CN109010342A - Pharmaceutical composition and method for acute-on-chronic liver failure and related liver disease - Google Patents
Pharmaceutical composition and method for acute-on-chronic liver failure and related liver disease Download PDFInfo
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- CN109010342A CN109010342A CN201810878423.1A CN201810878423A CN109010342A CN 109010342 A CN109010342 A CN 109010342A CN 201810878423 A CN201810878423 A CN 201810878423A CN 109010342 A CN109010342 A CN 109010342A
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- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940111263 potassium magnesium aspartate Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 description 1
- 229950000628 silibinin Drugs 0.000 description 1
- SEBFKMXJBCUCAI-DBMPWETRSA-N silybin Chemical compound C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-DBMPWETRSA-N 0.000 description 1
- 235000014899 silybin Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000007079 thiolysis reaction Methods 0.000 description 1
- 229960004402 tiopronin Drugs 0.000 description 1
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of for treating the composition and purposes of acute-on-chronic liver failure or related disease.The method includes the compositions according to dosage regimen to subject's application comprising Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt.
Description
Cross reference to related applications
It is entitled " for acute-on-chronic liver failure and the medicine of related liver disease this application claims what is submitted on June 14th, 2018
The full content of the equity of the U.S. Provisional Application No. 62/685,041 of compositions and method ", introduction is incorporated by reference into
Wen Zhong.
Technical field
The present invention relates generally to a kind of pharmaceutical compositions for acute-on-chronic liver failure and related liver disease.
Background of invention
Acute-on-chronic liver failure is a kind of common medical conditions, is treated at present using liver protecting drug.Liver is protected
Shield drug refers to the drug categories for liver function protecting, it is characterised in that it is able to maintain that liver function, reduces hepatocellular injury,
Promote the reparation and regeneration of wounded hepatocytes, and the function of detoxification of enhancing liver.Currently, lacking to the extensive of hepatic
Evidence-based medicine EBM and effect target research.Known current hepatic mainly includes removing toxic substances class (reduced glutathione, Tiopronin
Deng), liver cell regeneration promote class (hepatic cell growth promotive factor, Polyene Phosphatidylcholine), energetic supersession to promote class (water-soluble
Vitamin, coenzyme, Potassium Magnesium Aspartate, aspartic acid ornithine), cholagogue class (Ademetionine, methionine and vitamin B1,
Anethol Trithione) and anti-inflammatory Chinese traditional (silibinin (silibin), compound glycyrrbizic acid glycosides formulation).Any hepatocyte protection drug
Effect is all opposite, and most drugs (including most of hepatocyte protection drugs), all by liver metabolism, this is also one
Determine removing toxic substances and metabolic burden that liver is increased in degree.
In the presence of a variety of existing hepatics, but all there is single or unidentified action site and relatively limited
" liver protection " effect.Since most drugs (being not excluded for most of hepatics) are all by liver metabolism, liver is increased
Burden, this is significant in the patient with hepatic failure.It is most of to suffer from chronic liver disease and some trouble with acute liver disease
Person dies of terminal phase hepatic failure.For example, by virus, drug, alcohol, nonalcoholic fatty liver or autoimmunity or heredity and metabolism
All hepatopathys caused by property hepatopathy all can lead to hepatic failure.In recent years, hepatic failure mainly utilizes complex treatment, by preventing and controlling
Various clinical complications are treated, hepatocellular injury is delayed and wait liver cell regeneration to treat, but there is no effective drug to treat
Hepatic failure caused by various hepatopathys.
Yu describes Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyl] piperazine in PCT/CN2016/080219
Dihydrochloride) (TMZ) for acute hepatic failure, this is rare.However, Yu fails teaching or openly using TMZ for adding slowly
Acute hepatic failure or related disease.
Therefore, the purpose of the present invention is to provide the compositions and method for acute-on-chronic liver failure and related disease.
Implementation described below scheme solves the demand and purpose.
Summary of the invention
In one aspect of the invention, a kind of acute-on-chronic liver failure treated and have the subject of this demand is provided
(ACLF) or the purposes of related disease comprising according to dosage regimen, to subject's application comprising a effective amount of hydrochloric acid Sibutramine Hydrochloride he
The group of piperazine (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt
Close object.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or a effective amount of TMZ is administered to subject, the dosage regimen includes 4-12 hours every according to dosage regimen by all combinations
20-500mg is administered.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, dosage regimen include every 4-12 hours administration 20-500mg, continue 1 day course for the treatment of to 2 weeks.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, dosage regimen include every 4-12 hours administration 20-500mg, continue 1 day to the 1 month course for the treatment of.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, application include being administered orally.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, application include parenteral injection.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, application include that IV is applied.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, composition also include pharmaceutically acceptable carrier.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, pharmaceutical composition can produce one kind described in this section ([00016]) to each section of following [00017]-[00020]
Or multiple efficacies, such as reduce subject resting T lymphocytes be activated the lymphocyte for activation.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, pharmaceutical composition reduce the fatty acid metabolism in the liver cell of subject and promote the aerobic oxidation of glucose.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, pharmaceutical composition reduce the beta oxidation in the liver cell of subject and reduce the formation of ROS.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the blood alanine aminotransferase (ALT) that pharmaceutical composition reduces subject are horizontal.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the blood aspartate transaminase (AST) that pharmaceutical composition reduces subject are horizontal.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease do not include angina pectoris, coronary insufficiency, remote myocardial infarction, coronary heart disease, dizziness or
Tinnitus.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease are selected from by hepatopathy (without the hepatic injury of main inflammatory), hepatitis (with inflammation) and cirrhosis
The group of (structural damage may with or may be not accompanied by hepatic failure) composition.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease are selected from the group that is made up of: virus hepatitis, non-specific toxicity hepatitis, drug or
Medicine induction hepatic injury or damage, the hepatitis such as herbal medicine of toxin-induced or mushroom induction hepatitis or hepatopathy, alcoholic hepatitis,
Oneself immunity hepatitis, alcohol fatty liver or non-alcohol fatty liver (NAFLD), nonalcoholic fatty liver disease
(NASH), metabolism or genetic correlation hepatopathy (hemochromatosis, Wilson's disease), ischemic hepatic injury (shock liver), sepsis
The hepatic failure and congested hepatopathy (hepatic failure caused by heart failure) of disease (bacterium or other microorganism infections) induction.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, subject are human or animals.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, composition include second medicament.
In another aspect of the present invention, it provides a kind of comprising Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyls
Base] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt and carrier preparation, the preparation provides
The release characteristic of TMZ or its pharmaceutically acceptable salt, this feature include rapidly releasing for TMZ or its pharmaceutically acceptable salt
It puts, followed by the sustained release of TMZ or its pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations rapidly release 30mg to 180mg after applying TMZ or its pharmaceutically acceptable salt to patient
TMZ or its pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, sustained release within one day to one month a period of time every 4 to 6 hours release 10mg to 30mg TMZ or its
Pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, the sustained release of TMZ or its pharmaceutically acceptable salt are by by TMZ or its pharmaceutically acceptable salt packet
It is embedded in biocompatible polymeric material, mixes TMZ or its pharmaceutically acceptable salt and biocompatible polymeric material
It closes, or is provided with polymer material encapsulating or microencapsulation TMZ or its pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, preparation are oral preparation or ejection preparation.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, preparation include any composition disclosed herein.The composition can be such as aforementioned paragraphs [0009]-
[00025] composition described in any one in.
In some other embodiments of invention formulation, optionally in various embodiments as described herein appoint
A kind of or all combinations, preparation can be made into specifically excluding the composition of any embodiment disclosed herein.Described group
Closing object can be composition described in any one in such as aforementioned paragraphs [0009]-[00025].
In another aspect of the present invention, a kind of method for preparing preparation is provided, the method includes providing hydrochloric acid
Trimetazidine (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its is pharmaceutically acceptable
Salt；Carrier is provided；And preparation is formed, wherein the preparation provides TMZ or the release characteristic of its pharmaceutically acceptable salt,
This feature includes TMZ or the rapidly release of its pharmaceutically acceptable salt, followed by TMZ or its pharmaceutically acceptable salt are held
Continuous release.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations rapidly release 30mg to 180mg after applying TMZ or its pharmaceutically acceptable salt to patient
TMZ or its pharmaceutically acceptable salt.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, sustained release within one day to one month a period of time every 4 to 6 hours release 10mg to 30mg TMZ or its
Pharmaceutically acceptable salt.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the sustained release of TMZ or its pharmaceutically acceptable salt are by by TMZ or its pharmaceutically acceptable salt packet
It is embedded in biocompatible polymeric material, mixes TMZ or its pharmaceutically acceptable salt and biocompatible polymeric material
It closes, or is provided with polymer material encapsulating or microencapsulation TMZ or its pharmaceutically acceptable salt.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are oral preparations.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are ejection preparations.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation include any composition disclosed herein.The composition can be such as aforementioned paragraphs [0009]-
[00025] composition described in any one in.
In some other embodiments of the method for the present invention, optionally in various embodiments as described herein appoint
A kind of or all combinations, preparation can be made into specifically excluding the composition of any embodiment disclosed herein.Described group
Closing object can be composition described in any one in such as aforementioned paragraphs [0009]-[00025].
In another aspect of the present invention, it provides a kind of for treating the purposes of hepatopathy or related disease, the use
Way includes that preparation disclosed herein is applied to the patient for having this demand, and the preparation includes Trimetazidine Hydrochloride (1- [2,3,4-
Trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt and carrier, the preparation
TMZ or the release characteristic of its pharmaceutically acceptable salt are provided, this feature includes TMZ or the urgency of its pharmaceutically acceptable salt
Quick-release is put, followed by the sustained release of TMZ or its pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations rapidly release 30mg to 180mg after applying TMZ or its pharmaceutically acceptable salt to patient
TMZ or its pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, sustained release within one day to one month a period of time every 4 to 6 hours release 10mg to 30mg TMZ or its
Pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the sustained release of TMZ or its pharmaceutically acceptable salt are by by TMZ or its pharmaceutically acceptable salt packet
It is embedded in biocompatible polymeric material, mixes TMZ or its pharmaceutically acceptable salt and biocompatible polymeric material
It closes, or is provided with polymer material encapsulating or microencapsulation TMZ or its pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are oral preparations.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are ejection preparations.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, hepatopathy are acute-on-chronic liver failures.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease are selected from the group that is made up of: virus hepatitis, non-specific toxicity hepatitis, drug or
Medicine induction hepatic injury or damage, the hepatitis such as herbal medicine of toxin-induced or mushroom induction hepatitis or hepatopathy, alcoholic hepatitis,
Oneself immunity hepatitis, alcohol fatty liver or non-alcohol fatty liver (NAFLD), nonalcoholic fatty liver disease
(NASH), metabolism or genetic correlation hepatopathy (hemochromatosis, Wilson's disease), ischemic hepatic injury (shock liver), sepsis
The hepatic failure and congested hepatopathy (hepatic failure caused by heart failure) of disease (bacterium or other microorganism infections) induction.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation include any composition disclosed herein.The composition can be such as aforementioned paragraphs [0009]-
[00025] composition described in any one in.
In some other embodiments of purposes of the present invention, optionally in various embodiments as described herein appoint
A kind of or all combinations, preparation can be made into specifically excluding the composition of any embodiment disclosed herein.Described group
Closing object can be composition described in any one in such as aforementioned paragraphs [0009]-[00025].
Specific embodiment
In one aspect of the invention, a kind of acute-on-chronic liver failure treated and have the subject of this demand is provided
(ACLF) or the purposes of related disease comprising according to dosage regimen, to subject's application comprising a effective amount of hydrochloric acid Sibutramine Hydrochloride he
The group of piperazine (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt
Close object.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or a effective amount of TMZ is administered to subject, the dosage regimen includes 4-12 hours every according to dosage regimen by all combinations
20-500mg is administered.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, dosage regimen include every 4-12 hours administration 20-500mg, continue 1 day course for the treatment of to 2 weeks.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, dosage regimen include every 4-12 hours administration 20-500mg, continue 1 day to the 1 month course for the treatment of.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, application include being administered orally.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, application include parenteral injection.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, application include that IV is applied.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, composition also include pharmaceutically acceptable carrier.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the resting T lymphocytes that pharmaceutical composition reduces subject are activated the lymphocyte for activation.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, pharmaceutical composition reduce the fatty acid metabolism in the liver cell of subject and promote the aerobic oxidation of glucose.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, pharmaceutical composition reduce the beta oxidation in the liver cell of subject and reduce the formation of ROS.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the blood alanine aminotransferase (ALT) that pharmaceutical composition reduces subject are horizontal.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the blood aspartate transaminase (AST) that pharmaceutical composition reduces subject are horizontal.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease do not include angina pectoris, coronary insufficiency, remote myocardial infarction, coronary heart disease, dizziness or
Tinnitus.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease are selected from by hepatopathy (without the hepatic injury of main inflammatory), hepatitis (with inflammation) and cirrhosis
The group of (structural damage may with or may be not accompanied by hepatic failure) composition.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease are selected from the group that is made up of: virus hepatitis, non-specific toxicity hepatitis, drug or
Medicine induction hepatic injury or damage, the hepatitis such as herbal medicine of toxin-induced or mushroom induction hepatitis or hepatopathy, alcoholic hepatitis,
Oneself immunity hepatitis, alcohol fatty liver or non-alcohol fatty liver (NAFLD), nonalcoholic fatty liver disease
(NASH), metabolism or genetic correlation hepatopathy (hemochromatosis, Wilson's disease), ischemic hepatic injury (shock liver), sepsis
The hepatic failure and congested hepatopathy (hepatic failure caused by heart failure) of disease (bacterium or other microorganism infections) induction.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, subject are human or animals.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, composition include second medicament.
In another aspect of the present invention, it provides a kind of comprising Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyls
Base] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt and carrier preparation, the preparation provides
The release characteristic of TMZ or its pharmaceutically acceptable salt, this feature include rapidly releasing for TMZ or its pharmaceutically acceptable salt
It puts, followed by the sustained release of TMZ or its pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations rapidly release 30mg to 180mg after applying TMZ or its pharmaceutically acceptable salt to patient
TMZ or its pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, sustained release within one day to one month a period of time every 4 to 6 hours release 10mg to 30mg TMZ or its
Pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, the sustained release of TMZ or its pharmaceutically acceptable salt are by by TMZ or its pharmaceutically acceptable salt packet
It is embedded in biocompatible polymeric material, mixes TMZ or its pharmaceutically acceptable salt and biocompatible polymeric material
It closes, or is provided with polymer material encapsulating or microencapsulation TMZ or its pharmaceutically acceptable salt.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, preparation are oral preparation or ejection preparation.
In some embodiments of invention formulation, optionally any one of with various embodiments as described herein
Or all combinations, preparation include any composition disclosed herein.The composition can be such as aforementioned paragraphs
[00052] composition described in any one in-[00068].
In some other embodiments of invention formulation, optionally in various embodiments as described herein appoint
A kind of or all combinations, preparation can be made into specifically excluding the composition of any embodiment disclosed herein.Described group
Closing object can be composition described in any one in such as aforementioned paragraphs [00052]-[00068].
In another aspect of the present invention, a kind of method for preparing preparation is provided, the method includes providing hydrochloric acid
Trimetazidine (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its is pharmaceutically acceptable
Salt；Carrier is provided；And preparation is formed, wherein the preparation provides TMZ or the release characteristic of its pharmaceutically acceptable salt,
This feature includes TMZ or the rapidly release of its pharmaceutically acceptable salt, followed by TMZ or its pharmaceutically acceptable salt are held
Continuous release.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations rapidly release 30mg to 180mg after applying TMZ or its pharmaceutically acceptable salt to patient
TMZ or its pharmaceutically acceptable salt.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, sustained release within one day to one month a period of time every 4 to 6 hours release 10mg to 30mg TMZ or its
Pharmaceutically acceptable salt.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the sustained release of TMZ or its pharmaceutically acceptable salt are by by TMZ or its pharmaceutically acceptable salt packet
It is embedded in biocompatible polymeric material, mixes TMZ or its pharmaceutically acceptable salt and biocompatible polymeric material
It closes, or is provided with polymer material encapsulating or microencapsulation TMZ or its pharmaceutically acceptable salt.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are oral preparations.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are ejection preparations.
In some embodiments of the method for the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation include any composition disclosed herein.The composition can be such as aforementioned paragraphs
[00052] composition described in any one in-[00068].
In some other embodiments of the method for the present invention, optionally in various embodiments as described herein appoint
A kind of or all combinations, preparation can be made into specifically excluding the composition of any embodiment disclosed herein.Described group
Closing object can be composition described in any one in such as aforementioned paragraphs [00052]-[00068].
In another aspect of the present invention, it provides a kind of for treating the purposes of hepatopathy or related disease, the use
Way includes that preparation disclosed herein is applied to the patient for having this demand, and the preparation includes Trimetazidine Hydrochloride (1- [2,3,4-
Trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt and carrier, the preparation
TMZ or the release characteristic of its pharmaceutically acceptable salt are provided, this feature includes TMZ or the urgency of its pharmaceutically acceptable salt
Quick-release is put, followed by the sustained release of TMZ or its pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations rapidly release 30mg to 180mg after applying TMZ or its pharmaceutically acceptable salt to patient
TMZ or its pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, sustained release within one day to one month a period of time every 4 to 6 hours release 10mg to 30mg TMZ or its
Pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, the sustained release of TMZ or its pharmaceutically acceptable salt are by by TMZ or its pharmaceutically acceptable salt packet
It is embedded in biocompatible polymeric material, mixes TMZ or its pharmaceutically acceptable salt and biocompatible polymeric material
It closes, or is provided with polymer material encapsulating or microencapsulation TMZ or its pharmaceutically acceptable salt.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are oral preparations.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation are ejection preparations.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, hepatopathy are acute-on-chronic liver failures.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, associated disease are selected from the group that is made up of: virus hepatitis, non-specific toxicity hepatitis, drug or
Medicine induction hepatic injury or damage, the hepatitis such as herbal medicine of toxin-induced or mushroom induction hepatitis or hepatopathy, alcoholic hepatitis,
Oneself immunity hepatitis, alcohol fatty liver or non-alcohol fatty liver (NAFLD), nonalcoholic fatty liver disease
(NASH), metabolism or genetic correlation hepatopathy (hemochromatosis, Wilson's disease), ischemic hepatic injury (shock liver), sepsis
The hepatic failure and congested hepatopathy (hepatic failure caused by heart failure) of disease (bacterium or other microorganism infections) induction.
In some embodiments of purposes of the present invention, optionally any one of with various embodiments as described herein
Or all combinations, preparation include any composition disclosed herein.The composition can be such as aforementioned paragraphs [0009]-
[00025] composition described in any one in.
In some other embodiments of purposes of the present invention, optionally in various embodiments as described herein appoint
A kind of or all combinations, preparation can be made into specifically excluding the composition of any embodiment disclosed herein.Described group
Closing object can be composition described in any one in such as aforementioned paragraphs [0009]-[00025].
Definition
Trimetazidine and acute-on-chronic liver failure
Trimetazidine, it is characterised in that be used to prevent and treat the new application of hepatic failure as hepatic.
Trimetazidine as hepatic as described herein, wherein Trimetazidine can: inhibit resting T lymphocytes quilt
Activation is the lymphocyte and macrophage of activation, reduces the release of cell factor, and it is thin to reduce the liver as caused by immune system
Cellular damage；Inhibit the fatty acid metabolism in liver cell and optimizes the energy metabolism in liver cell；Maintain mitochondrial permeability
It converts the normal function in hole and reduces hepatocellular apoptosis.
Trimetazidine as hepatic as described herein, wherein Trimetazidine can: inhibit fatty acid metabolism, especially
It is to inhibit mitochondria ketoacyl thiolysis enzymatic activity, to inhibit cell fatty acid beta oxidation and reduce ROS reaction；Wherein Sibutramine Hydrochloride he
Piperazine can enhance mitochondria pyruvate dehydrogenase activity, to promote the aerobic oxidation of glucose, need in ischemic cell
Oxygen consumption more lower than beta oxidation is to obtain energy, and wherein Trimetazidine can optimize the energy process in liver cell, from
And energetic supersession appropriate is maintained during ischemic.
Trimetazidine is as hepatic as described herein, and wherein Trimetazidine mainly passes through following three aspects and realizes
Hepatoprotective effect:
(1) since lymphocyte activation needs ATP provided by fatty acid metabolism, Trimetazidine is able to suppress free fatty acid
(FFA) be metabolized, inhibit resting T lymphocytes be activated the lymphocyte for activation, thus reduce cell factor be activated it is thin
Cytotoxic T Lymphocytes release reduces exogenous cells necrosis or apoptosis, and reduces liver cell caused by human immune system
Damage.
(2) due to during hepatic failure liver cell be in the adverse environment of high ammonia, hypoxemia and high bilirubin, seriously affect ATP's
Cell generates, and then inhibits the development and growth of liver cell, and Trimetazidine is able to suppress the fatty acid metabolism in liver cell, promotes
Glucose glycolysis and subsequent TCA (tricarboxylic acid cycle) circulation, oxygen needed for reduction generates same amount of ATP in liver cell
Atom, and promote to carry out oxidizing glucose using limited oxygen atom with ATP needed for providing liver cell with synthetic active substance, packet
Include RNA, DNA and protein；Wherein in hepatic injury, especially during hepatic failure, the formation of microthrombus is led in damaged liver
It is common for causing the anaerobic condition of liver cell；Wherein Trimetazidine can also inhibit FFA (free fatty acid) to be metabolized, and it is thin to reduce liver
The formation of ROS in born of the same parents, and reduce secondary hepatocellular injury.
(3) since hepatocellular injury leads to injury of mitochondria, ATP synthesis and the innate immunity are reduced, it is characterized in that MPT opening and K+
It outflows with Ca2+, thus cause endogenous apoptosis, especially shown in the hepatocellular injury as caused by hyperammonemia, Trimetazidine
Suitably discharging and reducing hepatocellular apoptosis for calcium ion can be maintained by the hole MPT.
As used herein, term " acute hepatic failure " (ALF) is defined as " fast development of hepatic dysfunction, spy
It is not the change (encephalopathy) of the coagulopathy in the patient of not known the past hepatopathy and the state of mind ".
As used herein, " chronic liver failure (CLF) usually occurs in the case where cirrhosis term, itself is potentially
Many possible causes as a result, such as excessive consumption of alcohol, B-mode or hepatitis C, autoimmunity, heredity and metabolism reason (such as iron
Or copper overload, steatohepatitis or non-alcohol fatty liver)."
As used herein, term " acute-on-chronic liver failure " refers to the feature of the exhibition hepatic failure of the human hair with chronic liver disease
Situation.Many potential reasons may cause such case, such as alcohol abuse or infection.People with ACLF may be the state of an illness
It is serious, it needs to carry out intensive care, it is sometimes desirable to liver transfer operation.Treating the death rate is 50%.
The present invention provides a kind of for treating the treatment method of hepatopathy, to slow down or reverse patient progress as hepatic failure.
In this case, " hepatopathy " indicates that hepatic injury and inflammation may develop into the fatal forfeiture of liver function and/or power of regeneration
Illness.Therefore, " hepatopathy " used in this specification includes hepatitis, and wherein inflammation causes the damage of liver cell and liver function, nothing
By being by any viral (virus hepatitis), hepatotoxin (for example, alcoholic hepatitis), or by autoimmunity (autoimmune
Hepatitis) cause.In the present specification also by " hepatopathy " explanation are as follows: (A) fatty liver disease (hepatic steatosis), a kind of glycerol three
The big vacuole of ester fat accumulates the illness in liver cell, and (B) non-alcohol fatty liver, it includes with fat and metabolism
The relevant a variety of diseases of syndrome, wherein (A) or (B), which implies that hepatic injury is seriously arrived, leads to liver function and/or power of regeneration
Fatal forfeiture.
During hepatopathy, blood supply of the damage influence of normal liver structure to liver.Although so far, ischemic and
Anoxic is not considered as the characteristic feature of hepatopathy, but inventor has found that hepatic injury leads to the ischaemic and anoxic of liver.In addition,
Another main predisposing factors of hepatic injury are liver inflammation reactions, and the physiological function of liver and power of regeneration is caused to reduce.Base
The above-mentioned pathological characters of anoxic and inflammatory reaction in hepatopathy, the present invention provides a kind of for treating the new treatment side of hepatopathy
Method.Positive and beneficial result: as shown in clinical research and test result, when being administered to the patient with liver diseases and illness
When, TMZ can maintain liver function and reduce transaminase level (including alanine aminotransferase, aspartate transaminase etc.)
Aspect provides remarkable result, has the characteristics that shorten the course of disease, the reduction death rate, be used conveniently and safely and medical expense is low.By
It is mainly eliminated with prototype by urine in TMZ, elimination half-life period is about 6 hours and without liver metabolism, therefore hepatotoxicity is minimum,
There is significant hepatoprotective effect simultaneously.
It is related in the clinical test and research of 165 hepatic failures described in the PCT/CN2016/080219 of Yu, it will
TMZ tablet (20mg/ piece) is administered orally to the hepatic failure patients being hospitalized, each one, three times a day, the course for the treatment of for 4 weeks.Such as
Shown in clinical test results, compared with traditional therapy, the not dead rate in 30 days of the hepatic failure patients of TMZ treatment group is dropped from 44%
35% is down to about 18%, 90 day not dead rate from 68%.This shows that the earlier T MZ intervention of hepatic failure patients can significantly improve life
It deposits rate and improves its prognosis.In addition, laboratory test index shows that TMZ can improve alanine aminotransferase and day significantly
The reduced rate of aspartic acid transaminase.One patient receives the PET-CT test of liver imaging variation, the results showed that, take TMZ
Afterwards, the liver glucose metabolism of hepatic failure patients significantly improves.The clinical test results show hepatic failure patients early application
TMZ can improve its liver function significantly, inhibit liver inflammation reaction, enhance the metabolism of its liver glucose and energy utilization, and
Improve its chance for survival.
Preparation
It can be used for preparing comprising Trimetazidine or its medicine commonly used in the carrier of pharmaceutical preparation, excipient and other additives
Pharmaceutical composition of the acceptable salt as active constituent on.
Pharmaceutical composition can be configured to any suitable preparation.For example, administration form can be peroral dosage form, such as
Tablet, pill, capsule, particle, pulvis, emulsion, syrup, suspension, liquid preparation or non-oral dosage forms, such as be injected intravenously
Agent or intramuscular injection agent, suppository, subcutaneous medicament, transdermal reagent, intranasal medicament, inhalant.It is considered as symptom, the year of individual patient
Age, gender etc., appropriately to determine the dosage of compound.
In the present invention, tablet, pulvis, particle etc. be can be for the solid composite of oral administration.In this kind of solid
In composition, by one or more active materials and at least one inert excipient (such as lactose, mannitol, glucose, hydroxypropyl
Base cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminium-magnesium silicate etc.) mixing.According to conventional methods, composition is also
Inert additwe, such as lubricant (such as magnesium stearate), disintegrating agent (such as carboxymethyl shallow lake sodium) and cosolvent can be contained
(dissolution aid).If desired, tablet or pill can be coated with sugar-coat or stomach or enteric coating agents.
Liquid composition for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir
With common inert diluent (for example, pure water, ethyl alcohol).Besides inert diluents, the composition can also contain additive, example
Such as solubilizer, wetting agent and suspending agent and sweetener, corrigent, flavoring agent and preservative.
Injection for non-oral application includes sterile aqueous or non-aqueous liquid, suspension and emulsion.For
The diluent of aqueous solution may include (for example) distilled water for injection and physiological saline.Diluent for non-aqueous solution may include
(for example) propylene glycol, polyethylene glycol, vegetable oil (such as olive oil), alcohol (such as ethyl alcohol) and polysorbate80.These combinations
Object can also contain isotonic agent, preservative, wetting agent, emulsifier, dispersing agent, stabilizer, dissolution aids (dissolving aid)
Equal additives.These compositions can be sterilized by being filtered with bacteria retaining filter, fungicide being added or uses up irradiation.Separately
Outside, these compositions can be made into aseptic solid composite, then dissolve using preceding with sterile water or aseptic injection with solvent
Or it suspends.
Such as the transmucosal medicament of inhalant and intranasal medicament etc. can be solid, liquid or semisolid use state, and
And it can be prepared according to conventionally known method.For example, excipient (such as newborn sugar and starch) can be added as needed, pH is adjusted
Agent, preservative, surfactant, lubricant, stabilizer, thickener etc..Suitable sucking can be used or device for blowing carries out
Application.For example, metered dose inhaler or other conventionally known devices or sprayer can be used for being administered alone compound or
It is applied after preparation as mixture of powders.In addition, compound can also be combined with pharmaceutically acceptable carrier, and with solution or
Suspension application.Diskus etc. can be used for single dose or multi-dose, and dry powder or the capsule containing powder can be used.This
Outside, pressurised aerosol is equal by spraying can also be by using suitable propellant (for example, chlorofluoro-alkane, hydrofluoroalkane or suitable
Gas such as carbon dioxide) it is administered.
Dosage regimen
In general, daily dose of the compound for adult patient is about 0.001mg/kg in the case where oral administration
To 100mg/kg, single dose or it is divided into 2 to 4 times daily.In the case where intravenously being applied according to patient symptom, it is however generally that,
The daily dose of adult patient is 0.0001mg/kg to 10mg/kg, once a day to multiple.In addition, using inhalant application
In the case of, it is however generally that, the daily dose of adult patient is 0.0001mg/kg to 1mg/kg, once a day to multiple.
In one embodiment, adult patients can take orally daily containing about 30-180mg Trimetazidine or its pharmaceutically
Pharmaceutical composition of the acceptable salt as active constituent, with single dose or 2 to 4 separate doses, each dosage includes about 10-
60mg Trimetazidine.In one embodiment, adult patients can take orally daily contains about 60mg Trimetazidine or its pharmacy
Upper pharmaceutical composition of the acceptable salt as active constituent, with 3 separate doses, each dosage comprising about 20mg Sibutramine Hydrochloride he
Piperazine.[000112] TMZ have been found be as the drug of acute hepatic failure it is effective, as described in PCT/CN2016/080219,
Its teaching is incorporated herein by reference in their entirety.For concise description, the description to this teaching is omitted in text, but can hold
It changes places and reproduces and be incorporated in text without excessive burden.
Rapidly release and/or sustained release
In some embodiments, invention formulation, which can be formed in single formulation or dosage regimen, provides each of TMZ
Kind release characteristic.This release characteristic can be, for example, TMZ's rapidly discharges to meet acute hepatic failure patient and compel to TMZ
It is essential and wants, followed by the sustained release of TMZ to be to provide the TMZ of certain level, to generate liver protection.
The rapidly release of TMZ can be for example, by TMZ or its pharmaceutically acceptable salt (such as TMZ solution or discrete
TMZ particle can be used as solid powder or suspension application) injection or oral administration realize；And sustained release can
For example to be realized by extended release preparation, which includes that TMZ is embedded in biocompatible polymer material
In material, TMZ is mixed with biocompatible polymeric material, or with polymer material encapsulating or microencapsulation TMZ.Preferably, raw
Object compatible polymeric materials are degradable, so that the degradation rate of polymer controls the rate of release of TMZ.Polymer material
It can be natural polymeric material, such as liposome or synthetic polymer, such as polyester, such as polylactic acid.
In some embodiments, rapidly release-sustained release preparation of TMZ is provided preferably after application 30 minutes
The rapidly release of the interior TMZ that 30mg to 150mg is provided, and within one day to one month a period of time, when with 4-6 hours per
Between unit 10mg-30mg rate provide TMZ sustained release (for example), as long as the accumulated dose of TMZ be no more than regulation to prescription
The limit value of case setting.
The various preparation techniques for realizing required drug release characteristics have sufficiently been described.For example, whole by reference
The Encyclopedia of Controlled Drug Delivery being incorporated herein, the collection of volume 2, Edith Mathiowitz
(editor), John Willey&Sons (1999), which is provided, to be prepared about drug to realize referring generally to for various ideal release characteristics
It leads.
Second medicament
In some embodiments, composition of the invention may include the liver protecting drug for not being TMZ.In some implementations
In scheme, liver protecting drug is as described above.
In some other embodiments, second medicament can be pharmacy or physiologically beneficial drug or medicament,
Improve the overall state of subject.In this respect, this second medicament can be the medicament for for example improving subject immune system,
Improve the nerve of subject or the medicament of psychological condition, or improves the medicament of subject CNS illness.
Foregoing embodiments are provided and are merely to illustrate the preferred embodiments of the invention；However, the present invention is not limited to above-mentioned
Embodiment.In the knowledge of those of ordinary skill in the art, in the case where not departing from spirit and principles of the present invention, Ren Hexiu
Change, equivalent replacement and the improvement place of being regarded as within the scope of protection of this application.
Claims (22)
1. a kind of treat the purposes for having the acute-on-chronic liver failure (ACLF) or related disease of the subject of this demand comprising root
It include a effective amount of Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyl] piperazine to subject application according to dosage regimen
Piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmaceutically acceptable salt composition.
2. purposes according to claim 1, wherein according to dosage regimen, by a effective amount of TMZ be administered to it is described by
Examination person, the dosage regimen include every 4-12 hours administration 20-500mg.
3. purposes according to claim 1 continues wherein the dosage regimen includes every 4-12 hours administration 20-500mg
1 day to the course for the treatment of in 2 weeks or 1 day to the 1 month course for the treatment of.
4. purposes according to claim 1, wherein application includes being administered orally, parenteral injection or IV application.
5. purposes according to claim 1, wherein the composition also includes pharmaceutically acceptable carrier.
6. purposes according to claim 1, wherein described pharmaceutical composition generates following one or more effects:
The resting T lymphocytes for reducing the subject are activated lymphocyte for activation；
It reduces the fatty acid metabolism in the liver cell of the subject and promotes the aerobic oxidation of glucose；
It reduces the beta oxidation in the liver cell of the subject and reduces the formation of ROS；
The blood alanine aminotransferase (ALT) for reducing the subject is horizontal；Or
The blood aspartate transaminase (AST) for reducing the subject is horizontal.
7. purposes according to claim 1, wherein the associated disease do not include angina pectoris, coronary insufficiency,
Remote myocardial infarction, coronary heart disease, dizziness or tinnitus.
8. purposes according to claim 1 (is damaged wherein the associated disease is selected from by hepatopathy without the liver of main inflammatory
Wound), the group that forms of hepatitis (with inflammation) and cirrhosis (structural damage may with or may be not accompanied by hepatic failure).
9. purposes according to claim 1, wherein the associated disease is selected from the group being made up of: viral liver
The hepatitis such as herbal medicine or mushroom of hepatic injury or damage, toxin-induced that inflammation, non-specific toxicity hepatitis, drug or medicine induce
The hepatitis or hepatopathy of induction, alcoholic hepatitis, oneself immunity hepatitis, alcohol fatty liver or non-alcoholic fatty liver
Sick (NAFLD), nonalcoholic fatty liver disease (NASH), metabolism or genetic correlation hepatopathy (hemochromatosis, Wilson
Disease), the hepatic failure and congested hepatopathy of ischemic hepatic injury (shock liver), septicemia (bacterium or other microorganism infections) induction
(hepatic failure caused by heart failure).
10. purposes according to claim 1, wherein the composition includes second medicament.
11. a kind of preparation, it includes Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Sibutramine Hydrochloride he
Piperazine or TMZ) or its pharmaceutically acceptable salt and carrier, the preparation provides releasing for TMZ or its pharmaceutically acceptable salt
Put feature, the feature includes TMZ or the rapidly release of its pharmaceutically acceptable salt, followed by TMZ or its can pharmaceutically connect
The sustained release for the salt received.
12. preparation according to claim 11, wherein applying the TMZ or its pharmaceutically acceptable salt to patient
Afterwards, described rapidly to release 30mg to 180mg TMZ or its pharmaceutically acceptable salt.
13. preparation according to claim 11, wherein the sustained release is every 4 within one day to one month a period of time
To 6 hours release 10mg to 30mg TMZ or its pharmaceutically acceptable salt.
14. preparation according to claim 11, wherein the sustained release of TMZ or its pharmaceutically acceptable salt is logical
Cross the TMZ or its pharmaceutically acceptable salt are embedded in biocompatible polymeric material, by TMZ or its pharmaceutically may be used
The salt of receiving is mixed with biocompatible polymeric material, or with polymer material encapsulating microencapsulation TMZ or its pharmaceutically may be used
The salt of receiving provides.
15. preparation according to claim 11 is oral preparation or ejection preparation.
16. a kind of method for preparing preparation comprising
Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its medicine is provided
Acceptable salt on；
Carrier is provided；And
Preparation is formed,
Wherein the preparation provides TMZ or the release characteristic of its pharmaceutically acceptable salt, and the feature includes TMZ or its medicine
The rapidly release of acceptable salt on, followed by the sustained release of TMZ or its pharmaceutically acceptable salt.
17. according to the method for claim 16, wherein applying the TMZ or its pharmaceutically acceptable salt to patient
Afterwards, described rapidly to release 30mg to 180mg TMZ or its pharmaceutically acceptable salt.
18. according to the method for claim 16, wherein the sustained release is every 4 within one day to one month a period of time
To 6 hours release 10mg to 30mg TMZ or its pharmaceutically acceptable salt.
19. a kind of for treating the purposes of hepatopathy or related disease comprising apply preparation, the system to the patient for having this demand
Agent includes Trimetazidine Hydrochloride (1- [2,3,4- trimethoxy benzyl] piperazine dihydrochloride) (Trimetazidine or TMZ) or its pharmacy
Upper acceptable salt and carrier, the preparation provide TMZ or the release characteristic of its pharmaceutically acceptable salt, the feature packet
Include the TMZ or the rapidly release of its pharmaceutically acceptable salt, followed by TMZ or its pharmaceutically acceptable salt are persistently released
It puts.
20. purposes according to claim 19, wherein applying the TMZ or its pharmaceutically acceptable salt to patient
Afterwards, described rapidly to release 30mg to 180mg TMZ or its pharmaceutically acceptable salt.
21. purposes according to claim 19, wherein the sustained release is every 4 within one day to one month a period of time
To 6 hours release 10mg to 30mg TMZ or its pharmaceutically acceptable salt.
22. purposes according to claim 19, wherein the hepatopathy is acute-on-chronic liver failure.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16/028,228 | 2018-07-05 | ||
| US16/028,228 US20190381034A1 (en) | 2018-06-14 | 2018-07-05 | Pharmaceutical composition and method for acute on chronic liver failure and related liver diseases |
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| CN109010342A true CN109010342A (en) | 2018-12-18 |
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ID=64649298
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| CN201810878423.1A Pending CN109010342A (en) | 2018-07-05 | 2018-08-03 | Pharmaceutical composition and method for acute-on-chronic liver failure and related liver disease |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058888A (en) * | 2009-05-01 | 2011-05-18 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Pharmaceutical composition for treatment of abnormal energy metabolism and application thereof |
| EP2394644A2 (en) * | 2010-05-04 | 2011-12-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Trimetazidine Formulation With Different Release Profiles |
| US20160354366A1 (en) * | 2015-04-28 | 2016-12-08 | Zujiang Yu | Novel use of trimetazidine as a hepatoprotective medicine in prevention and treatment of liver diseases and conditions |
-
2018
- 2018-08-03 CN CN201810878423.1A patent/CN109010342A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058888A (en) * | 2009-05-01 | 2011-05-18 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Pharmaceutical composition for treatment of abnormal energy metabolism and application thereof |
| EP2394644A2 (en) * | 2010-05-04 | 2011-12-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Trimetazidine Formulation With Different Release Profiles |
| US20160354366A1 (en) * | 2015-04-28 | 2016-12-08 | Zujiang Yu | Novel use of trimetazidine as a hepatoprotective medicine in prevention and treatment of liver diseases and conditions |
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