosure provides a solid oral dosage form in which the flavonoid dodecanoic acid is 30% by weight to 50% by weight, 35% by weight to 55% by weight, 40% by weight to 60% by weight, and 45% by weight- 65% by weight, 50% by weight to 70% by weight, 55% by weight to 75% by weight, or 60% by weight to 80% by weight.

In some aspects, the present disclosure provides the administration of sustained release formulations of domperidone, wherein the dose is 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/ Day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/ Days, 190 mg/day, 200 mg/day, 210 mg/day, 220 mg/day, 230 mg/day, 240 mg/day or 250 mg/day.

In some aspects, the present disclosure provides the administration of sustained release formulations of leukoderma, wherein the dosage is 45 mg/day-55 mg/day, 55 mg/day-65 mg/day, 65 mg/ Day-75 mg/day, 75 mg/day-85 mg/day, 85 mg/day-95 mg/day, 95 mg/day-105 mg/day, 105 mg/day-115 mg/day, 115 mg/day Day-125 mg/day, 125 mg/day-135 mg/day, 135 mg/day-145 mg/day, 145 mg/day-155 mg/day, 155 mg/day-165 mg/day, 165 mg/day Day-175 mg/day, 175 mg/day-185 mg/day, 185 mg/day-195 mg/day, 195 mg/day-205 mg/day, 205 mg/day-215 mg/day, 215 mg/day Day-225 mg/day, 225 mg/day-235 mg/day, 235 mg/day-245 mg/day or 245 mg/day-255 mg/day.

In one aspect, the present disclosure provides a solid oral dosage form, wherein the HMPC is 0% by weight to 10% by weight, 0% by weight to 5% by weight, 0% by weight to 4% by weight, 0% by weight to 3% by weight, 0% by weight to 2% by weight or 0% by weight to 1% by weight.

In one aspect, the present disclosure provides a solid oral dosage form comprising: 40-60% by weight of leukoderma oleate and 0-3% by weight of HPMC, or 60-80% by weight The side skin Duoyi acid and 0% to 5% by weight of HPMC.

In one aspect, the present disclosure provides a solid oral dosage form, wherein the pharmaceutical dosage form comprises: 60.0% w/w's side skin multi-acid; 37.3% w/w microcrystalline cellulose; 0.7 w/w of hydroxypropyl methyl cellulose; and 2% w/w sodium lauryl sulfate.

In one aspect, the present disclosure provides a solid oral dosage form, wherein the pharmaceutical dosage form comprises: 60.0% w/w's side skin multi-acid; 9.3% w/w microcrystalline cellulose; 28.0% w/w microcrystalline cellulose/carboxymethyl cellulose sodium; 0.7% w/w hydroxypropyl methyl cellulose 2.0% w/w sodium lauryl sulfate.

In one aspect, the present disclosure provides a solid oral dosage form, wherein the pharmaceutical dosage form comprises: 60.0% w/w's side skin multi-acid; 33.7% w/w microcrystalline cellulose; 3.7% w/w sodium carboxymethyl cellulose; 0.7% w/w of hydroxypropyl methyl cellulose; and 2.0% w/w sodium lauryl sulfate.

In some aspects, the present disclosure provides a pharmaceutical composition, wherein the composition comprises at least 40% and not more than 80% of flavonoids w/w, at least 45% and not more than 80% of flavonoids Acid, at least 50% and not more than 80% of scalp dodecanoic acid w/w, at least 55% and not more than 80% of scalp dodecanoic acid w/w, at least 60% and not more than 80% of scalp scalp Propionic acid w/w, at least 65% and not more than 80% of scalp dodecanoic acid w/w, at least 70% and not more than 80% of scalp dodecanoic acid w/w, at least 75% and not more than 80% The edge of the skin is more acid w/w.

In some aspects, the present disclosure provides a pharmaceutical composition, wherein the composition comprises at least 5% and not more than 50% polymer w/w, at least 10% and not more than 50% polymer w/w, at least 15% and not more than 50% polymer w/w, at least 20% and not more than 50% polymer w/w, at least 25% and not more than 50% polymer w/w, at least 30% and not more than 50% polymer w/w, at least 35% and not more than 50% polymer w/w, at least 40% and not more than 50% polymer w/w, at least 45% and not more than 50% polymer w/w.

In some aspects, the present disclosure provides a pharmaceutical composition wherein the polymer component is hydroxypropyl methyl cellulose (HPMC) and is at least 0.1% and not more than 10% HPMC w/w, at least 0.5% And not more than 10% HPMC w/w, at least 1% and not more than 10% HPMC w/w, at least 5% and not more than 10% HPMC w/w.

In some aspects, the present disclosure provides a pharmaceutical composition wherein the polymer is microcrystalline cellulose and is at least 1% and not more than 60% microcrystalline cellulose w/w, at least 5% and not more than 60% Microcrystalline cellulose w/w, at least 10% and not more than 60% microcrystalline cellulose w/w, at least 15% and not more than 60% microcrystalline cellulose w/w, at least 20% and not more than 60 % Microcrystalline cellulose w/w, at least 25% and not more than 60% microcrystalline cellulose w/w, at least 30% and not more than 60% microcrystalline cellulose w/w, at least 35% and not more than 60% microcrystalline cellulose w/w, at least 40% and not more than 60% microcrystalline cellulose w/w, at least 45% and not more than 60% microcrystalline cellulose w/w, at least 50% and not More than 60% of microcrystalline cellulose w/w, at least 55% and not more than 60% of microcrystalline cellulose w/w.

In some aspects, the present disclosure provides a pharmaceutical composition wherein the polymer is sodium carboxymethyl cellulose, and is at least 1% and not more than 50% carboxymethyl cellulose sodium w/w, at least 5%, and Not more than 50% sodium carboxymethyl cellulose w/w, at least 10% and not more than 50% sodium carboxymethyl cellulose w/w, at least 15% and not more than 50% sodium carboxymethyl cellulose w /w, at least 20% and not more than 50% of sodium carboxymethyl cellulose w/w, at least 25% and not more than 50% of sodium carboxymethyl cellulose w/w, at least 30% and not more than 50% Sodium carboxymethyl cellulose w/w, at least 35% and not more than 50% sodium carboxymethyl cellulose w/w, at least 40% and not more than 50% sodium carboxymethyl cellulose w/w.

In some aspects, the present disclosure provides a pharmaceutical composition comprising sodium lauryl sulfate and at least 0.1% and not more than 10% sodium lauryl sulfate w/w, at least 0.5% and not more than 10% lauryl Sodium sulfate w/w, at least 1% and not more than 10% sodium lauryl sulfate w/w, at least 5% and not more than 10% sodium lauryl sulfate w/w.

In some aspects, the present disclosure provides a pharmaceutical composition comprising sodium starch glycolate and at least 0.1% and not more than 10% sodium starch glycolate w/w, at least 0.5% and not more than 10% glycolic acid Sodium starch w/w, at least 1% and not more than 10% sodium starch glycolate w/w, at least 5% and not more than 10% sodium starch glycolate w/w.

In some aspects, the present disclosure provides a pharmaceutical composition comprising about 4 to 1 ratio of flavonol tonic acid to polymer.

In some aspects, the present disclosure provides a pharmaceutical composition comprising about 3 to 2 ratio of flavonol to acid to polymer.

In some aspects, the present disclosure provides a pharmaceutical composition comprising about 2 to 1 ratio of leukoderma to polymer.

In some aspects, the present disclosure provides solid dosage forms in which the average particle size is 1-200 μm. In some aspects, the present disclosure provides a solid dosage form in which the average particle size is 1-150 μm. In some aspects, the present disclosure provides a solid dosage form in which the average particle size is 1-125 μm. In some aspects, the present disclosure provides solid dosage forms in which the average particle size is 10-100 μm. In some aspects, the present disclosure provides solid dosage forms in which the average particle size is 20-100 μm. In some aspects, the present disclosure provides solid dosage forms in which the average particle size is 40-100 μm. In some aspects, the present disclosure provides a solid dosage form in which the average particle size is 50-100 μm. In some aspects, the present disclosure provides solid dosage forms in which the average particle size is 80-100 μm. Threshold and saturation

When the rate of rise and/or the actual serum plasma concentration of dodecanoic acid exceeds the threshold maximum tolerable concentration (MTC), toxicity-related side effects usually occur after administration. At the same time, in order to obtain a therapeutic effect, the concentration needs to be maintained above the minimum effective concentration (MEC).

In some aspects, the present disclosure provides a solid dosage form in which the maximum serum concentration is measured within the dosing interval when dosing as recommended.

In some aspects, the present disclosure provides a solid dosage form wherein the minimum serum concentration (MEC) is measured within the interval between doses (ie, the period between repeated doses) when dosed as recommended.

In some aspects, the present disclosure provides a solid dosage form in which the concentration of pleurotropin is maintained between MEC and MTC for up to: at least 8 hours and not more than 48 hours; at least 12 hours and not more than 48 Hours; or at least 24 hours and not more than 36 hours.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of leukolide in a 24 hour period when administered to an individual. In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of leukolide in a 36-hour period when administered to an individual. In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of leukolide in a 48-hour period when administered to an individual. Unit dose

Unit dosage form is a term commonly understood by those skilled in the art. Unit dosage forms are commercially available pharmaceutical products for specific purposes. Pharmaceutical products include one or more active ingredients and any inactive components, most often in the form of polymers and pharmaceutically acceptable carriers or excipients.

In some aspects, the sustained-release composition is formulated in one (1) unit dosage form, which is effective for at least twelve (12) hours, eighteen (18), twenty-four (24), thirty (30) , Thirty-six (36) or forty-eight (48) hours.

In some aspects, the sustained release composition is formulated in at least two (2) separate unit dosage forms with different release profiles. Pharmacokinetics

API formulations administered orally must be absorbed and circulated throughout the body before they become bioavailable. For most drugs/APIs, pre-systemic clearance occurs at the GI tract site, and it significantly affects drug/API absorption. The degradation of drugs administered orally occurs to some extent due to hydrolysis in the stomach and upper GI or digestion of enzymes in the intestine. In addition, the drug is metabolized by microorganisms in the intestine and enzymes in the liver (ie, first pass effect). These degradation processes can affect variable or undesirable drug absorption. It is generally observed that the higher the absorption efficiency of the drug/API, the higher the bioavailability of the API. A measure of bioavailability, inter alia, _{the maximum} C, _maximum value T and the AUC. The plasma concentration of dombydodecanoic acid in an individual can be determined by clinical analysis well known to those skilled in the art to determine the pharmacokinetic parameter values and tolerate the clinical effect and tolerate the clinical effect and the plasma concentration of leukolide. Correlation between.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form C provides _{a maximum} of at least 8 μg / L of acid side Pinedo benefits.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form provides at least 0.6 ng*hour/mL of leukolide acid per mg.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form provides tannin with a T _1/2 of at least 24 hours.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form C provides _{a maximum} of at least 10 μg / L of the activated acid side Pinedo benefits.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form provides activated flavonoid dodecanoic acid with a _maximum C of 60 µg/mL, 57 µg/mL, 55 µg/mL, 53 µg/ mL, 50 µg/mL, 47 µg/mL, 45 µg/mL or 40 µg/mL.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form provides an activated leukotopic acid of at least 0.8 ng*hour/mL per mg of leukotopic acid.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form provides at least 28 hours of activated leukotopic acid.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form provides an AUC of 1.1 ng*hour/mL per mg of dermatological dodecanoic acid after oral administration of a single 180 mg dermatological dodecanoic acid capsule.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid dosage form provides at least 50 µg*hour/L per mg of activated dermatological dodecanoic acid after oral administration of a single 180 mg dermatological dodecanoic acid capsule Of AUC. Zero-level release

The ideal release of API from a given dosage form maintains the therapeutic blood and tissue content of the drug for an extended period of time, usually greater than 8 hours. This maintenance concentration is usually achieved by obtaining a zero-order release rate of the API from the dosage form. Zero-order release is API release from the dosage form (ie, constant release rate) independent of the amount of drug in the delivery system.

In one aspect, the present disclosure provides a solid oral pharmaceutical dosage form that has a zero-order release rate when the dissolution test is performed at 50°C in a 50 mM phosphate buffer using a US Pharmacopeia device 2 (paddle 50 rpm) For at least 12 hours, the solid oral pharmaceutical dosage form comprises: leukoderma acid and polymer matrix, wherein the pharmaceutical dosage form has a hardness of 2-30 kg and is shaped into a sphere or has a thickness to diameter effective to allow erosion and penetration control The ratio of the erosion and penetration control is sufficient to control the surface erosion during dissolution testing.

In one aspect, the present disclosure provides a solid oral pharmaceutical dosage form having a zero-order release rate for at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours , At least 20 hours, at least 22 hours, at least 24 hours, or at least 36 hours. In some aspects, when using the US Pharmacopoeia Device 2 (paddle 50 rpm) in a 50 mM phosphate buffer solution at 20°C for dissolution testing, each solid corresponding to a zero-order release period of 6-36 hours The oral medicine dosage form maintains a zero-order release rate during this period of time. PH and eluting

Solid dosage forms can release API according to erosion (dissociation) and/or diffusion mechanisms, depending on the nature of the polymer matrix and the chemical and physical properties of the API.

The erosion (dissociation) of many API formulations and especially known flavonoid acid formulations is prone to dose "dumping". That is, once the dosage form has solvated beyond a certain threshold, a large amount of API will leak out of the composition in an uncontrolled manner. On their systems under erosion control, the pH of the local medium has the greatest effect on API release. Under relatively high and low pH media, API formulations are prone to hydrolysis or degradation, thereby making the dosage form fully solvated, which makes erosion and dumping more likely.

The sustained-release solid oral dosage form of pipidolic acid disclosed herein is also characterized (at least in part) by its physical properties, namely the physical properties of the dosage form providing a certain dissolution profile of pipidolic acid.

Disclosed herein is a sustained release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises dermatophyllic acid and a polymer matrix and wherein the solid oral dosage form does not pour off dermal pitol acid after administration for 24 h. In one aspect, the present disclosure provides a solid oral dosage form that does not pour more than 10% of leukoderma acid in a pH 8 medium after 30 minutes.

剩餘質量(%) =

Among other things, the uptake of solid dosage form erosion and dissolution medium uptake can be determined gravimetrically under the same conditions as used for the dissolution test. The basic calculation is shown below. Dissolution medium uptake (%) =

Remaining mass (%) =

Those skilled in the art use the rotating disk system of the USP Wood device or the USP dissolution device 2 (US Pharmacopoeia 34/National Formulary 29, 2011, General Rule <711> Dissolution, which is incorporated herein by reference in its entirety, see also Remington , JP (1995). Remington, The Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co., 21st Edition, Chapter 35, pages 679-687, which is also incorporated by reference in its entirety. ) To determine the dissolution curve or dissolution rate of sustained-release dosage forms. In short, the device has three components: steel punch, die and bottom plate. Attach the mold base to the bottom plate, and insert the fixing screws on the bottom plate to the mold. Insert the punch into the mold cavity, thereby pressing the internal material. The pellets and mold assembly are then inserted into the bottom of the dissolution vessel (1 liter) with the pellets facing upward. The important thing is that the container is flat-bottomed. The paddles of the USP device 2 stir the material and take care that no bubbles are formed on the surface of the pellets and no temperature (37°C) changes occur.

The dissociation device can be USP Type I, Type II, Type IV and Type VII, namely the spinning basket, propeller, flow cell and reciprocating support. In the dissociation medium, those skilled in the art can choose certain parameters based on API stability and analytical sensitivity, requiring leak tank conditions where the final drug concentration is at least three times lower than the saturation concentration. It is worth noting that the current USP dissolution test exerts minimal mechanical force on solid dosage forms.

In one aspect, the present disclosure provides a sustained release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: Dodecanoic acid dispersed in a polymeric matrix, where the solid oral dosage form exhibits a substantial correspondence when the dissolution test is performed using a US Pharmacopoeia device 2 (paddle 50 rpm) in 50 mM phosphate buffer at 20°C Drug release curve in the following modes: After 2 hours, it releases more than 30% of the total mass of the scalp dodecanoic acid; After 4 hours, it releases more than 75% of the total mass of pleurotropin; and After 8 hours, it releases more than 90% of the total mass of the scalp dodecanoic acid.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form comprises: Dodecanoic acid dispersed in a polymeric matrix, where the solid oral dosage form exhibits a substantial correspondence when the dissolution test is performed using a US Pharmacopoeia device 2 (paddle 50 rpm) in 50 mM phosphate buffer at 20°C The drug release curve in the following mode: after 1 hour, the release of pleurotrope acid does not exceed 8% of the total mass, or the release of pleurotrope acid does not exceed 10% of the total mass, or the release does not exceed the total mass 6% of flavonoid oleoresin, or release of no more than 4% of the total mass of flavonoid oleoresin, or release of no more than 3% of the total mass of flavonoid oleoresin.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form comprises: Dodecanoic acid dispersed in a polymeric matrix, where the solid oral dosage form exhibits a substantial correspondence when the dissolution test is performed using a US Pharmacopoeia device 2 (paddle 50 rpm) in 50 mM phosphate buffer at 20°C The drug release curve in the following mode: after 2 hours, the release of pleurotrope acid does not exceed 30% of the total mass, or the release of pleurotrope acid does not exceed 25% of the total mass, or the release does not exceed the total mass 20% of the scalp pleurotropin, or the release of no more than 15% of the total mass of the scalp pleurotropin, or the release of no more than 13% of the total mass of the scalp creosote.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form comprises: Dodecanoic acid dispersed in a polymeric matrix, where the solid oral dosage form exhibits a substantial correspondence when the dissolution test is performed using a US Pharmacopoeia device 2 (paddle 50 rpm) in 50 mM phosphate buffer at 20°C The drug release curve in the following mode: after 3 hours, the release of pleuroderma dodecanoic acid does not exceed 50% of the total mass, or the release of pleuroderma dodecanoic acid does not exceed 45% of the total mass, or the release does not exceed the total mass 40% of the scalp pleurotropin acid, or bleaching pleurotrope acid that does not release more than 35% of the total mass, or 33% of the total mass.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form comprises: Dodecanoic acid dispersed in a polymeric matrix, where the solid oral dosage form exhibits a substantial correspondence when the dissolution test is performed using a US Pharmacopoeia device 2 (paddle 50 rpm) in 50 mM phosphate buffer at 20°C The drug release curve in the following mode: after 4 hours, the release of pleurotrope acid does not exceed 75% of the total mass, or the release of pleurotrope acid does not exceed 65% of the total mass, or the release does not exceed the total mass 60% of flavonoids, or flavonoids that release no more than 55% of the total mass, or 53% of the total mass.

In some aspects, the present disclosure provides a solid dosage form, wherein the solid oral dosage form comprises: Dodecanoic acid dispersed in a polymeric matrix, where the solid oral dosage form exhibits a substantial correspondence when the dissolution test is performed using a US Pharmacopoeia device 2 (paddle 50 rpm) in 50 mM phosphate buffer at 20°C Drug release curve in the following mode: after 8 hours, the release of pleurotropin acid does not exceed 90% of the total mass, or the release of pleurotropeic acid does not exceed 85% of the total mass, or the release does not exceed the total mass 80% of the flavonoid oleoresin, or the release of no more than 78% of the total mass of the flavonoid oleoresin, or the release of no more than 75% of the total mass of the flavonoid oleoresin.

In some aspects, the sustained release composition is during a given 5-minute period up to 8 hours after administration, during a given 15-minute period up to 8 hours after administration, and up to 8 hours after administration Do not release more than 3 mg of dermatophyllic acid during a given 30-minute period or during a given 1-hour period up to 8 hours after administration. Preparation of formulations

There are many references that inform those skilled in the art how to prepare the sustained-release pharmaceutical compositions (and solid oral dosage forms) disclosed herein, see (for example) the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (edited by Lieberman, Lachman and Schwartz), published by Marcel Dekker, Inc., and Remington's Pharmaceutical Sciences (edited by Arthur Osol) (current edition), all of which are incorporated by reference in their entirety . In short, many commercially available excipients and pharmaceutical media are used in the preparation of sustained release formulations in oral dosage forms. For example, suitable excipient carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, starches, sugars, diluents, granulating agents, lubricants, binders , Disintegrants and the like, many of which are disclosed in the section entitled "Excipients" above. Specific excipients may include, for example, sucrose, mannitol, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium lauryl sulfate, cremophor, tween ), span, pluronic, microcrystalline cellulose, calcium phosphate, talc, fumed silica, wax and fatty acids.

As mentioned above, solid oral dosage forms belong to the categories of matrix-based lozenges/pills, multiparticulate solids and osmotic solids. A variety of different or separate processes can be used for all or any of the three methods, however there are some preferred or common processes for each.

The formulation process used to prepare matrix-based tablets or pills is based on both diffusion and dissolution (ie, matrix erosion) control systems. Drug release from a hydrophilic matrix system involves both diffusion and dissolution. This is because as more drugs/APIs are released, the matrix size decreases, so the amount of drug/API released also decreases, which leads to non-zero-order release . It is generally observed that typical lipophilic matrix systems are only under diffusion control. The solid dosage form disclosed herein may comprise a hydrophilic matrix or a lipophilic matrix.

Those skilled in the art can use a variety of granulation processes to formulate the matrix-based solid dosage forms disclosed herein. Such processes include dry blending (direct compression), roller compaction, wet granulation, fluidized bed granulation, foam granulation and melt extrusion granulation, all of which can be used to prepare matrix lozenges.

For this purpose, the processes used to prepare solid dosage forms include general processes, such as manufacturing by wet granulation technology. For example, a solvent (such as methanol) is used to blend the leukoderma acid and the polymer into a granulation fluid. The remaining excipients were dissolved in a portion of the granulation fluid, and this mixture was wet blended, slowly added to the tannin acid and continuously mixed in the blender. The granulation fluid is added until a wet blend is produced, and then the wet blend is forced through a predetermined screen onto an oven tray. The blend was dried in a forced air oven at 24°C to 40°C for 18 to 24 hours. The dried particles are then sieved. The lubricant (eg magnesium stearate) is then granulated into the mixture and then placed in a grinding jar. Grinding involves mixing on a pot mill for about 10-30 minutes. Thereafter, the composition is then co-compressed and can be coated with another excipient.

Considerations for the process used include drug loading, fluidity, and compactability. For example, both wet granulation and fluidized bed granulation may not be optimal for moisture-sensitive drugs, and melt extrusion granulation may not be suitable for thermally unstable drugs.

On the other hand, the multiparticulate solid dosage form contains both drug/API and layered beads or microspheres. Fluidized bed granulation, extrusion and spheronization, hot melt extrusion granulation, spray coagulation or rolling are several common methods used to micronize and coat the particles of these dosage forms. Bead formation can be performed by crosslinking the non-covalent alginate layer with calcium cations to form alginate beads.

Finally, solid dosage form osmotic lozenges (such as those developed by Alza Corporation) usually contain four components: drug/API compartment, swelling compartment containing osmotic active salt, membrane, and micropores for release. The drug/API and swelling compartments are prepared by the granulation process described above for the matrix-based system. Osmotic lozenges work by using drugs/APIs and swelling compartments to form various "push-pull" osmotic pumps. The two compartments are compressed into bilayer tablets, and the tablets are coated with a film containing holes (produced by laser drilling) (see the spray drying process above and the Remington reference). The membrane allows free diffusion of water, but does not allow free diffusion of drugs. When the lozenge is exposed to water or any fluid in the body, water will flow into the lozenge due to the difference in osmotic pressure. For the preparation process of osmotic lozenges, see, for example, US Patent Nos. 8,629,179 and 8,163,798 and Remington's Pharmaceutical Sciences (edition by Arthur Osol; current edition).

The most significant advantage of the osmotic system is that the dosage form is independent of pH to a certain extent, and it can be extended even when the dosage form moves through the uneven microenvironment (about pH, salinity, ion concentration, etc.) of various parts of the GI tract. Provide a stable release rate over a period of time. Santus and Baker, incorporated in this article by reference in full text, "Osmotic drug delivery: a review of the patent literature," pages 1-21 of the Journal of Controlled Release 35 (1995) are a good overview of these systems . In addition, US patents issued to ALZA Corporation describe how to prepare and use osmotic dosage forms, each of which is incorporated herein by reference in its entirety: US Patent Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719; 4,111,202 No. 4,160,020; No. 4,327,725; No. 4,519,801; No. 4,578,075; No. 4,681,583; No. 5,019,397; and No. 5,156,850.

Some exemplary swellable polymers used in permeable systems include, but are not limited to, L poly(alkylene oxide) with a number average molecular weight of 1 million to 15 million (as represented by poly(ethylene oxide)) And poly(carboxymethyl cellulose alkali metal) with an average molecular weight of 500,000 to 3,500,000 (alkali metal: sodium, potassium or lithium), acidic carboxyl polymer, acrylic acid cross-linked with polyalkenyl ether or divinyl glycol , Cross-linked homopolymers and copolymers of acrylic acid (including divinyl glycol and/or C10-C30 alkyl acrylate and allyl neopentyl alcohol cross-linked as copolymers), the number average molecular weight is 250,000 to 4,000,000 Of acrylic acid and polyallyl sucrose cross-linked polymer; acrylic polymer, polypropylene amide; cross-linked water-swellable indene maleic anhydride polymer; polyacrylic acid with a number average molecular weight of 80,000 to 200,000; from condensed glucose Units composed of acrylate polymer polysaccharides, such as diester crosslinked polydextrose; and the like. Some hydrogel-forming polymers include those described in U.S. Patent No. 3,865,108, U.S. Patent No. 4,002,173, U.S. Patent No. 4,207,893, and Handbook of Common Polymers, Scott and Roff, Chemical Rubber Co., Cleveland, OH, etc. . Suitable penetrant solutes include (but are not limited to): sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium dihydrogen phosphate, mannitol, urea, inositol, Magnesium succinate, tartaric acid, raffinose, sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates. Suitable solvents suitable for the manufacture of dosage form components include aqueous or inert organic solvents that do not adversely harm the materials used in the system. Such solvents include (but are not limited to): aqueous buffer solvents such as phosphate buffers, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic compounds, aromatic compounds, heterocyclic solvents and mixtures thereof . Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone , N-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, dichloromethane, dichloroethane, dichloropropane, carbon tetrachloride nitroethane, nitropropane tetrachloroethane Alkanes, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, containing inorganic salts (e.g. Aqueous solvents and mixtures of sodium chloride, calcium chloride, and the like (for example, acetone and water, acetone and methanol, acetone and ethyl alcohol, dichloromethane and methanol, and dichloroethane and methanol).

Finally, techniques for drilling holes in the outer membrane (including mechanical and laser drilling) are disclosed in US Patent No. 3,916,899 and US Patent No. 4,088,864, both of which are incorporated herein by reference in their entirety .

Therefore, the present disclosure provides a sustained release pharmaceutical dosage form comprising a solid oral osmotic dosage form containing dominoic acid and a polymer matrix. In some aspects, the present disclosure provides a sustained-release pharmaceutical dosage form comprising a solid oral osmotic dosage form containing dominoic acid and a polymer matrix, wherein the polymer is selected from the group consisting of: hydroxypropylmethyl Cellulose (HPMC), microcrystalline cellulose and sodium carboxymethyl cellulose. Instructions

This article discloses a method of treating an individual's cardiovascular disease or reducing the risk of cardiovascular disease, which is implemented by administering a sustained-release composition comprising tannin and a polymer matrix.

Administration of the pharmaceutical composition usable according to the present invention to an individual, preferably administered as "therapeutically effective amount"/"therapeutically effective concentration" (same meaning) or "preventively effective amount" (as the case may be, but prevention can be regarded as therapy ), which is enough to show the benefits to the individual. The actual amount administered and the rate and timing of administration will depend on the nature and severity of the disease being treated. The course of treatment and prescription (eg, dose determination, etc.) are the responsibility of the general practitioner and other physicians, and usually take into account the condition to be treated, the condition of the individual patient, the delivery site, the method of administration, and other factors known to the practitioner. Exemplary therapeutically effective amounts are 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day or 500 mg/day, more preferably 50 mg/day, 100 mg/day or 200 mg/day, even better 90 mg/day or 180 mg/day. Exemplary preventive effective doses are 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day or 500 mg/day, more preferably 50 mg/day, 100 mg/day or 200 mg/day, even better 90 mg/day or 180 mg/day.

In one aspect, the present disclosure provides a method of treating an individual's cardiovascular disease or reducing the risk of cardiovascular disease, the method comprising: Administer an effective amount of a solid oral dosage form to an individual in need thereof, wherein the solid oral dosage form contains dermatophyllic acid and a polymer, and wherein when USP 2 (paddle 50 rpm) is used in 50 mM phosphate buffer When the dissolution test is performed in liquid, the solid oral dosage form exhibits a drug release curve substantially corresponding to the following pattern: After 2 hours, release no more than 30% of the scalp dodecanoic acid; After 4 hours, do not release more than 75% of the skin's dodecanoic acid; After 8 hours, release no more than 90% of the skin's dodecanoic acid; and Wherein the solid oral dosage form provides a therapeutically effective concentration of leukoderma multi-acid in a 24-hour period when administered to an individual to treat cardiovascular disease or reduce cardiovascular disease risk.

In one aspect, the present disclosure provides that when a solid oral dosage form is dissolved in 50 mM phosphate buffer at a pH of 8.5 at 20°C, it does not release more than 95% of the dermatophyllic acid after 8 hours method.

In one aspect, the present disclosure provides a method of inhibiting ATP-citrate lyase (ACL) in an individual, the method comprising administering to the individual a pharmaceutical dosage form of any one disclosed herein.

In one aspect, the present disclosure provides a method in which the solid oral dosage form contains 5 mg to 500 mg of tannin. In one aspect, the present disclosure provides a method in which the solid oral dosage form contains 5 mg to 100 mg of tannin. In one aspect, the present disclosure provides a method in which the solid oral dosage form contains 5 mg to 50 mg of tannin. In one aspect, the present disclosure provides a method in which the solid oral dosage form contains 180 mg to 240 mg of tannin. In one aspect, the present disclosure provides a method in which the solid oral dosage form contains 200 mg to 240 mg of tannin.

In one aspect, the present disclosure provides methods in which the polymer is microcrystalline cellulose. In one aspect, the present disclosure provides methods in which the polymer is a mixture of microcrystalline cellulose and polycellulose. In one aspect, the present disclosure provides a method in which the polymer is a mixture of microcrystalline cellulose and hydroxypropyl methyl cellulose (HPMC). In one aspect, the present disclosure provides a method in which the polymer is hydroxypropyl methyl cellulose (HPMC). In one aspect, the present disclosure provides methods in which the polymer is polycellulose. Cardiovascular disease and clinical end point of delivery of dodecanoic acid

In one aspect, the present disclosure provides methods for reducing blood lipid, lipoprotein, or cholesterol levels in an individual. In some aspects, the reduction is determined by comparing the amount of analyte measured from samples obtained from the individual before and after administration of the drug. In some aspects, the reduction is based on comparing the results of clinical trials comparing matched populations (one receiving a drug and one receiving a placebo). In one aspect, the present disclosure provides a method of reducing low density lipoprotein cholesterol (LDL-C) in an individual.

In one aspect, the present disclosure provides a method of reducing total cholesterol (TC) in an individual. In one aspect, the present disclosure provides a method wherein the method reduces total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) in an individual. In one aspect, the present disclosure provides methods for lowering total cholesterol (TC) when administered to human individuals with hypercholesterolemia, mixed dyslipidemia, type II diabetes, obesity, chronic liver disease, or kidney disease. In one aspect, the present disclosure provides for lowering total cholesterol (TC) and low density when administered to human subjects with hypercholesterolemia, mixed dyslipidemia, type 2 diabetes, obesity, chronic liver disease, or kidney disease Lipoprotein-cholesterol (LDL-C) method.

In one aspect, the present disclosure provides a method of reducing the content of very low density lipoprotein (VLDL) in an individual.

In one aspect, the present disclosure provides a method of reducing the size of VLDL particles in an individual.

In one aspect, the present disclosure provides a method of reducing lipoprotein element B (ApoB) content in an individual. In one aspect, the present disclosure provides a method of reducing the content of lipoprotein element A-1 (ApoA1) in an individual.

In one aspect, the present disclosure provides a method of reducing the ratio of lipoprotein element B (ApoB) to lipoprotein element A-1 (ApoA1) in the individual below. In one aspect, the present disclosure provides a method that does not change the ratio of lipoprotein element B (ApoB) to lipoprotein element A-1 (ApoA1) in an individual.

In one aspect, the present disclosure provides a method in which the individual has hypercholesterolemia. In one aspect, the present disclosure provides a method wherein the individual has mixed dyslipidemia, type II diabetes, obesity, chronic liver disease, kidney disease, or any combination thereof.

In one aspect, the present disclosure provides methods in which each system is a mammal. In one aspect, this disclosure provides methods, each of which is human. Treatment window

The therapeutic window can also be generally expressed as the ratio between the minimum effective concentration (MEC, also known as the minimum inhibitory concentration (MIC)) and the minimum toxic concentration (MTC) of (drug/API). An important goal of drug delivery is to maintain the plasma content of the drug between MEC and MTC to provide the most beneficial and risk-free therapeutic effect. If the drug concentration exceeds MTC, a toxic effect will be observed; on the other hand, if the drug concentration cannot exceed MEC, the treatment suffers from treatment failure.

The therapeutic index (TI) describes the relationship between the dose of a drug that causes lethal or toxic effects and the dose that causes a therapeutic effect. It can be calculated by the following: Therapeutic Index (TI) = LD ₅₀ /ED ₅₀ where LD ₅₀ is the lowest amount of drug that causes adverse effects in 50% of the population. LD ₅₀ can also be replaced by toxic dose (TD ₅₀ ). ED ₅₀ is the amount of drug that can produce the desired therapeutic effect in 50% of the population.

In some aspects, the present disclosure provides a method in which, after administration, the concentration of leukoderma is between MEC and MTC for a duration of 20 minutes to 8 hours. In some aspects, the present disclosure provides a method in which, after administration, the concentration of pleuroderma is between MEC and MTC for the following duration: 20 minutes to 9 hours, 20 minutes to 10 hours, 20 Minutes to 12 hours, 20 minutes to 14 hours, 20 minutes to 16 hours, 20 minutes to 18 hours, 20 minutes to 20 hours, 20 minutes to 24 hours, 20 minutes to 36 hours or 20 minutes to 48 hours.

In some aspects, the present disclosure provides a method in which the pharmaceutical dosage form provides AUC of bianpitoylic acid in a 7.5 mg/kg or 30 mg/kg bianpitoi acid capsule in rats. In some aspects, the present disclosure provides a method in which, after oral administration of a single 7.5 mg/kg or 30 mg/kg bianpi dodecanoic acid capsule, the pharmaceutical dosage form provides per mg of bistriptoic acid in rats AUC of 661 ng*hour/mL of activated blepharodolic acid.

In some aspects, the present disclosure provides a method wherein the pharmaceutical dosage form is administered to a 1 kg male Sprague-Dawley rat at a unit dose of 180 mg bilobaldolic acid, the largest plasma of bilobaldolic acid in the rat The concentration (C _max ) does not exceed 60 µg/mL and is within the range of 45 µg/mL-59 µg/mL within 24 hours after administration.

In some aspects, the present disclosure provides a method in which, after oral administration of a single 50 mg, 100 mg, 200 mg, or 180 mg benzilotoxan lozenge, the pharmaceutical dosage form provides more than 8 hours in rats T is the _largest .

In some aspects, the present disclosure provides a method of administering dominoic acid, the method comprising: administering an effective amount of a pharmaceutical dosage form comprising a solid oral dosage form to an individual in need, wherein the solid oral dosage form comprises Dodecanoic acid and polymers, and the maximum plasma concentration ( _Cmax ) of the administration does not exceed 60 µg/mL when analyzed in standard pharmacokinetic analysis (eg, rats), and After this, the maximum plasma concentration ( _Cmax ) was within the range of 45 µg/mL-60 µg/mL for 24 hours.

In some aspects, the present disclosure provides a method in which bilobalide is delivered at a rate that is independent of the amount of bilobalide in the dosage form. In these aspects, the method provides zero-order release of dominoic acid. In some aspects, the present disclosure provides a method in which the leukodermic acid is delivered at a nearly constant rate (meaning that the average delivery rate does not vary by more than +/- 10% over the effective delivery life of the dosage form) for at least 2 hours , At least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, but not longer than 36 hours (Ie, covering a period of 2-36 hours).

In some aspects, the method described can be practiced by administering the pharmaceutical dosage form of leukolide in the application. Combination therapy and dosage form

In some aspects, the present disclosure provides methods and compositions, wherein the sustained release pharmaceutical composition further comprises a therapeutically effective amount of ezetimibe (Ezetimibe). In these aspects, the formulation does not need to provide sustained release of ezetimibe, but according to the present disclosure provides sustained release of domperidone.

In some aspects, the present disclosure provides methods and compositions, wherein the sustained release pharmaceutical composition further comprises a therapeutically effective amount of statins. In these aspects, the formulation does not need to provide sustained release of statins, but according to the present disclosure provides sustained release of dombyotonic acid.

In some aspects, the present disclosure provides methods in which the sustained-release pharmaceutical composition is administered simultaneously or sequentially in combination with other lipid-lowering treatments, depending on the clinical condition of the cardiovascular condition being treated.

In some aspects, the present disclosure provides methods and compositions wherein the sustained-release pharmaceutical composition further comprises a therapeutically effective amount of proprotein convertase subtilisin-kexin type 9 Antibody (PCSK9 inhibitor). In some aspects, the present disclosure provides methods and compositions wherein the sustained release pharmaceutical composition further comprises a therapeutically effective amount of a bile acid clamp.

In some aspects, the present disclosure provides methods and compositions wherein the sustained release pharmaceutical composition further comprises a therapeutically effective amount of biguanide (eg, metformin), or adenosine monophosphate activated protein kinase (AMPK) activator, or alpha -Glucosidase inhibitors, or amyloid analogs, or dipeptidyl peptidase 4 inhibitors, or incretin mimetics, or meglinitide, or sulfonylurea, or non-sulfonylurea, Or sodium-glucose transporter-2 (SGLT2) inhibitor, or thiazolidinedione, or glucagon-like peptide-1 (GLP-1) and/or combinations thereof.

In some aspects, the present disclosure provides methods and compositions wherein the sustained release pharmaceutical composition further comprises a therapeutically effective amount of farnesoid-X-receptor (FXR) and/or bile acid receptor agonist Agents, or peroxisome proliferator-activated receptor (PPAR)-α agonists, or PPAR-γ agonists, or PPAR-δ agonists, or PPAR-α/γ agonists, PPAR-α/δ agonists , Or pan-PPAR agonists, or cysteine depleting agents, or phosphodiesterase-4 (PDE-4) inhibitors, or apoptosis signal-regulated kinase 1 (ASK-1) inhibitors, or chemotaxis-mediated Receptor inhibitors (including CCR2/CCR5 inhibitors) or combinations thereof.

In some aspects, the present disclosure provides methods and compositions wherein the sustained-release pharmaceutical composition further comprises a therapeutically effective amount of alanine aminotransferase, alkaline phosphatase, total bilirubin or triglycerides, or cytokeratin Compound (inhibitor) with protein-18 content. Investment schedule

In some aspects, the present disclosure provides methods in which the sustained release pharmaceutical composition is administered twice daily, once daily, or once every two days. Treatment of metabolic syndrome / disorders with metabolic syndrome of tannin

Metabolic syndrome and/or metabolic disorders are associated with conditions such as increased obesity, insulin resistance, dyslipidemia, fatty liver, inflammation, and atherosclerosis. These abnormalities are to some extent related to the process of atherogenesis. Although dominoic acid can improve the metabolic disorder pathways associated with some of these abnormalities, it is unclear whether therapeutic efficacy is limited by pharmacodynamic parameters.

In this article, the present inventors revealed that the use of sustained release formulations of dermatophyllic acid targeting enzymes ACL and AMPK increases the formation efficiency, residence life and therapeutic efficacy of activated dermatological domenoic acid, which in turn is used in the treatment of metabolism such as NAFLD, NASH, fatty liver, inflammation, fibrosis or any combination of these syndromes and diseases provide significantly more therapeutic value.

In one aspect, the present disclosure provides a method of treating an individual's metabolic syndrome and/or metabolic disorder, the method comprising administering to the individual an effective amount of any of the sustained release formulations/dosage forms disclosed herein. In one aspect, the present disclosure provides a method of treating fatty liver in an individual, the method comprising administering to the individual an effective amount of any of the sustained release formulations/dosage forms disclosed herein. In one aspect, the present disclosure provides a method of treating inflammation or fibrosis in an individual, the method comprising administering to the individual an effective amount of any of the sustained release formulations/dosage forms disclosed herein.

In one aspect, the present disclosure provides treatment of an individual's metabolic syndrome, metabolic disorder, fatty liver, inflammation, fibrosis or any combination thereof diagnosed or measured by the liver biopsy pathology or imaging methods disclosed herein Method. Non-alcoholic fatty liver disease (NAFLD)

If the rate of lipid delivery to and in the liver does not match the rate of fatty acid β-oxidation and VLDL secretion, hepatocytes will increase lipid droplet formation and NAFLD will then occur. Since NAFLD is closely related to obesity, dyslipidemia, and type 2 diabetes, it is a liver manifestation of metabolic syndrome (for example, see Asrih, M. and FR Jornayvaz. 2015. Molecular and Cellular Endocrinology. 418: 55-65). NAFLD covers a range of conditions ranging from simple steatosis to steatohepatitis.

NAFLD is mostly asymptomatic in the early stages. The standard used to diagnose NAFLD is liver biopsy. Non-invasive NAFLD diagnosis includes methods using imaging modalities, plasma markers, and scoring algorithms. Imaging is performed using ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), transient elastography or FibroScan®. Plasma markers used to evaluate liver function include alanine and aspartate aminotransferases (ALT and AST, respectively), albumin, platelet count, glucose, insulin, TG and cholesterol (for example, see Machado, MV and H Cortez-Pinto. 2013. Journal of Hepatology. 58: 1007-1019; Pacana, T. and AJ Sanyal. 2015. F1000Prime Rep. 7: 28). In addition to age, gender, body mass index, insulin resistance and glycemia, hypertension, and results from imaging tools, there are many scoring algorithms that use these plasma measurements.

This article discloses sustained release formulations comprising blepharodolic acid that are effective in treating NAFLD, NASH, and/or NAFL.

In one aspect, the present disclosure provides a method of treating NAFLD in an individual, the method comprising administering to the individual an effective amount of any of the sustained release formulations/dosage forms disclosed herein. Non-alcoholic steatohepatitis (NASH)

NAFLD progresses to a very serious disease called nonalcoholic steatohepatitis (NASH). The signs of this disease are increased inflammation and fibrosis. NASH is histologically presented as simple steatosis with hepatocyte swelling, mononuclear infiltration, and collagen deposition (see, for example, Yeh, MM and EM Brunt. 2014. Gastroenterology. 147: 754-764). The increase in fibrosis and inflammation seen by NASH greatly increases the risk of liver cancer.

In one aspect, the present disclosure provides a method of treating NASH in an individual, the method comprising administering to the individual an effective amount of any of the sustained release formulations/dosage forms disclosed herein.

In one aspect, the present disclosure provides a method of treating NAFLD, NAFL, and/or NASH, wherein the individual is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes, or any combination thereof . Examples

The following are examples of specific embodiments for implementing the present invention. These examples are provided for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure the accuracy of the numbers used (such as quantity, temperature, etc.), but of course some experimental errors and deviations should be allowed.

Unless otherwise indicated, the practice of the present invention will employ conventional medicinal chemistry and pharmacology methods well known to those skilled in the art. These techniques are fully explained in the literature. For example, see Remington's Pharmaceutical Sciences , 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Example 1-Experimental conditions and protocols for pharmacokinetic (PK) studies in animals Animals and administration

Male Han Wistar [Crl:WI (Han)] rat strains were purchased from Charles River and adapted to the study conditions for four days before the initial dose administration. Freely provide certified rodent feed number 2016C (Envigo RMS, Inc.) at any time. Provide fresh water freely every day at any time. Animals were assigned to one of three groups, where group 1 received an oral bolus dose of ETC-1002 (30 mg/kg), and group 2 was divided into 4 doses at approximately 7.5 mg/kg intervals for 4 hours ETC-1002 (30 mg/kg) was received, and group 3 did not receive the dose (Table 1). Animals were identified through individual cage cards and implantable microchip identification devices in the right back waist area. Dose, collection and analysis

Individual doses were calculated based on the body weight recorded the day before the dose administration, and the oral doses were administered via oral gavage. According to the schedule in Table 2, by syringe and needle (approximately 0.3 mL) through the jugular vein or by cardiac puncture under appropriate anesthesia before and about 2 hours, 4 hours, 6 hours, 8 hours, and 10 hours after administration , 12 hours, 14 hours, 20 hours and 24 hours to collect blood samples. Transfer blood to a tube (serum separator tube) without anticoagulant.

The blood was allowed to clot at ambient temperature, and then centrifuged to obtain serum. Centrifugation starts within 1 hour of collection. Place the serum in a suitable tube and keep it on dry ice before storing at about -70°C. Liver samples were collected from 3 animals/group/time point approximately 2 hours, 6 hours, 10 hours, 14 hours, 20 hours, and 24 hours after dosing (Table 2). Use pre-cooled forceps to harvest the liver as quickly as possible. Afterwards, the tissue and jaws were immediately frozen by immersion in liquid nitrogen. After freezing, the tissues were packaged in foil and kept on dry ice before being stored at approximately -70°C.

表 2.

調配物 Then use the verified LC-MS/MS method to analyze the serum ETC-1002 content, and after extracting the homogenate in MeOH-formic acid in the liver sample, determine ETC-1002-CoA (activated tannin acid) and Acetyl-CoA content. A standard concentration curve of acetyl-CoA was generated in the control liver homogenate, and the unknown sample concentration was calculated using a linear curve fitting model. ETC1002-CoA content is expressed as the change in peak area (acetyl-CoA µg equivalent). Study Design Table 1.

Table 2.

Formulation

實例2：例示性立即釋放邊皮多益酸調配物之動物中之單次濃注PK研究The ETC-1002 formulation was prepared in an appropriate volume of 0.5% CMC (pH 7-8) and stirred throughout the drug administration process. The specific information about dosage preparation is in Table 3. Table 3.

Example 2: Exemplary single bolus injection PK study in an animal that immediately releases the formulation of dominoic acid

Existing oral administration formulations are rapidly absorbed in the small intestine (for example, see Bilen et al., Curr Atheroscler Rep ., 2016; 18(10): 61). The purpose of this example is to establish the baseline pharmacodynamic characteristics of an exemplary immediate release flavonol formulation. The experimental procedures used are described in "Example 1-Experimental Conditions and Protocols for Pharmacokinetic (PK) Studies in Animals" above. result

Single bolus PK-based measured values: T _max = 2 hours, _{the maximum} C = 97.1 μg / mL and AUC _{0-24 hr} = 1244.0 μg · hr / mL. Serum content of dominoic acid provides a peak maximum concentration close to 100,000 ng/mL (100 μg/ml) within 1 hour after administration. In addition, a single bolus injection provides a liver ETC-1002-CoA concentration of less than 250 ng/gm over a 20-hour period. Example 3: Multiple separate PK studies in animals to simulate sustained release formulations of tannin

Multiple administrations are used to simulate the sustained release of the skin's tannin. In view of biological metabolism, this article tests the effect of the absorption of dombyotonic acid on the properties of PK. The purpose of this study was to determine the pharmacodynamic characteristics of a representative sustained-release dombyid acid formulation. The following procedure is described in "Example 1-Experimental Conditions and Protocols of Pharmacokinetic (PK) Studies in Animals" as described above. result

The separate measured value PK several lines: T _max = 10 hours, C _maximum = 55.5 μg / mL and AUC _{0-24 hr} = 661 μg · hr / mL. Separate multiple administrations provide a serum content of dominoic acid with a maximum concentration of approximately 60,000 ng/mL within 10 hours after administration. In addition, multiple separate bolus injections showed that AUC _{0-24 of} liver ETC-1002-CoA increased _SS by approximately 28% and AUC _{0-24 hours} by approximately 24%. Example 4: Comparison of PK study of sustained-release and immediate-release dombyid acid formulations in rats

The purpose of this example is to provide a proof-of-concept for the sustained release formulation of Epithelium Dodecanoic Acid (ETC-1002) with increased PK activity by showing an improved pharmacokinetic profile in the liver and plasma stand by. The improved PK characteristics are defined as the ETC-1002-CoA AUC in the liver is higher for _{0-24 hours} and the serum ETC-1002 C is _maximum or the AUC is equal to or lower than _{0-24 hours} for any given dose, or in the liver Equal amount of ETC-1002-CoA AUC _{0-24 hours} and serum ETC-1002 C _maximum or AUC _{0-24 hours} decreased. result

A significant difference in serum pharmacokinetics was observed between a single bolus injection and multiple separate administrations of multiple edible acid. Surprisingly, no matter how fast the absorption is, simulating the continuous release of multiple separate bolus injections provides a slow rise in the serum concentration of dodecanoic acid. This single administration of the contrast bolus, wherein serum levels of beneficial Pinedo acid administered a single bolus of the short sides and providing T _max, which then drops sharply (FIG. 1A) within 22 hours after.

During the entire 24-hour study duration, liver acetyl-CoA in both groups was inhibited ( Figure 1B ). However, multiple separate administrations (ie, simulated sustained release) showed that despite achieving a lower maximum serum exposure, liver acetyl-CoA activity was more significantly reduced (47%, Figure 1B ).

In addition, compared to a single bolus injection, the simulated sustained release achieves greater liver ETC-1002-CoA exposure. Interestingly, the ratio of simulated sustained-release liver ETC-1002-CoA exposure to serum ETC-1002 exposure was more than doubled ( Figure 1C ). These findings support the conclusion that the conversion efficiency of prodrugs is increased by the rate of absorption of dodecanoic acid in the intestinal tract. Example 5: Sustained-release formulations of tannin and its respective dissolution data formulations

Several formulations were prepared containing pleurotropin and hydrophilic cellulose polymer matrix, hydroxypropyl methyl cellulose (HPMC) and tested in USP dissolution analysis. Construct the formulation into solid particles. Screen each formulation.

表 5.

表 6.

表 7.

表 8.

表 9.

表 10.

表 11.

表 12.

表 13.

溶 離 分析 Individual batches are formulated differently to include the compounds described in Tables 4-13 below. Table 4.

Table 5.

Table 6.

Table 7.

Table 8.

Table 9.

Table 10.

Table 11.

Table 12.

Table 13.

Eluting Analysis

The USP dissociation experiment evaluates the rate and extent of compound formation under carefully controlled conditions. Dissolution testing helps to evaluate the performance of pharmaceutical products. For a detailed description of device setup and experimental procedures, see United States Pharmacopeial Convention, USP35 NF30, 2012: US Pharmacopoeia National Formulary, The United States Pharmacopeia , 2011, Chapter 711, 5642-5648.

The physical properties of dosage forms such as unit dose wettability, permeability, swelling, disintegration, and depolymerization affect the dissolution of pharmaceutical dosage forms.

-數值表示為自調配物中邊皮多益酸之起始總量釋放至溶液中之百分比。*批次CU07-105及CU07-107在期望之16/30篩截止範圍內具有相對低之產率。批次CU07-117及CU07-115在製造製程期間展現出黏著行為且亦具有相對低之總體產率。720 min時間點係無窮時間點。 實例6：邊皮多益酸之立即釋放(IR)及持續釋放(SR)調配物之藥物產品之組成The results of dissolution analysis are described in Table 14 below and presented in Figure 2A and Figure 2B , respectively. Table 14- Dissolution analysis results Time (minutes)

-The value is expressed as a percentage of the initial total amount of leukoderma acid in the formulation released into the solution. *Batch CU07-105 and CU07-107 have relatively low yields within the expected 16/30 screen cutoff. Batches CU07-117 and CU07-115 exhibit adhesive behavior during the manufacturing process and also have a relatively low overall yield. The 720 min time point is an infinite time point. Example 6: Composition of pharmaceutical products of immediate release (IR) and sustained release (SR) formulations

This example illustrates the composition of both immediate-release and sustained-release products and formulations of tannin.

縮寫：IND=研究性新藥；LDL-C=低密度脂蛋白-膽固醇。^a 在處理期間去除。Table 15 describes the composition of the immediate release (IR) formulation of Lepidotropin. Pinedo acid side benefits of an immediate release formulation of the composition of Table 15-- composition of 180 mg tablets of beneficial acid side Pinedo

Abbreviations: IND=new research drug; LDL-C=low density lipoprotein-cholesterol. ^{a Removed} during processing.

Table 16 describes the medicinal products of IR formulations of dermatophyllic acid and placebo lozenges. Table 16-Research Pharmaceutical Products (IMP) of Immediate Release Formulations of Bentoic Acid and Placebo Tablets

^a 值已捨入至所示最接近之十進制小數。總和係自準確值確定且可不代表所示之捨入個別值。^b 水及HPMC 606將作為預混合溶液添加。^c 水係處理助劑且不包括在最終調配物中。因此，「總量」不包括水。^d 膠囊殼包含二氧化鈦(E171) (2.9079%)作為遮光劑及明膠(量足以達到100%)。 對邊皮多益酸之持續釋放調配物之膠囊球之描述Table 17 describes the composition of the SR formulation of Lepidotropin. Composition of Sustained-release formulations of Lepidotropinic Acid Table 17- Composition of Sustained-release formulations of Lepidotropeic Acid Capsules

^The value of a has been rounded to the nearest decimal decimal point shown. The sum is determined from the exact value and may not represent the rounded individual value shown. ^b Water and HPMC 606 will be added as a pre-mixed solution. ^c Aqueous treatment aid and not included in the final formulation. Therefore, "total" does not include water. ^{d The} capsule shell contains titanium dioxide (E171) (2.9079%) as sunscreen and gelatin (enough to achieve 100%). Description of Capsule Ball of Sustained-Release Blend of Dodecanoic Acid

Sustained-release (SR) benpyolic acid capsules are white opaque hard gelatin capsules, which are filled with spheres made from benpyral acid and excipients. Two capsule sizes and dosages can be used for NASH research: 　• "No. 3 size" for 50 mg of dermal multi-purpose acid SR capsule 　• "No. 0 size" for 200 mg tannin dodecanoic acid SR capsules Example 7-Administering a representative sustained release flavonoid acid formulation to humans

The main objective was to evaluate the LDL-C lowering efficacy of a representative oral leukotopic acid sustained-release solid oral dosage form (lozenge) administered daily for up to 6 weeks in patients with elevated LDL-C relative to placebo.

Evaluation of secondary objectives: 1. Sustained-release formulations of tannin-derived acid against non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein element B (ApoB), and high-sensitivity C-reactive protein relative to placebo (hs-CRP), TG and HDL-C effects. 2. The effect of sustained release solid oral dosage form (lozenge) of dominoic acid (180 mg) on the percentage of patients who achieve LDL-C content <70 mg/dL. 3. The effect of sustained release solid oral dosage form (lozenge) of dominoic acid (180 mg) relative to placebo on the percentage of patients who achieved a LDL-C reduction of ≥50%. 4. The safety and tolerability of sustained release solid oral dosage form (lozenge) of dominoic acid (180 mg) relative to placebo.

The primary endpoint used to assess the goals of this study is the percentage change in LDL-C content from baseline to week 6. The secondary endpoint also includes the percentage change of non-HDL-C, TC, ApoB, hs-CRP, TG, and HDL-C content from baseline to Week 6, and the percentage of patients with LDL-C <70 mg/dL at Week 6 The percentage change from baseline to week 6 and the percentage of patients with a LDL-C reduction of ≥50% from baseline to week 6. Drug Administration - Patient Treatment

During the treatment period, patients were randomized to receive a sustained-release bilirubicin solid dosage form or placebo IMP once a day. The daily dispense of IMP contains one lozenge dodecanoic acid lozenge in a blister pack. The placebo blister contains the corresponding matching placebo of the solid dosage form of Pinotic acid. Instruct the patient to ingest the IMP once a day with or without food. On the day of the clinic visit, the patient was instructed to delay IMP intake until all study procedures were completed. Example 8: Single-dose study of immediate release formulations of dominoic acid in healthy individuals (IR Study 1)

This example illustrates a single-dose study to assess the safety, tolerability, and pharmacokinetics of domperidone in healthy individuals. Figure 6 summarizes the design of this study.

The key objective of this study is to evaluate and characterize the pharmacokinetic (PK) characteristics of pleural tonic acid and its metabolites after a single incremental oral dose is administered to healthy individuals.

This is a single-center, randomized, double-blind, placebo-controlled, escalating, single-dose crossover study. The crossover design involves 2 cohorts, with 9 individuals in each cohort. Each cohort is carefully incremented by 3 single-dose groups. Each dose group consisted of 6 randomized individuals receiving dominoic acid and 3 randomized individuals receiving placebo. The randomization scheme ensures that the individual receives a total of 2 divided doses of active drug and a single placebo administration. Between the administration of study agents, the dosage groups are separated by a clearance period of not less than 10 days. Dose escalation depends on acceptable safety, tolerability and pharmacokinetic data, and follows well-defined stopping rules, including exposure limits. In this study, the exposure limit of AUC _0-24 for 200 μg·hr/mL of _{dermatophyllin was} higher than the estimated therapeutic exposure of 36 μg·hr/mL to 72 μg·hr/mL, thus providing the most The opportunity to fully explore the upper limit of the dose range during the control phase. result

^a 參數分別劑量校正至50 mg、100 mg或200 mg劑量。 實例9：在患有輕度異常血脂症之個體中邊皮多益酸之立即釋放調配物之多次遞增劑量研究(IR研究2)Table 18 shows the measured and dose-corrected pharmacokinetic (PK) parameters after a single dose of immediate release (IR) formulation of dominoic acid in healthy individuals. Table 18- PK parameters measured and dose-corrected after a single dose of the immediate release formulation of Dodecanoic Acid from IR Study 1 .

^{The a} parameters were dose corrected to 50 mg, 100 mg or 200 mg doses respectively. Example 9: Multiple escalating dose studies of immediate release formulations of dombynoic acid in individuals with mild dyslipidemia (IR Study 2)

This example illustrates multiple escalating dose studies of flavo-dodecanoic acid in individuals with mild dyslipidemia. Figure 7 summarizes the design of this study.

The key objective of this study is to evaluate and characterize the pharmacokinetics (PK) of dombyotonic acid and its metabolites after multiple escalating doses of dombyotonic acid are administered to individuals with mild dyslipidemia Characteristics and pharmacodynamic (PD) end points, such as low density lipoprotein-cholesterol (LDL-C) content.

This is a single-center, randomized, double-blind (sponsor open), placebo-controlled, incremental, and multi-dose study with 4 incremental cohorts, followed by the optional fifth cohort. The first 4 cohorts each included 8 male and female individuals with slightly elevated LDL-C content (6 active agents/2 placebos) who were treated in the clinical unit for a duration of 14 days. The dose escalation of the first 4 cohorts depends on the acceptable safety, tolerability and PK data and will follow the well-defined stopping rules, including the sum of ESP15228 for the flavonol and its metabolite, AUC _0- The predetermined exposure limit for ₂₄ is 200 μg·h/mL. If the safety profiles from the first 4 cohorts are acceptable, then 24 free-living male and female individuals (18 active agents) with 28 days of LDL-C and triglyceride levels that are slightly elevated /6 placebo) optional 5th cohort.

Use Bipyrogalolic acid capsules (20 mg) or placebo capsules for this study. Administer multiple oral doses of 20 mg, 60 mg, 100 mg, and 120 mg to individuals in the fasting state of the same group 1 to 4, and the total sum of dodecanoic acid and its metabolite ESP15228 is not Exceeds the predetermined exposure limit of AUC _0-24 of 200 μg·h/mL. result

實例10：在健康個體中邊皮多益酸之立即釋放調配物之多次遞增劑量研究(IR研究3)Table 19 shows the measured and dose-corrected pharmacokinetic (PK) parameters after a single dose of immediate release (IR) formulation of dominoic acid in healthy individuals. Table 19- Percent change in LS mean value of LDL-C from baseline after a single dose of immediate release formulation of Dodecanoic Acid from IR Study 2

Example 10: Multiple escalating dose studies of immediate release formulations of dominoic acid in healthy individuals (IR Study 3)

This example illustrates multiple escalating dose studies of dodecanoic acid in the healthy individual at doses above 120 mg/day. Figure 8 summarizes the design of this study.

The key objective of this study is to assess and characterize the pharmacokinetic (PK) characteristics and pharmacodynamics (PD) of dermatophyllic acid and its metabolites after multiple escalating doses of dermatophyllic acid to healthy individuals ) End point, such as low density lipoprotein-cholesterol (LDL-C) content.

This is a single-center, randomized, double-blind (sponsor open), placebo-controlled, incremental, multi-dose study, which has about 4 increasing cohorts, each cohort has treatment in clinical units up to Eight healthy male or female individuals with a duration of 14 days (6 active agents/2 placebos). The next dose increase in the cohort depends on the acceptable safety, tolerability, and PK data and follows well-defined stopping rules, including the sum of ESP15228 and its metabolite ESP15228, the average AUC _0-24 The predetermined exposure limit is 400 μg·h/mL.

For the study, edema dodecanoic acid 20 mg capsule or placebo capsule was used. Multiple oral doses of 140 mg/day, 180 mg/day, 220 mg/day, and 260 mg/day are administered to individuals under fasting conditions, and the sum of ESP15228 and its metabolite is not The predetermined exposure limit of the average AUC _0-24 exceeding 400 μg·h/mL. result

^a 假設線性動力學，自180 mg劑量數據預測。^b 中值。Table 20 shows the average steady-state PK parameters of the immediate release formulations of Lepidotropin. Table 20- Average steady-state PK parameters of immediate release formulation ^a of dermatophyllic acid from IR Study 3

^a Assuming linear kinetics, predicted from 180 mg dose data. ^b Median.

實例11：在超重/肥胖但其他方面健康個體中之邊皮多益酸之持續釋放調配物之單次及重複劑量研究(SR研究)Table 21 shows the percent change in the least squared mean of LDL-C from baseline after a single dose of immediate release formulation of dermatophyllic acid from IR Study 3. Table 21- Percent change in LS mean of LDL-C from baseline after a single dose of immediate release formulation from IR Study 3

Example 11: Single- and repeated-dose studies of sustained-release formulations of pleurotropin in healthy individuals who are overweight/obese but otherwise healthy (SR study)

This example illustrates a single and repeated-dose study of sustained release formulations of pleurotropin in individuals who are overweight/obese but otherwise healthy. Figure 9 summarizes the design of this study.

The formulations of the sustained release lozenge of Lepidotropin used in this study can be seen in Tables 13 and 17.

The key objective of this study is to evaluate the pharmacokinetics, safety, tolerability, and pharmacodynamic endpoints (eg, LDL-C) of sustained release dominoic acid therapy in individuals who are overweight/obese but otherwise healthy.

Phase 1 evaluates single dose PK, safety and tolerability. Stage 1 is randomized, but not blinded or placebo-controlled. Screen up to 21 days before randomization. Individuals were admitted to the Clinical Research Unit (CRU) on the evening of Day -1 until the morning of Day 2. On the morning of Day 1, individuals were randomized to receive a single dose of 50 mg (n = 6), 100 mg (n = 6), or 200 mg (n = 6) of leukotopic acid sustained release formulation. Sustained release formulations of Lepidotropin are summarized in Tables 13 and 17. These treatments are administered concurrently (non-sequentially). Continuous testing of PK was conducted on the first day. On the morning of the second day, collect other blood samples, provide meals, and if appropriate, allow the individual to leave the CRU. On Day 3, Day 5, Day 7, Day 9, and Day 11, the individual returned to the CRU for a morning outpatient visit to collect other blood samples. Prior to the start of Phase 2, the preliminary PK, safety and tolerability data from Phase 1 were evaluated.

Phase 2 evaluates repeated dose PK, safety, and tolerability during the 14-day treatment period. Lipid regrowth was evaluated on days -7 and 1 and PD biomarkers were evaluated on day 13. Stage 2 is randomized, placebo-controlled, and double-blind. Screen up to 28 days before randomization. Individuals stay in the CRU at 3 different times. The first opportunity is on the afternoon of day -8, after which the lipid regrowth is tested on day -7 and leaves CRU. The second opportunity is for the individual to be admitted to the CRU on the afternoon of Day -1, and then on the first day, the first dose of Dodecanoic Acid SR, test lipid regrowth, and to leave the CRU. Randomize qualified individuals on Day 1 and receive 50 mg (n = 10), 100 mg (n = 10), or 200 mg (n = 10) sustained release formulations or placebo (n = 10) Up to 14 days. Sustained release formulations of Lepidotropin are summarized in Tables 13 and 17. These treatments are administered concurrently (non-sequentially). The third time for individuals to stay in the CRU is from the evening of the 13th day to the morning of the 15th day for continuous PK sampling. From Day 3 to Day 13, the individual reports to the CRU in the morning for dosing and, if necessary, PK sample collection. On the morning of the 17th and 22nd days, the individual returned to the clinic for PK sampling and safety monitoring. Lipid regrowth was evaluated during phase 2 at baseline (day -7) and in the case of a single dose of study drug (day 1). Before each lipid nascent evaluation, a stable isotope tracer ( ² H ₂ O) was provided in advance for 2 days, in which 3 small doses of ² H ₂ O were taken daily. Started in the morning of the lipid neonatal evaluation for 10 hours, oral fatty acid synthesis was stimulated every 30 minutes to stimulate liver fatty acid synthesis and blood samples were collected every hour to evaluate the incorporation of markers into circulating very low density lipoprotein (VLDL) triglycerides.

During both phases 1 and 2, the individual receives the study drug and up to 8 ounces of water after a minimum of 10 hours of fasting. On the day when continuous PK blood samples were collected (Phase 1 = Day 1; Phase 2 = Day 14), an additional fast of 4 hours after dosing and a standardized diet at 4 and 10 hours after dosing. The PK parameters were evaluated from continuous blood samples by measuring the concentration of tannin acid and metabolite ESP15228. result

^a 邊皮多益酸之持續釋放調配物闡述於表13及17中。Table 22 shows the measured PK parameters of the patient after the administration of a single dose of sustained release lozenge of dominoic acid. Table 22- PK parameters measured after sustained release formulation in single dose SR study

^a Sustained-release formulations of Lepidotropin are described in Tables 13 and 17.

^a 中值Table 23 shows the average steady-state PK parameters for the sustained-release lozenge of leukoplakia. Table 23- Average steady-state PK parameters of sustained release formulations of flavonol multi-acid tablets (SR study )

^a median

Table 24 describes the percent change in LDL-C content from baseline in patients treated with the sustained release formulation of dombynoic acid during Phase 2 of this study. Table 24 - Patients after treatment of the sustained release beneficial side Pinedo acid formulation of LDL-C in the percentage change from baseline during phase 2 SR Research

^a 統計學係基於協方差分析(ANCOVA)模型利用針對治療之固定項及基線LDL-C含量來估計。ANCOVA分析(LS平均值及p值)係在事後實施，而不用進行重複量測。基線定義為在第一劑量之研究藥物之前所收集的最後值。 Table 25 shows the average percent change in the least squares (LS) of the patient's LDL-C from baseline after administration of the sustained release formulation lozenge of dominoic acid on the 14th day during Phase 2. Table 25- Percent change in LS mean value of LDL-C from baseline after ^a single dose of sustained release formulation of dermatophyllic acid from SR Study ^a

^a Statistics are estimated based on the analysis of covariance (ANCOVA) model using fixed terms for treatment and baseline LDL-C content. ANCOVA analysis (LS mean and p-value) is carried out afterwards, without repeated measurement. The baseline is defined as the last value collected before the first dose of study drug.

In addition to the results in Table 31, Figure 5 further shows the change in LDL-C between patients receiving placebo and patients receiving sustained-release formulations of 100 mg lozenge dodecate tablets, of which In patients with sustained-release tablets, the estimated change in LDL-C content from baseline was -24.7%. Example 12: Comparison of PK parameters and PD endpoints from IR studies 1, 2 and 3 with their PK parameters and PD endpoints from SR studies

This example compares various PK parameters and PD endpoints from IR Study 1 (Example 8), IR Study 2 (Example 9) and IR Study 3 (Example 10) with their PK parameters and PD endpoints from SR Study (Example 11) .

^a 參數分別劑量校正至50 mg、100 mg或200 mg劑量。^b 邊皮多益酸之持續釋放調配物闡述於表13及17中。Table 26 shows the comparison between the dose-corrected PK parameters of IR Study 1 and the dose-corrected PK parameters obtained from the SR study at doses of 50 mg, 100 mg, and 200 mg, respectively. Table 26- PK comparison between IR Study 1 and SR Study

^{The a} parameters were dose corrected to 50 mg, 100 mg or 200 mg doses respectively. ^b Sustained-release formulations of Lepidotropin are described in Tables 13 and 17.

^a 中值^b 邊皮多益酸之持續釋放調配物闡述於表13及17中。^c 假設線性動力學，自180 mg劑量數據預測Table 27 shows the comparison of the average steady-state PK parameters of IR Study 3 and their average steady-state PK parameters obtained from the SR study. Table 27- Comparison of average steady-state PK parameters for IR study 3 and SR study

The sustained release formulations of ^a median ^b leukotropin are described in Tables 13 and 17. ^c Assuming linear kinetics, predicted from 180 mg dose data

As can be clearly seen from Tables 26 and 27, the SR formulation provides delayed delivery of dermatine tonic acid compared to the IR formulation. This is because compared with other patients receiving the IR formulation, at similar times and Lesser amounts of leukoderma were detected in patients who received SR formulations in doses.

^a 統計學係基於協方差分析(ANCOVA)模型利用針對治療之固定項及基線LDL-C含量來估計。ANCOVA分析(LS平均值及p值)係在事後實施，而不用進行重複量測。基線定義為在第一劑量之研究藥物之前所收集的最後值。Table 28 shows a comparison of the least squared mean percentage change in LDL-C content in patients from IR Study 1, IR Study 2, and SR Study. Table 28- Comparison of the average percentage change in LDL-C content in patients from IR Study 2 , IR Study 3, and SR Study .

^a Statistics are estimated based on the analysis of covariance (ANCOVA) model using fixed terms for treatment and baseline LDL-C content. ANCOVA analysis (LS mean and p-value) is carried out afterwards, without repeated measurement. The baseline is defined as the last value collected before the first dose of study drug.

As shown in Table 28, treatment with SR formulations of leukodermoic acid in obese/overweight but otherwise healthy patients provided sustained and dose-related LDL-C reductions of up to 27% from baseline. In addition, treatment with the SR formulation of dominoic acid provides cross-dose reductions in LDL-C, which is consistent with the treatment of IR formulations from similar studies (ie, IR studies 1, 2 and 3). Example 13 : Preparation of a sustained release formulation of Lepidotropin

The following is a description of the process used to prepare the sustained-release formulations of Lepitolide. The process consists of four general steps: granulation, extrusion, spheronization and drying. During the granulation step, the raw materials Bettoic acid, microcrystalline cellulose, sodium carboxymethyl cellulose and sodium lauryl are dispensed. Separately, add HPMC 606 or hydroxypropyl methyl cellulose to the treated water and mix until the solution is homogeneous. Next, the GMX high-shear granulator is equipped with a four-liter basin equipped with an impeller and shredder. The remaining raw materials were added to the bowl, and the resulting composition was mixed at 560 RPM using only an impeller. After 2 minutes, the composition inside the GMX bowl was mixed at 1800 rpm with the addition of a chopper, while maintaining the impeller at 560 RPM. At the same time, the HMPC 606 solution was added to the GMX bowl via the pump at a rate of 30 g/min, and after the addition of the HPMC 606 solution was completed, the resulting composition was mixed for another minute. The granulator is then temporarily stopped to ensure that all the composition inside the GMX bowl is scraped to the center of the bowl. Then mix for another minute. Then the granulation process is stopped and the granulated composition is collected.

Next, the DG-L1 extruder was assembled with a 0.8 mm plate and 5 shims for the extrusion step. The granulated composition containing ETC-1002 was then extruded at a speed of 60 RPM, and the accurate speed, time and amperage during this process were recorded. Next, the QJ-230 rounder with a 2 mm plate was assembled for the rounding step. The ETC-1002 extrudate from the extrusion step was then rounded at 1350 RPM. The resulting spheres were collected from a spheronizer onto a drying tray, and then placed in an oven preheated to 40°C. The wet sphere containing ETC-1002 is then dried until its moisture content is less than 2% as measured by loss on drying (LOD). The tray containing the ETC-1002 spheres was removed from the oven, and the individual ETC-1002 spheres were placed in polyethylene bags.

Although the present invention has been specifically shown and described with reference to the preferred embodiments and various alternative embodiments, those skilled in the relevant art will understand that various changes can be made to the forms and details therein without departing from the spirit and scope of the invention .

For all purposes, all references, granted patents and patent applications cited in the body of this specification are incorporated herein by reference in their entirety.

In view of the following description and drawings, these and other features, aspects, and advantages of the present invention will be better understood, among which:

Figure 1A shows that after 1. single bolus injection of cisplatin (circle) and 2. multiple separate bolus injections of cisplatin (square), male Han Wistar rat liver midrib A graph of the serum concentration of Tonic Acid (ETC-1002).

Figure 1B shows the liver acetonitrile in male Han Wistar rats after 1. single bolus injection of dombyopic acid (circle) and 2. multiple separate bolus injections of dombyotropic acid (square) Graph of the concentration of base-CoA.

Figure 1C shows the active substances in the liver of male Han Wistar rats after (1) a single bolus injection of dominoic acid (circle) and (2) multiple separate administrations of dominoic acid (square) A graph of the concentration of ETC-1002-CoA.

Figure 2A is a graph showing the concentration of dermatophyllic acid released from various dermatological dodecanoic acid formulations versus time when tested in the USP dissolution analysis.

Figure 2B is a graph showing the concentration of leukoderma multi-acid released from leucoderma multi-acid formulations CU07-101 and CU07-118 when tested in the USP dissolution analysis versus time.

Fig. 3 is a graph showing the average plasma concentration of leukolide in human subjects after the immediate release lozenge containing 180 mg of leukolide.

Figure 4 shows the average plasma concentration of pipidolic acid in obese but otherwise healthy individuals after administration of a single dose of sustained-release lozenges containing 50 mg, 100 mg, and 200 mg pipidolic acid. chart.

Figure 5 is a graph showing the percentage change in LDL-C content from the baseline 14 days after administration of a sustained-release tablet containing 100 mg of leukolide.

Figure 6 summarizes the study design of the immediate release (IR) study 1.

Figure 7 summarizes the study design of the immediate release (IR) study 2.

Figure 8 summarizes the study design of the immediate release (IR) study 3.

Figure 9 summarizes the study design of the sustained release (SR) study.

Claims (47)

A pharmaceutical formulation comprising the following components: (i) 50%-70% bempedoic acid, (ii) filler, (iii) diluent or solubilizer, and (iv) adhesive , Wherein the formulation is formulated for the sustained release of domino acid. The pharmaceutical formulation of claim 1, wherein the filler is selected from the group consisting of microcrystalline cellulose, sodium carboxymethyl cellulose, and a combination of microcrystalline cellulose and sodium carboxymethyl cellulose. The pharmaceutical formulation of claim 1, wherein the diluent or solubilizer is selected from the group consisting of sodium lauryl sulfate and sodium starch glycolate. The pharmaceutical formulation of claim 1, wherein the binder is hydroxypropyl methylcellulose (HMPC). The pharmaceutical formulation according to any one of claims 1 to 4, wherein the formulation is formulated as a solid. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the formulation is formulated for oral administration. The pharmaceutical formulation according to any one of claims 1 to 6, wherein the formulation comprises: Dodecanoic acid dispersed in the polymer matrix, and Wherein the formulation exhibits a drug release curve corresponding to the following pattern: After 2 hours, it releases more than 30% of the total mass of the scalp dodecanoic acid; After 4 hours, it releases more than 75% of the total mass of pleurotropin; and After 8 hours, it releases more than 90% of the total mass of the scalp dodecanoic acid. The pharmaceutical formulation according to any one of claims 1 to 7, wherein a US Pharmacopoeia Apparatus 2 (United States Pharmacopoeia Apparatus 2) (paddle 50 rpm) is measured in a 50 mM phosphate buffer at 20°C Dissolve. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the formulation provides a therapeutically effective concentration of leukolide in a 24-hour period when administered to a human subject. The pharmaceutical formulation according to any one of claims 1 to 9, wherein the formulation is a gelatin capsule. The pharmaceutical formulation according to claim 10, wherein the gelatin capsule further contains a powder excipient. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the formulation is a lozenge. The pharmaceutical formulation according to any one of claims 1 to 12, wherein the filler component is microcrystalline cellulose and is 5%-50% w/w. The pharmaceutical formulation according to any one of claims 1 to 13, wherein the filler component is sodium carboxymethyl cellulose and is 5%-50% w/w. The pharmaceutical formulation according to any one of claims 1 to 14, wherein the diluent or solubilizer component is sodium lauryl sulfate and is about 1%-5% w/w. The pharmaceutical formulation according to any one of claims 1 to 15, wherein the binder component is HPMC and is about 0.1%-1.5% w/w. The pharmaceutical formulation according to any one of claims 1 to 16, wherein the formulation comprises: 50%-70% w/w of flavonoids, 30%-45% w/w filler component, 1%-5% w/w thinner or solubilizer component and 0.1%-1.5% w/w adhesive component. The pharmaceutical formulation according to any one of claims 1 to 17, wherein the formulation comprises: 55%-65% w/w of flavonoid dodecanoic acid, 30%-45% w/w of filler component, 1%-5% w/w thinner or solubilizer component and 0.1%-1.5% w/w adhesive component. The pharmaceutical formulation according to any one of claims 1 to 18, wherein the formulation comprises 60% w/w of flavonoid polyacid, 30%-45% w/w filler component, 1%-5 % w/w diluent or solubilizer component and 0.1%-1.5% w/w adhesive component. The pharmaceutical formulation according to any one of claims 1 to 19, wherein the formulation comprises 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg or 220 mg bilobalide. The pharmaceutical formulation of any one of claims 1 to 20, wherein the dissolution of the formulation has a zero order release rate for at least 12 hours. The pharmaceutical formulation as claimed in claim 21, which contains leukoderma acid and a polymer matrix, wherein the formulation has a hardness of 2-30 kg and the formulation is shaped into a sphere or has a thickness pair effective to allow erosion and penetration control The diameter ratio, the erosion and penetration control are sufficient to control the surface erosion during the dissolution test. The pharmaceutical formulation according to any one of claims 1 to 22, wherein the formulation provides a therapeutically effective concentration of leukolide in a 24-hour period when administered to a human subject. The pharmaceutical formulation according to any one of claims 1 to 23, wherein the formulation provides a maximum plasma concentration ( _Cmax ) of dombynoic acid of not more than 60 µg/mL when administered to a human individual. The request to any of items 1 to 24 of a pharmaceutical formulation, wherein the formulation provides a maximum plasma concentration within the edge / mL range of 45 μg / mL to 57 μg acid Pinedo benefits of the human subject after administration (C _maximum ) For 24 hours. A method for administering dombyotonic acid, comprising: administering an effective amount of a pharmaceutical formulation to a human individual in need thereof, wherein the formulation includes dombyotonic acid and a polymer matrix, and wherein the administration is such that The maximum plasma concentration ( _Cmax ) of dominoic acid does not exceed about 60 µg/mL, and the plasma concentration in the range of about 45-57 µg/mL after administration for 24 hours. A method for treating an individual's cardiovascular disease or reducing the risk of cardiovascular disease, the method includes: An effective amount of a pharmaceutical formulation is administered to a human individual in need thereof, wherein the formulation includes components of pleiotrophin and a polymer, and wherein the dissolution of the formulation exhibits a drug release curve corresponding to the following pattern: After 2 hours, release no more than 30% of the flaky dodecanoic acid; After 4 hours, do not release more than 75% of the flaky dodecanoic acid; After 8 hours, release no more than 90% of the flaky dodecanoic acid; and Wherein the formulation when administered to the individual provides a therapeutically effective concentration of pleurotropin within a 24-hour period to treat cardiovascular disease or reduce the risk of cardiovascular disease. The method according to claim 26 or 27, wherein the formulation does not release more than 95% of the flavonoid acid after 8 hours. The method of any one of claims 26 to 28, wherein the polymer is hydroxypropyl methyl cellulose (HPMC). The method according to any one of claims 26 to 29, wherein the tannin is about 30-80% by weight, and the polymer is hydroxypropyl methylcellulose (HPMC) and is 15-35% by weight . The method according to any one of claims 26 to 30, wherein when administered to a human subject suffering from hypercholesterolemia, mixed dyslipidemia, type II diabetes, obesity, chronic liver disease or kidney disease, the method reduces the total Cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). The method of any one of claims 26 to 31, wherein the method reduces the content of very low density lipoprotein (VLDL) in the individual to be lower than the content of a control individual receiving a placebo. The method of any one of claims 26 to 32, wherein the method reduces the size of VLDL particles in the individual to be lower than the size of a control individual receiving a placebo. The method of any one of claims 26 to 33, wherein the method reduces the ratio of lipoprotein element B (ApoB) to lipoprotein element A-1 (ApoA1) in the individual to be lower than a control individual receiving a placebo Ratio. The method of any one of claims 26 to 34, wherein the individual has hypercholesterolemia. The method of any one of claims 26 to 35, wherein the method reduces the content of low density lipoprotein cholesterol (LDL-C) in the individual. The method of any one of claims 26 to 36, wherein the method reduces the LDL-C content by at least 5%, 10%, 15%, or 20% relative to the original untreated or placebo-treated individual . The method of any one of claims 26 to 36, wherein the method reduces the LDL-C content by at least 5%, 10%, 15%, or 30% relative to the original untreated or placebo-treated individual . The method of any one of claims 26 to 36, wherein the method reduces the LDL-C content by 5%-40% relative to the original untreated or placebo-treated individual. The method of any one of claims 26 to 39, wherein the method is at least as effective as an equivalent dose of immediate-release dombyid acid formulation to reduce LDL-C content in an individual. The method of claim 40, wherein the method is at least as effective as a higher dose of immediate-release dombyid acid formulation to reduce LDL-C content in an individual, wherein the higher dose is 180 mg/day. A method of inhibiting ATP-citrate lyase (ACL) in an individual, the method comprising administering to the individual the pharmaceutical dosage form of any one of claims 1 to 25. A method for treating an individual's metabolic syndrome, the method comprising administering an effective amount of a pharmaceutical dosage form as in any one of claims 1 to 25. The method of claim 43, wherein the individual is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes, or any combination thereof. The method of claim 43, wherein the individual has hypercholesterolemia. The method of any one of claims 43 to 45, wherein the metabolic syndrome is non-alcoholic fatty liver disease (NAFLD). The method of any one of claims 43 to 45, wherein the metabolic syndrome is non-alcoholic steatohepatitis (NASH).

Images