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WO2015070396A1 - 无肝副作用的对乙酰胺基酚新复方组合 - Google Patents

无肝副作用的对乙酰胺基酚新复方组合 Download PDF

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Publication number
WO2015070396A1
WO2015070396A1 PCT/CN2013/087049 CN2013087049W WO2015070396A1 WO 2015070396 A1 WO2015070396 A1 WO 2015070396A1 CN 2013087049 W CN2013087049 W CN 2013087049W WO 2015070396 A1 WO2015070396 A1 WO 2015070396A1
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Prior art keywords
content
liver
peg
hepatotoxicity
acetaminophen
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PCT/CN2013/087049
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English (en)
French (fr)
Inventor
胡幼圃
石东原
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财团法人国防教育研究基金会
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Priority to PCT/CN2013/087049 priority Critical patent/WO2015070396A1/zh
Priority to CN201380058666.6A priority patent/CN105188756B/zh
Priority to ES13897632T priority patent/ES2929945T3/es
Priority to KR1020177019405A priority patent/KR102017550B1/ko
Priority to RS20221004A priority patent/RS63704B1/sr
Priority to PT138976329T priority patent/PT3069733T/pt
Priority to EP13897632.9A priority patent/EP3069733B1/en
Priority to PL13897632.9T priority patent/PL3069733T3/pl
Priority to US14/441,317 priority patent/US10420737B2/en
Priority to JP2016515604A priority patent/JP2016520100A/ja
Priority to EA201591435A priority patent/EA029454B1/ru
Application filed by 财团法人国防教育研究基金会 filed Critical 财团法人国防教育研究基金会
Priority to EP22183582.0A priority patent/EP4173619A3/en
Priority to HRP20221344TT priority patent/HRP20221344T1/hr
Priority to DK13897632.9T priority patent/DK3069733T3/da
Priority to KR1020157023533A priority patent/KR101881074B1/ko
Priority to LTEPPCT/CN2013/087049T priority patent/LT3069733T/lt
Priority to CN202010418123.2A priority patent/CN111904924A/zh
Priority to HUE13897632A priority patent/HUE060309T2/hu
Publication of WO2015070396A1 publication Critical patent/WO2015070396A1/zh
Priority to US16/411,861 priority patent/US11534416B2/en
Priority to US17/993,183 priority patent/US20230082397A1/en

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the invention relates to a new compound combination of acetaminophen (APAP) without liver function, in particular to a method for inhibiting the activity of cytochrome P450 2E1 (CYP2E1) enzyme by combining acetaminophen.
  • APAP acetaminophen
  • CYP2E1 cytochrome P450 2E1
  • Acetaminophen also known as paraceamol or N-acetyl-para-aminophenol, or APAP
  • APAP N-acetyl-para-aminophenol
  • NAC antidote N-acetylcysteine
  • the third phase begins about 3-4 days after taking it, and the extent and prognosis of liver damage can be estimated. Symptoms of hepatotoxicity can range from mild symptoms with increased liver function (AST > 1,000 IU/L) to severe violent hepatitis with metabolic acidosis, jaundice, hypoglycemia, AST > 10,000 IU/L, abnormal coagulation And liver and brain lesions.
  • the fourth phase can cause oliguric renal failure, which can lead to death.
  • Acetaminophen can reach peak blood concentration 1 to 2 hours after oral administration, most of which is metabolized from the liver, and more than 90% is combined with glucuronide and sulfate to form non-toxic metabolites. Only less than 5% are metabolized via different CYPs, including: CYP2E1, CYP1A2, and CYP3A4, of which CYP2E1 and CYP1A2 are major metabolic enzymes.
  • NAPQI reacts immediately with intracellular glutathione to form a non-toxic mercaptide.
  • the rate of glutathione consumption in the cell is greater than the rate of synthesis.
  • the intracellular glutathione content is lower than 30% of normal, NAPQI binds to the macromolecule or nucleotide containing cysteine in the cell.
  • causes damage to liver cells. Staining from cell tissue demonstrates that NAPQI forms a covalent bond with the cysteine in the central region of the hepatic lobules prior to hepatocyte necrosis.
  • liver disease For patients with liver disease, alcohol abuse, or taking to induce liver cytochrome P450 enzyme activity, patients with: Carbamazepine, Ethanol, Isoniazid, Phenobarbital (may be other barbiturates), Phenytoin, Sulfinpyrazone, Sulfonylureas ⁇ Rifampin, Primidone, etc. All belong to high-risk groups that cause severe liver toxicity of APAP. At this time, if the patient has complications such as adult respiratory distress syndrome, cerebral edema, uncontrolled bleeding, infection, or multiple tube failure, it is easy to cause death. Taking alcohol as an example, alcohol is mainly metabolized by CYP2E1 in the liver.
  • the mechanism for inducing APAP poisoning can be divided into three stages.
  • the first stage is the receptor for alcohol and APAP to compete for liver CYP2E1.
  • the concentration of NAPQI will be first.
  • the second stage is that alcohol will increase the half-life of CYP2E1 from 7 hours to 37 hours, which will increase the content of CYP2E1 in the liver, and the concentration of NAPQI will slowly rise.
  • the third stage is when the alcohol is absent, the liver is more More CYP2E1 to metabolize acetamide
  • the phenol which causes a significant increase in the toxic metabolites of acetaminophen, causing liver cell damage.
  • diallyl sulfide can effectively prevent hepatotoxic damage caused by acetaminophen in mice, and further found that diallyl sulfide has the effect of inhibiting CYP2E1 enzyme activity, and inferred that diallyl sulfide prevents the cause of acetaminophen.
  • the protective mechanism should be to inhibit the production of the active intermediate NAPQI by acetaminophen.
  • Invasive and non-invasive methods are used to test liver function in rats to monitor the development of liver damage and to screen for liver disease.
  • the most commonly used method involves measuring aspartate aminotransferase (AST) in serum.
  • liver function quantitative test is based on the concentration of the serum in the liver that is almost exclusively metabolized by the liver.
  • the clearance of these receptors is based on the portal vein and hepatic artery blood.
  • the flow rate and the effect of the liver cells on these receptors are related to the quality of the liver supplied to the liver. Conversely, the removal of the receptor is determined by the ability of the liver to metabolize.
  • Galactose is a sugar with a high extraction ratio and 90% metabolism in the liver.
  • galactose is subjected to differential stereoisomerization by galactokinase ( Epimerization), which is converted to Glucose-1-phosphate; the action of galactose kinase is the rate-limiting step of the galactose metabolic pathway in hepatocytes.
  • the high extraction rate of galactose makes galactose metabolism, which depends on liver blood flow and liver function, the most important way to detect liver function. There is no rule to evaluate the residual liver function of rats.
  • the metabolic ability of an exact compound eg, galactose
  • the results showed that the galactose single-point method can accurately detect these liver diseases; the galactose single-point method has been successfully applied to test patients with liver disease. Residual liver function of drugs such as promazine and antibiotic cefoperazone.
  • the galactose single-point method has become one of the recommended methods for testing liver function in the guidelines published by the US Food and Drug Administration (FDA). It can be seen that the above-mentioned idioms of acetaminophen still have many defects, which are not excellent designs and need to be improved. Summary of the invention
  • the object of the present invention is to provide a new combination of no-hepatic side effects for improving the hepatotoxicity of Acetaminophen (APAP) drug, comprising: (a) a pharmaceutically effective amount of p-acetamido phenol; And (b) - or two or more compounds which reduce the hepatotoxicity produced by the liver enzyme CYP2E1 metabolite.
  • APAP Acetaminophen
  • the compound is at least one selected from the group consisting of: polyoxyethylene (20) sorbitan monolaurate (Tween 20), microcrystalline township Microcrystalline cellulose, Dicalcium phosphate dihydrate, polyoxyethylene 23 lauryl ether (Brij 35), saccharin (Saccharin), mannitol (Mannitol), polyoxyethylene alkyl ether ( Cremophor RH40), Sucralose, Crospovidone, Sodium starch glycolate, Acrylic S100 (Eudragit S100), Croscarmellose sodium, Polyoxyethylene polyoxygen Propylene (Pluronic F68), Menthol (Menthol), Low-substituted hydroxypropyl cellulos, Pregelatinized starch, Dextrates NF hydrated, Citric acid, Castor oil Cremophor EL, colloidal silica (Aerosil 200), polyethylene glycol monostearate (Myrj 52), sorbic acid (Sorbic acid
  • the compound composition is at least one selected from the group consisting of or any combination thereof, and the effective dosage of the composition is limited: polyoxyethylene (20) sorbitan monolaurate (Polyethylene) Glycol sorbitan monolaurate; Tween 20)
  • the content is 0.17-5.5 grams
  • the content of microcrystalline cellulose is 100 ⁇ 1000 mg
  • the content of Dicalcium phosphate dihydrate is 10 ⁇ 250 mg
  • Mannitol content of 10 ⁇ 250 mg
  • Sucralose is 10 ⁇ 250mg
  • Crospovidone is 0.17 ⁇ 5.5g
  • Sodium starch glycolate is 0.17 ⁇ 5.5 g
  • Pregelatinized starch is 1.7-5.5 g
  • Dextrates NF hydrated is 0.17-5.5 g
  • Citric acid is 10-42 mg
  • castor oil polyoxyethylene ether ( Cremophor EL) content of 1.7 ⁇ 5.5 grams
  • colloidal silica (Aerosil 200) content of 0.17 ⁇ 5.5 grams
  • polyethylene glycol monostearate (Myrj 52) content of 1.4 ⁇ 5.5 grams
  • Yamanashi Sorbic acid is 6 ⁇ 24 mg
  • Lemon oil is 0.17 5.5 g
  • Hydroxypropyl cellulose is 0.17-5.5 g
  • Sorbitol The content is 0.17 ⁇ 5.5g
  • the content of Acesulfame potassium is 1.4 ⁇ 5.5g
  • the content of Hydroxypropylmethylcellulose is 0.17 ⁇ 5.5g
  • single Lactose monohydrate is 6 ⁇ 24 mg
  • Maltodextrin is 0.17 ⁇ 5.5 g
  • Brij 58 is 0.17 ⁇ 5.5 g
  • Brij 76 0.
  • £0 400 is 1.4 ⁇ 5.5g
  • PEG 4000 is 1.4-5.5g
  • PEG 8000 is 1.4 ⁇ 5.5g
  • Span 60 is 1.4 ⁇ 5.5g
  • Sodium benzoate The content is 2.9 ⁇ 11.9 mg
  • the content of Hydroxyethylmethylcellulose is 0.17-5.5 g
  • the content of Methylcellulose is 0.17-5.5 g
  • the content of Span 80 is 1.4.
  • the compound is selected from Mannitol and is preferably combined with Sucalose.
  • the combination is used separately, simultaneously or sequentially.
  • the compound of the paracetamol and/or the hepatotoxicity which can reduce the metabolism of the liver enzyme CYP2E1 is a gel, a spray, a pasty, a lozenge or a dispersible tablet.
  • the combination is included in a medical kit, kit or patient pack.
  • Another object of the present invention is to provide a use in combination with the manufacture of a medicament for the treatment of a liver-free side effect of improving the hepatotoxicity of an acetaminophen drug.
  • FIG. 1 is a diagram showing the metabolic pathway of acetaminophen (APAP) in the liver;
  • Figure 2 shows (A) normal control group, (B) APAP hepatotoxicity group, (C) dicalcium hydroribate, (D) mannitol, (E) menthol, (F) sucralose, (G) nectar Alcohol + sucralose (1.67 + 1.67 mg / kg) and (H) mannitol + sucralose (0.83 + 0.83 mg / kg) liver protection test group, rat liver tissue section after a single dose of tube: (A Liver tissue type in the normal control group; (B) Hepatocytes in the peripheral central vein (V) showed fragmentation, and inflammatory cells were produced, causing necrosis and vacuolization; compared with the APAP hepatotoxic group, liver protection Rats in the experimental group, except the dicalcium phosphate test group, the rats in the other experimental groups had complete hepatocytes around the central vein, the nucle
  • the new compound of paracetamol without hepatotoxicity firstly uses a combination of acetaminophen phenolic new compound to induce hepatotoxicity in rats, and studies the use of CYP2E1 inhibitor in combination with one or any combination thereof. Effects of acetaminophen-induced hepatotoxicity in rats; except for the use of general hepatotoxicity markers, pathological tissue sections, quantitative measurement of residual liver function in rats by galactose single-point method (GSP), further Evaluation.
  • GSP galactose single-point method
  • kits pharmaceutical packs or patients - packs (patient packs), wherein two or more compounds/agents are co-packaged or co-presented (eg, as part of a unit dosage).
  • the present invention is exemplified by the following examples, but the present invention is not limited by the following examples.
  • the drugs and biological materials used in the present invention are commercially available and are easily available.
  • the following are only examples of available channels.
  • Acetaminophen is a combination of a safe, pharmaceutically acceptable conventional excipient in one or any combination thereof to improve drug hepatotoxicity in an animal test.
  • mice Male SD (Sprague-Dawley) rats weighing 175-280 g were purchased from the National Laboratory Animal Center (Taiwan). Animal experiments were performed in accordance with the guidelines of the National Animal Health Laboratory. All rats were placed in an air/humidity environment. Under the light and dark for 12 hours, the supply of water and feed is not limited. During the test, the body weight of the rats is continuously monitored, and the water is supplied as usual.
  • Liver protection experimental animals were administered 1.67 mg of dicalcium phosphate per kilogram of body weight of the rats; or 1.67 mg of mannitol per kg of body weight tube; or 1.67 mg of menthol per kg of body weight tube; or per kg of body weight tube Feed 1.67 mg of HUEXC041; or 1.67 mg of mannitol and 1.67 mg of sucralose per kg of body weight tube; or 0.83 mg of mannitol and 0.83 mg of sucralose per kg of body weight tube; or Each kilogram of body weight tube was fed with 0.42 mg of mannitol and 0.42 mg of sucralose; or 0.17 mg of mannitol and 0.17 mg of sucralose per kg of body weight tube, and a single dose of 1000 mg of APAP per kg of body weight tube.
  • hepatic inflammation by measuring aspartate aminotransferase (AST) and alanine transaminase (ALT) in plasma; measuring galactose single point method (GSP) before administration and 16 hours after administration ), quantitative analysis of residual liver function in rats; simultaneous analysis of liver histopathological changes in each group of rats, to assess the mechanism of liver damage or liver protection.
  • AST aspartate aminotransferase
  • ALT alanine transaminase
  • the rats were sacrificed by acetic anesthesia, the blood was taken from the rat tail artery, placed in a test tube containing EDTA, and the plasma was centrifuged at 13,000 g for 15 minutes at 4 ° C. The separated plasma was dispensed into trace amounts. Store in a small tube (Eppendorf tube) at -80 °C.
  • Hepatocyte damage is measured by measuring aspartate aminotransferase (AST) and alanine transaminase (ALT) activity in plasma.
  • AST and ALT activity are commonly used indicators of hepatotoxicity, using the Synchron LXi 725 system. To measure (Beckman Instruments, USA).
  • the rat liver was sacrificed immediately after histological analysis.
  • the liver samples were fixed with phosphate-buffered formalin in 10% solution, then dehydrated and embedded in paraffin (paraffin) at 5 ⁇ m
  • the sections were sliced, and the samples were stained with hematoxylin and eosin, and subjected to a liver glycosylation test (PAS). After staining, histological observation was performed by light microscopy.
  • Rats received a rapid intravenous injection within 30 seconds, 0.5 g/ml BW galactose solution 0.5 g/kg; 10, 15, 30, 45, and 60 minutes of blood stasis, blood samples taken from the tail vein; galactose content measured by colorimetric galactose dehydrogenase, test concentration range of 50 to 1,000 g /ml, the within-day variation of each concentration is calculated from the standard deviation and the coefficient of variation (CV) percentage.
  • the maximum allowable coefficient of variation is 10% CV; the day-to-day variation is checked by comparing the slope and intercept of the calibration curves; the galactose single point method (GSP) is 30.
  • the concentration of galactose in the blood at 60 minutes after the stop of the second injection.
  • AST transaminase
  • ALT alanine transaminase
  • the activities of transaminase (AST) and alanine transaminase (ALT) were significantly higher than those of the normal control group (the AST activity in the plasma of the normal control group was 202 ⁇ 34 IU/L; the AST activity in the plasma of the APAP hepatotoxic group was 499 ⁇ 112 KS/ , p ⁇ 0.005; ALT activity in plasma of normal control group was 56 ⁇ 14 IU/L; ALT activity in plasma of APAP hepatotoxic group was 368 ⁇ 71 IU/L, p ⁇ 0.005, showing APAP Liver toxicity occurred in the hepatotoxic group; except for the test group of the hydrous dihydrogen phosphate, the liver damage phenomenon was improved by using common safety excipients such as mannitol, menthol, and sucralose.
  • the experimental data are shown in Table 1, in which mannitol was combined with sucralose. Best, normal control The group is no different.
  • mice such as dicalcium hydroperoxide, mannitol, menthol and sucralose, galactose single point method (GSP) after tube feeding single dose test Analysis, aspartate transaminase (AST), alanine transaminase (ALT) activity and pathological tissue section Total HAI-score, numerical calculations for mean SD Liver function parameters GSP (mg/L) AST (IU/L) ALT (IU/L) Total
  • Test group 244 ⁇ 19*** 190 ⁇ 23*** 65 ⁇ 19*** 0.7 ⁇ 0.5***
  • Test group 371 ⁇ 49*** 298 ⁇ 49* 101 ⁇ 24*** 2.1 ⁇ 1.2*
  • liver structure in normal control rats is normal, the liver cells are intact, and they are arranged neatly, without vacuolization (as shown in Figure 2A); and mannitol, menthol, sucralose Liver tissue sections of the liver protection test group showed that the hepatocytes were more intact, the nucleus was obvious and the vacuoles were less (as shown in Figure 2C, D, F, G, H), showing mannitol, menthol, trichloro
  • the liver tissue of rats in the liver protection test group such as sucrose was closer to the liver tissue of normal rats.
  • the combination of mannitol and sucralose had the best protective effect and was positively correlated with the dose. The higher the dose, the better the protective effect.
  • the galactose single-point method (GSP) values of the normal control group and the APAP hepatotoxicity group were highly significantly different (GSP values of 289 ⁇ 38 mg/L in the normal control group; APAP liver)
  • the GSP value of the rats in the toxic group was 848 ⁇ 123 mg/L,; ⁇ 0.005).
  • the GSP values of the rats in the liver protection test group such as dicalcium hydroperoxide, mannitol, menthol and sucralose were 444 ⁇ 60 mg/L, 253 ⁇ 29 mg/L, 289 ⁇ 20 mg/L, 218 ⁇ 31 mg/L, compared with APAP hepatotoxicity group, liver protection test group such as mannitol, menthol and sucralose
  • the GSP values of the rats were significantly different from the rats in the APAP hepatotoxic group (?? ⁇ 0.005); the GSP values of the rats with hepatotoxicity were significantly increased by the administration of APAP alone; however, the combination of mannitol and menthol was applied in APAP.
  • cytochrome P450 2E1 CYP2E1
  • CYP2E1 inhibitors were screened using rat and human species liver microsomes for screening, and cytochrome P450 2E1 (CYP2E1) inhibitors were screened for 55 common and safe edible excipients.
  • CZX Chlorzoxazone
  • the amount of the metabolite standard 6-OH-CZX ( 6 _Hydroxy-Chlorzoxazone) was calculated, and the CYP 2E1 inhibition rate of the test sample was calculated based on the amount of 6-OH-CZX produced by the control.
  • the reagents required for screening cytochrome CYP2E1 inhibitors using rat liver or human liver microsomes in this example are as follows:
  • CYP2E1 100 mM potassium phosphate (H 7.4) contains 10 mg/mL P450 protein concentration.
  • Control Protein 10 mg/mL P450 Protein is dissolved in 100 mM Potassium Phosphate (pH 7.4).
  • Cofactors Contains 100 mM NADP+ and 10 mM Glucose 6-Phosphate.
  • Glucose 6-Phosphate Dehydrogenase 2000 units/ml is dissolved in sterile water.
  • Chlorzoxazone Substrate, 16 mM Chlorzoxazone is dissolved in 10% methanol.
  • DDTC Diethyldithiocarbamic acid: CYP2E1 selective inhibitor (positive control), 20 mM DDTC dissolved in 10% methanol.
  • NADPH-regenerating System 530 uL Cofactors, 40 uL G6PDH (Glucose 6-Phosphate Dehydrogenase Solution) and 100 uL Control Protein were added to 3.42 mL.
  • the experimental procedures for screening for cytochrome CYP2E1 inhibitors using rat liver or human liver microsomes are as follows: (1) 0.1 M phosphate buffer (pH 7.4) containing 0.5 mg/mL rat liver or human liver microsomes, 5 mM MgCl 2 for 15 minutes in a 4 ° C water bath environment;
  • CYP2I1 inhibition rate (%) [ 1 - ,,,,,,,; j 100%
  • the inhibition rate of CYP 2E1 measured by the positive control group (DDTC) of the positive control group is shown in Table 2. It can be seen from Table 2 that when the concentration of DDTC is 100 ⁇ , the inhibition rate of CYP 2E1 can reach 89.2%. .
  • the inhibition rate of CYP 2E1 measured by the excipient in rat liver microsomes is shown in Table 2. From the results, it can be seen that each excipient is at different concentrations (66 ⁇ , 33 ⁇ , 16.5 ⁇ ; 0.167%, 0.08%, 0.042%, w Under conditions of /v), the cytochrome P450 2E1 has different degrees of inhibitory effect, of which 0.167% Brij 58 The best inhibition effect (100.0 ⁇ 0.00%)
  • Aerosil 200 (0.167%) (0.084%) (0.024%) Polyethylene glycol monostearate 20.5 ⁇ 0.3 18.5 ⁇ 0.6 17.5 ⁇ 1.5 Myrj 52 (0.167%) (0.084%) (0.024%)
  • Methylcellulose phthalate 10.3 ⁇ 1.7 5.2 ⁇ 0.3 5.0 ⁇ 1.1 Methylcellulose (0.167%) (0.084%) (0.024%)
  • the inhibition rate of CYP 2E1 measured by the excipients in human liver microsomes is shown in Table 3. From the results, it can be seen that the various excipients are at different concentrations (66 ⁇ , 33 ⁇ , 16.5 ⁇ ; 0.167%, 0.08%, 0.042%, w Under the conditions of /v), the cytochrome P4502E1 had different degrees of inhibitory effect, among which 0.167% Brij 58 had the best inhibitory effect (91.2 ⁇ 1.3%).
  • Cremophor EL (0.167%) (0.084%) (0.024%)
  • Pregelatinized starch (0.167%) (0.084%) (0.024%) Polyethylene glycol monostearate 18.1 ⁇ 2.6 15.7 ⁇ 2.8 14.6 ⁇ 1.7
  • Aerosil 200 (0.167%) (0.084%) (0.024%)
  • the effective dose range of each excipient at different concentrations is : Polyethylene glycol sorbitan monolaurate (Tween 20) with a content of 0.17-5.5 g, microcrystalline cellulose (Microcrystalline cellulose) content of 100 ⁇ 1000 mg, Dicalcium phosphate dihydrate content of 10 ⁇ 250 mg, polyoxyethylene 23 lauryl ether (Brij 35), content of 100 ⁇ 1000 mg, saccharin (Saccharin) is 10 ⁇ 40 mg, Mannitol is 10 ⁇ 250 mg, and Cremophor RH40 is 0.17-5.5 g and Sucralose.
  • Crospovidone is 0.17 ⁇ 5.5g
  • sodium starch glycolate is 0.17 ⁇ 5.5g
  • acrylic resin S100 is 0.17 ⁇ 5.5g
  • the content of Croscarmellose sodium is 0.17 ⁇ 5.5g
  • polyoxyethylene polyoxypropylene (Pluronic F68) is 1.4 ⁇ 5.5g
  • Menthol is 8 ⁇ 34mg, low.
  • the content of Low-substituted hydroxypropyl cellulos is 0.19 ⁇ 0.82g, and the content of pregelatinized starch is 1.7 ⁇ 5.5g, Dextrates NF hyd Rated content is 0.17 ⁇ 5.5g, Citric acid content is 10 ⁇ 42mg, castor oil Cremophor EL content is 1.7 ⁇ 5.5g, colloidal silica (Aerosil 200)
  • the content is 0.17 ⁇ 5.5g
  • the content of polyethylene glycol monostearate (Myrj 52) is 1.4 ⁇ 5.5g
  • the content of sorbic acid (Sorbic acid) is 6 ⁇ 24mg
  • the content is 0.17 ⁇ 5.5g
  • the content of Hydroxypropyl cellulose is 0.17 ⁇ 5.5g
  • the content of Sorbitol is 0.17 ⁇ 5.5g
  • the content of Acesulfame potassium is 1.4 ⁇ 5.5g, Hydroxypropylcellulose, Hydroxypropylmethylcellulose), the content of 0.17 ⁇ 5.5g, Lac
  • the new compound of acetaminophen without hepatic side effects provided by the present invention is compared with the test results of acetaminophen alone, in biochemical analysis (ALT, AST value), pathological analysis and residual liver function
  • ALT, AST value biochemical analysis
  • pathological analysis pathological analysis
  • residual liver function residual liver function
  • this case is not only innovative in the application of acetaminophen, but also can be used to improve the hepatotoxic side effects caused by the use of acetaminophen in combination with common and safe common excipients.

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Abstract

一种用以改善对乙酰胺基酚（Acetaminophen，APAP）药物肝毒性的无肝副作用的新复方组合，包括（a）一药学有效量的对乙酰胺基酚，（b）合并使用一或两种以上可降低经肝脏酵素 CYP2E1代谢药物所产生肝毒性安全、药学上可接受的常用赋型剂化合物组成，该化合物是选自于下列群组：Tween 20、微晶纤维素、磷酸氢二钙、聚氧乙烯23月桂基醚、糖精、甘露醇、聚氧乙烯烷基醚、三氯蔗糖、吡咯烷酮、羟基乙酸淀粉钠、丙烯酸树脂S100、羧甲基纤维素钠、聚氧乙烯聚氧丙烯、薄荷醇、低取代烃丙纤维素、预胶化淀粉、Dextrates NF hydrated、柠檬酸、蓖麻油聚氧乙烯醚、胶态二氧化硅、聚乙二醇单硬脂酸酯、山梨酸、柠檬油、羟丙基纤维素、山梨糖醇、乙鲜舒泛钾、羟丙甲纤维素酞酸酯、单水合乳糖、麦芽糖糊精、Brij 58、Brij 76、Tween 80、Tween 40、 PEG 400、PEG 4000、PEG 2000等，以降低由对乙酰胺基酚所引起肝毒性的副作用。

Description

无肝副作用的对乙酰胺基酚新复方组合 技术领域
本发明是关于一种无肝作用的对乙酰胺基酚 (Acetaminophen, APAP)新复 方组合， 特别是指一种将对乙酰胺基酚合并使用具有抑制细胞色素 P450 2E1(CYP2E1)酵素活性的一种或其任意组合安全、 药学上可接受的常用赋型 剂， 以降低由对乙酰胺基酚所引起的肝毒性等副作用的对乙酰胺基酚新复方。 背景技术
对乙酰胺基臉 (Acetaminophen , 俗称普拿疼）， 又称为 paracetamol或 N-acetyl-para-aminophenol , 简称 APAP , 是市面上使用最普遍的解热镇痛剂， 每年经常有许多因 APAP使用不当而中毒或用于自杀的案例发生。 APAP引起 的肝脏损伤是造成重症及死亡的最主要因素。 已有许多的临床经验证明 APAP 的肝毒性是可以预防的，早期的诊断和实时的给予解毒剂 N-acetylcysteine简称 NAC可有效预防肝毒性的发生。
对乙酰胺基酚服药过量的早期发现是有必要的， 因为在中毒后的 8小时内 给予解毒剂可达到最佳的预后效果。 药物中毒的早期征兆包括身体不适、 恶 心和呕吐， 但有些病人对乙酰胺基酚的血中浓度已达中毒浓度且肝功能也有 明显异常， 初期仍无症状（第一期）， 肝毒性的征兆如腹痛、 持续呕吐、 黄胆、 右上腹疼痛等， 是在大量摄取后的 24~48小时才会变得比较明显 (第二期）。 血 清的转胺酶通常是在服用后的 16小时开始上升， 伴随着临床症状开始出现。 第三期大约是在服用后的 3-4天才开始出现， 此时肝损伤的程度和预后情形就 可以被预估出来。 肝毒性的症状可以从轻微的症状伴随着肝功能值上升 (AST > 1,000IU/L)到严重的猛暴性肝炎并发代谢性酸中毒、 黄疸、 低血糖、 AST > 10,000IU/L、 凝血异常及肝脑病变等。 第四期会引发寡尿性肾衰竭， 严重者会 导致死亡。
有些对乙酰胺基酚中毒的病人其肝脏的伤害很轻， 却有严重的肾毒性产 生， 主要是因 APAP直接在肾小管上的细胞色素 P-450s (cytochrome P450s, 简 称 C VPs)代谢造成肾毒性。但急性肾衰竭也有可能是因急性肝衰竭产生的肝肾 辨是原发性肾损伤 （FeNa > l) 或是肝肾症候群 （FeNa < 1)。 FeNa的计算公 式： (Sodiumurinary ÷ Creatinineurinary) ÷ (Sodiumplasma ÷ Creatinineplasma) χ 100。
对乙酰胺基酚口服后 1~2小时可达尖峰血中浓度， 大部份是从肝脏代谢， 90%以上是与 glucuronide和 sulfate结合形成无毒性的代谢产物。 只有小于 5%是 经由不同的 CYPs代谢， 包括： CYP2E1、 CYP1A2及 CYP3A4 , 其中 CYP2E1 与 CYP1A2是主要代谢酵素。 经由这些酵素代谢所产生的代谢产物 N-acetyl-p-benzoquinoneimine , 简称 NAPQI(如图 1 )是活性很强的亲电物质 (electrophile)。 在正常情况下， NAPQI会立即和细胞内的 glutathione反应形成 无毒的硫醇化合物 （mercaptide)。 当对乙酰胺基酚使用过量时， 使得细胞内 glutathione的消耗速率大于合成速率， 细胞内 glutathione含量低于正常的 30% 时， NAPQI便会和细胞内含有 cysteine的大分子或核苷酸结合， 导致肝细胞损 伤。 从细胞组织染色可以证明在肝细胞坏死前， NAPQI会和 cysteine的疏醇基 在肝小叶中心区域形成共价键结。
对于有肝脏疾病、酗酒、或是有服用会诱导肝脏细胞色素 P450酵素活性， ^口： Carbamazepine、 Ethanol、 Isoniazid、 Phenobarbital (可能是其他 barbiturates)、 Phenytoin、 Sulfinpyrazone、 Sulfonylureas ^ Rifampin、 Primidone等药物的病人 均属于会引起 APAP严重肝毒性的高危人群。 此时病人若有成人呼吸窘迫症候 群、 脑水肿、 无法控制的出血、 感染或多器管衰竭等并发症产生时， 就很容 易造成死亡。 以酒精为例， 酒精主要是由肝脏的 CYP2E1代谢， 其诱发 APAP 中毒的机转可分为三个阶段， 第一阶段是酒精和 APAP竟争肝脏 CYP2E1的接 受器， 此时 NAPQI的浓度会先降低， 第二阶段是酒精会使得 CYP2E1的半衰期 从 7小时延长到 37小时， 使得肝脏 CYP2E1的含量增加， 此时 NAPQI的浓度会 慢慢回升； 第三阶段是当酒精戒断时， 肝脏有较多的 CYP2E1来代谢对乙酰胺 基酚， 使得对乙酰胺基酚的毒性代谢产物明显增加， 造成肝细胞损伤。 近年 来研究证实， 利用 diallyl sulfide 可有效预防对乙酰胺基酚在小鼠体内所引起 的肝毒性伤害， 并进一步发现 diallyl sulfide具有抑制 CYP2E1酵素活性作用， 推论 diallyl sulfide预防对乙酰胺基酚引起的肝毒性的伤害， 其保护机制应是通 过抑制对乙酰胺基酚产生活性中间产物 NAPQI。
利用侵入式及非侵入式方法测试大鼠肝功能， 以监测肝损害的发展以及 筛选肝脏疾病， 其中最常使用的方法包含测量血清中的天门冬氨酸转胺酶 (aspartate aminotransferase, AST)、 丙氨酸转胺酶 (alanine aminotransferase, ALT) 以及碱性磷酸酶 (alkaline phosphatase)数值， 以及测量肝细胞产物如： 胆红素 (bilirubin)、 白蛋白 (albumin) , 以及利用量测前凝血素时间 (prothrombin time) 来检测凝血因子 (coagulation factors)等； 肝功能定量测试是根据几乎只经过肝 脏代谢的受质在血清中的浓度而定， 这些受质的清除是依肝门静脉、 肝动脉 血流量以及由肝细胞对这些受质的作用而定， 肝脏血流量与提供给肝脏的受 质量有关， 反之， 该受质的清除则决定于肝脏代谢的能力。
半乳糖 (galactose)是一种具有高萃取率 (extraction ratio)、 90%在肝脏中代 谢的醣类， 在肝脏中， 半乳糖是由半乳糖激酶 (galactokinase)经过差向立体异 构化反应（epimerization), 将其转换成 1-磚酸葡萄糖 (Glucose-1-phosphate); 半 乳糖激酶的作用反应为肝细胞中半乳糖代谢途径的速率决定步骤 (rate-limiting step)。 半乳糖的高萃取率使得依赖肝脏血流量及肝脏功能的半乳糖代谢作用 成为检测肝功能最主要的方式， 目前并无一定的规则来评估大鼠的残余肝功 能 (residual liver function), 量测一确切化合物 (如： 半乳糖)的代谢能力， 可推 测肝脏中一代谢作用的速率决定步骤， 亦可能取得残余肝功能的代表数质。
本案发明人以半乳糖单点法测试慢性肝炎、 肝硬化以及肝癌病患， 结果 显示半乳糖单点法可精确测出这些肝脏疾病； 半乳糖单点法已被成功的应用 到测试肝病患者排除如丙嗪 (promazine)及抗生素头孢酮 (cefoperazone)等药物 的剩余肝功能。 此外， 半乳糖单点法已在美国食品药物管理局 (FDA)所出版的 指南 (Guidance for Industry)中成为建议釆用测试肝功能的方法之一。 由此可见， 上述对乙酰胺基酚的习惯用法仍有诸多缺失， 并非优良设计， 而 待加以改良。 发明内容
本案发明人鉴于上述对乙酰胺基酚的习惯用法所导致肝毒性等副作用的 缺点， 极其想要加以改良创新， 并经多年研究后， 终于成功研发完成本件无 肝副作用的对乙酰胺基酚新复方。
本发明的目的即在于提供一种用以改善对乙酰胺基酚 (Acetaminophen, APAP)药物肝毒性的无肝副作用的新复方组合， 包含：（a)—药学有效量的对乙 酰胺基酚； 及 (b)—或两种以上可降低经肝脏酵素 CYP2E1代谢药物所产生肝 毒性的化合物。
为达成前述发明目的， 其中该化合物是选自下列群组中的至少一种或其 任意组合： 聚氧乙烯（20)山梨糖单月桂酸酯（Polyethylene glycol sorbitan monolaurate; Tween 20)、 微晶乡千维素 (Microcrystalline cellulose)、 碑酸氢二 4丐 (Dicalcium phosphate dihydrate)、 聚氧乙烯 23 月桂基醚 (Brij 35)、 糖精 (Saccharin), 甘露醇 (Mannitol)、 聚氧乙烯烷基醚 (Cremophor RH40)、 三氯蔗糖 (Sucralose)、 吡咯烷酮（Crospovidone)、 羟基乙酸淀粉钠（Sodium starch glycolate), 丙烯酸树脂 S100(Eudragit S100)、 羧曱基纤维素钠 (Croscarmellose sodium), 聚氧乙烯聚氧丙烯 (Pluronic F68)、 薄荷醇 (Menthol), 低取代烃丙纤 维素 (Low-substituted hydroxypropyl cellulos)、 予贞股化淀粉 (Pregelatinized starch)、 Dextrates NF hydrated , 柠檬酸 (Citric acid)、 蓖麻油聚氧乙烯醚 (Cremophor EL)、 胶态二氧化硅 (Aerosil 200)、 聚乙二醇单硬脂酸酯 (Myrj 52)、 山梨酸（Sorbic acid) , 柠檬油（Lemon oil)、 羟丙基纤维素（Hydroxypropyl cellulose)、 山梨糖醇 (Sorbitol)、 乙鲜舒泛钾 (Acesulfame potassium)、 羟丙曱纤 维素 酞酸酯 (Hydroxypropyl methylcellulose) 、 单水合乳糖 (Lactose monohydrate), 麦芽糖糊精 (Maltodextrin)、 Brij 58、 Brij 76、 Tween 80、 Tween 40、 PEG 400、 PEG 4000、 PEG 8000、 Span 60、 苯曱酸钠 (Sodium benzoate)、 羟乙曱纤维素酞酸酯（Hydroxy ethylmethylcellulose)、 曱纤维素酞酸酯 (Methylcellulose), Span 80、甜蜜素（Sodium cyclamate)、甘油山 酸酯 (Glyceryl behenate) , 氧化铁红 (Oxide red) , 甘油单硬脂酸酯（Glycerin monostearate)、 Copovidone K28、 淀粉醋酸酯（Starch acetate), 硬脂酸镁 (Magnesium stearate), 月桂基硫酸钠 (Sodium lauryl sulfate), Providone K30、 及 PEG 2000。
为达成前述发明目的， 其中该化合物组成是选自下列群组中的至少一种 或其任意组合， 并限定其组合物的有效使用剂量： 聚氧乙烯 (20)山梨糖单月桂 酸酉 (Polyethylene glycol sorbitan monolaurate; Tween 20)其中含量为 0.17-5.5 克、 微晶纤维素 (Microcrystalline cellulose)其中含量为 100~1000毫克、 磷酸氢 二钙 (Dicalcium phosphate dihydrate)其中含量为 10~250毫克、 聚氧乙烯 23月 桂基醚 (Brij 35)其中含量为 100~1000毫克、 糖精 (Saccharin)其中含量为 10~40 毫克、甘露醇 (Mannitol)其中含量为 10~250毫克、 聚氧乙烯烷基醚 (Cremophor RH40)其中含量为 0.17~5.5克、 三氯蔗糖 (Sucralose)其中含量为 10~250毫克、 吡咯烷酮 (Crospovidone)其中含量为 0.17~5.5 克、 羟基乙酸淀粉钠（Sodium starch glycolate)其中含量为 0.17~5.5克、 丙烯酸树脂 S100 (Eudragit S100)其中 含量为 0.17~5.5 克、 羧曱基纤维素钠 （Croscarmellose sodium)其中含量为 0.17~5.5克、 聚氧乙烯聚氧丙烯 (Pluronic F68) 其中含量为 1.4~5.5克、 薄荷 醇（Menthol)其中含量为 8~34 毫克、 低取代烃丙纤维素（Low-substituted hydroxypropyl cellulos)其中含量为 0.19~0.82 克、 预胶化淀粉 (Pregelatinized starch)其中含量为 1.7~5.5克、 Dextrates NF hydrated其中含量为 0.17~5.5克、 柠檬酸 (Citric acid)其中含量为 10~42毫克、 蓖麻油聚氧乙烯醚 (Cremophor EL) 其中含量为 1.7~5.5克、 胶态二氧化硅 (Aerosil 200)其中含量为 0.17~5.5克、 聚乙二醇单硬脂酸酯 (Myrj 52)其中含量为 1.4~5.5克、 山梨酸 (Sorbic acid)其中 含量为 6~24毫克、 柠檬油 (Lemon oil)其中含量为 0.17 5.5克、 羟丙基纤维素 (Hydroxypropyl cellulose)其中含量为 0.17~5.5克、 山梨糖醇 (Sorbitol)其中含量 为 0.17~5.5克、 乙鲜舒泛钾 (Acesulfame potassium)其中含量为 1.4~5.5克、 羟 丙曱纤维素酞酸酯 (Hydroxypropyl methylcellulose)其中含量为 0.17~5.5克、 单 水合乳糖（Lactose monohydrate)其中含量为 6~24 毫克、 麦芽糖糊精 (Maltodextrin)其中含量为 0.17~5.5克、 Brij 58其中含量为 0.17~5.5克、 Brij 76 其中含量为 0.17~5.5克、 Tween 80其中含量为 0.17~5.5克、 Tween 40其中含 量为 1.4~5.5克、？£0 400其中含量为 1.4~5.5克、 PEG 4000其中含量为 1.4-5.5 克、 PEG 8000其中含量为 1.4~5.5克、 Span 60其中含量为 1.4~5.5克、 苯曱 酸钠（Sodium benzoate)其中含量为 2.9~11.9 毫克、 羟乙曱纤维素酞酸酯 (Hydroxy ethylmethylcellulose)其中含量为 0.17~5.5 克、 曱纤维素酞酸酯 (Methylcellulose)其中含量为 0.17~5.5克、 Span 80其中含量为 1.4~5.5克、 甜 蜜素（Sodium cyclamate)其中含量为 3.3~13.2 毫克、 甘油山嵛酸酯 (Glyceryl behenate)其中含量为 17.4~69.9 毫克、 氧化铁红（Oxide red)其中含量为 11.3-45.2毫克、甘油单硬脂酸酯 (Glycerin monostearate)其中含量为 1.4~5.5克、 Copovidone K28其中含量为 0.17~5.5克、 淀粉醋酸酯 (Starch acetate)其中含量 为 0.17~5.5克、硬脂酸镁 (Magnesium stearate)其中含量为 9.7~39.0毫克、 月桂 基硫酸钠 (Sodium lauryl sulfate)其中含量为 4.7~19.0毫克、 Providone K30其中 含量为 0.18-0.73毫克、 及 PEG 2000其中含量为 1.4-5.5克。
为达成前述发明目的， 其中该化合物是选自甘露醇 (Mannitol)并用三氯蔗 糖 (Sucalose)组合为最佳。
为达成前述发明目的， 其中该组合是经分开、 同时或依序地使用。
为达成前述发明目的， 其中该对乙酰胺基酚和 /或可降低经肝脏酵素 CYP2E1代谢药物所产生肝毒性的化合物是系以胶、 喷剂、 软锭剂、锭剂或可 分散性片剂的形式投予。
为达成前述发明目的， 其中该组合被包含于医药包、 套组或病患包。 本发明的另一目的是系在于提供一种组合于制造治疗改善对乙酰胺基酚 药物肝毒性的无肝副作用的药剂上的用途。 附图说明
图 1为对乙酰胺基酚 (APAP)在肝脏中的代谢途径图; 图 2为 (A)正常对照组、 （B)APAP肝毒性组、 （C)碑酸氢二钙、 （D)甘露醇、 (E)薄荷醇、（F)三氯蔗糖、（G)甘露醇 +三氯蔗糖 （1.67+1.67 mg/kg)与 (H)甘露醇 +三氯蔗糖 （0.83+0.83 mg/kg)肝保护试验组， 于管喂单一剂量后大鼠肝脏组织 切片： （A)正常对照组肝组织型态； （B)在周围中央静脉 (V)的肝细胞呈现碎裂， 且有发炎细胞产生， 产生坏死现象及空泡化； 相较于 APAP肝毒性组， 肝保 护试验组大鼠， 除磷酸氢二钙试验组外， 其余试验组大鼠中央静脉周围肝细 胞较为完整， 细胞核明显， 且空泡较少 (D、 E、 F、 G、 H) , 又以 (F)、 （G)最 接近正常大鼠肝脏组织 （H&E染色， 200X)。 具体实施方式
本发明将就下列实施例作进一步说明， 然该等实施例仅为例示说明之用 , 而不应被解释为实施本发明的限制。
本案发明人鉴于上述对乙酰胺基酚的习惯用法所导致肝毒性等副作用的 缺点， 极其想要加以改良创新， 并经多年苦心孤诣潜心研究后， 终于成功研 发完成本件无肝副作用的对乙酰胺基酚新复方。
为达成上述发明目的的无肝副作用的对乙酰胺基酚新复方， 本发明首先 以对乙酰胺基酚新复方诱导大鼠产生肝毒性为模式， 研究合并使用一或其任 意组合的 CYP2E1 抑制剂对大鼠体内对乙酰胺基酚引发的肝毒性的影响； 除 使用一般肝毒性标记、 病理组织切片外， 以半乳糖单点法 (GSP)进行大鼠的残 余肝功能的定量量测， 进一步评估。
本说明书中所述的所有技术性及科学术语， 除非另外有所定义， 皆为所 属领域普通技术人员可共同了解的意义。
在用于本文中之时， 术语"组合物 (combination)", 在应用于两种或更多种 化合物和 /或药剂（在本文中也称为成分)之时， 意欲定义其中有该两种或更多 种化合物 /药剂结合的材料。 术语"组合"（"combined"和" combining")在本文中 皆据此诠释。
医药套组 (pharmaceutical kits)、 医药包 (pharmaceutical packs)或病患-包 (patient packs), 其中有两种或更多种化合物 /药剂经共-包装或共 -呈现 (如作为 单位剂批的部份者)。
本发明是以下面的实施例予以示范阐明， 但本发明不受下述实施例所限 制。 本发明所用的药物、 生物材料皆市售易于取得， 下列仅为示例可取得的 渠道。
实施例 1
对乙酰胺基酚合并使用一种或其任意组合安全、 药学上可接受的常用赋 型剂于改善药物肝毒性动物试验。
材料与方法
1. 试验材料
所有的有机溶剂均为 HPLC 等级， 购自 Tedia有限公司（Fairfield, OH, USA), APAP购自 Sigma化学公司（St. Louis, MO USA), 半乳糖注射溶液由南 光化学制药股份有限公司制备， 系将 400克半乳糖 (Sigma)溶于 1公升含有适 当緩冲溶液系统以及等张盐类的蒸馏水中， 供作注射使用。
2. 试一险动物
体重为 175-280公克的雄性 SD(Sprague-Dawley)大鼠购自国家实验动物中 心（台湾）， 动物实验是遵照国卫院动物实验指南进行， 所有的大鼠均置于空气 /湿度调节环境下， 光照与黑暗各 12小时， 水及饲料的供给不限， 在试验期间 大鼠体重均持续监测， 水分照常供给。
3. 试验处理
挑选于体外筛选 CYP2E1有效抑制剂， 进行 APAP不并服或并服抑制剂 于改善 APAP 引起肝毒性的动物试验。 肝毒性试验动物是以大鼠每公斤体重 管喂给予 APAP单一剂量 1000毫克以产生肝毒性。 肝保护实验动物是以大鼠 每公斤体重管喂给予磷酸氢二钙 1.67毫克；或每公斤体重管喂给予甘露醇 1.67 毫克； 或每公斤体重管喂给予薄荷醇 1.67 毫克； 或每公斤体重管喂给予 HUEXC041 1.67 毫克； 或每公斤体重管喂给予甘露醇 1.67 毫克与三氯蔗糖 1.67毫克； 或每公斤体重管喂给予甘露醇 0.83毫克与三氯蔗糖 0.83毫克； 或 每公斤体重管喂给予甘露醇 0.42毫克与三氯蔗糖 0.42毫克； 或每公斤体重管 喂给予甘露醇 0.17毫克与三氯蔗糖 0.17毫克， 并每公斤体重管喂给予 APAP 单一剂量 1000 毫克。 以测量血浆中的天门冬氨酸转胺酶 (AST)与丙氨酸转胺 酶 (ALT)来代表肝发炎指标； 于给药前与给药后 16 小时进行测定半乳糖单点 法 (GSP), 分析定量大鼠剩余肝功能； 同时分析每一组试验大鼠之肝脏组织病 理变化， 评估其肝损伤或肝保护的机制。
4. 血液样本
处理完毕后， 大鼠以乙酸麻醉牺牲， 血液由大鼠尾动脉抽取， 置于含有 EDTA的试管中， 血浆 (plasma)以 13,000g于 4°C离心 15分钟， 分离后的血浆 分装到微量小管 (Eppendorf tube)中并置于 -80°C中储存。
5. 生化分析
肝细胞损伤以量测血浆中天门冬氨酸转胺酶 (AST)与丙氨酸转胺酶 (ALT) 活性以进行定量， AST与 ALT活性是肝脏毒性常用的指标，系以 Synchron LXi 725系统来量测（Beckman Instruments, 美国）。
6. 光学显微镜
大鼠牺牲后肝脏随即进行组织学分析； 肝脏样本以 10%碑酸緩冲液配制 的福尔马林 (phosphate-buffered formalin)固定， 随后脱水并包埋于石蜡 (paraffin) 中， 以 5 μπι厚度切片， 切片样本以苏木精 (hematoxylin)与伊红 (eosin)染色， 并进行肝糖染色试验 (Periodic acid Schiff stain, PAS), 染色后以光学显微镜进 行组织学观察。
7. 肝功能的定量测试
试验结束后， 所有大鼠均进行半乳糖单点法 (GSP)测试， 大鼠接受在 30 秒内的快速静脉注射， 注射 0.4 g/ml BW半乳糖溶液 0.5 g/kg; 自注射后 5、 10、 15、 30、 45以及 60分钟各釆血一次， 血液样本取自尾部静脉； 以半乳糖 脱氢酶比色法 (colorimetric galactose dehydrogenase)量测半乳糖含量，测试浓度 范围为 50至 1,000 g/ml, 每个浓度的日内差异 (within-day variation)是由标准 偏差（standard deviation)以及变异系数 (coefficient of variation, CV)百分比计算， 最大容许的变异系数为 10% CV; 日间差异 (day-to-day variation)则由比较标准 检量线 (calibration curves)的斜率及截距来检验；半乳糖单点法 (GSP)为 30秒注 射停止后 60分钟时血液中半乳糖浓度。
8. 统计分析
所有的数据皆以平均士标准偏差 (SD)表示， 试验结果以单因子变异数分析 (ANOVA)测试法来计算是否具有统计上的显著差异，使用 Statistical Package of the Social Science program (Version 13, SPSS Inc.)软件包来计算； 随后使用事后 比较 (post hoc test)最小差异显著性 (least significant difference)方法 #丈多重比 较， 以确认族群间的显著差异； 族群平均的显著差异为；? < 0.05。
结果
1. 生化分析结果
试验结束时， 测量试验动物的体重及相对肝重量， 与正常对照组动物相 较之下并无显著差异； 血液生化分析结果如表 1所示， 除 APAP肝毒性组血 浆中的天门冬氨酸转胺酶 (AST)与丙氨酸转胺酶 (ALT)活性明显高于正常对照 组 (正常对照组血浆中的 AST活性为 202±34 IU/L; APAP肝毒性组血浆中的 AST活性为 499±112 KS/ , p < 0.005; 正常对照组血浆中的 ALT活性为 56士 14 IU/L; APAP肝毒性组血浆中的 ALT活性为 368士 71 IU/L, p < 0.005), 显示 APAP肝毒性组产生生化上的肝损伤； 除碑酸氢二钙试验组未如预期外， 此肝 损伤现象可被同时并用如甘露醇、 薄荷醇、 三氯蔗糖等常用安全赋形剂所改 善， 所测得肝发炎指标 AST、 ALT, GSP与代表病理组织切片肝病变严重程 度 Total HAI-score评估均有显著性地下降， 实验数据如表 1所示， 其中又以 甘露醇并用三氯蔗糖组合最佳， 与正常对照组无异。
表 1 正常对照组、 APAP肝毒性组及碑酸氢二钙、 甘露醇、 薄荷醇、 三 氯蔗糖等肝保护试验组小鼠， 于管喂单一剂量试验后， 半乳糖单点法 (GSP)分 析、 天门冬氨酸转胺酶 (AST)、 丙氨酸转胺酶 (ALT)活性与病理组织切片 Total HAI-score, 数值的计算为平均士 SD Liver function parameters GSP (mg/L) AST (IU/L) ALT (IU/L) Total
HAI- score
1. 正常对照组 （n=6) 289 ±38 202 ± 34 56 ± 14 0.0 ±0.0
2. APAP肝毒性组 （n=6) 848 ± 123 499 ± 112 368 ±71 4.9 ± 1.8
3. 碑酸氢二钙 （1.67
444 ± 60*** 315 ±42* 196 ±65* 3.1士 1.1* mg/kg) 试 -验组 (； n=6)
4. 甘露醇 （1.67 mg/kg)
253 ±29*** 201 ± 30*** 79士 34*** 0.8士 0.3*** 试验组 (n=6)
5. 薄荷醇 （1.67 mg/kg)
289 ± 20*** 187 ± 21*** 109±23*** 1.1士 1.2** 试验组 (n=6)
6. 三 氯蔗糖 (1.67
218 ±31*** 199 ± 24*** 83 ± 23*** 0.6 ± 0.4*** mg/kg) 试 -验组 (； n=6)
7. 甘露醇 + 三氯蔗糖
(1.67 + 1.67 mg/kg) 试验组 236 ±33*** 198 ± 37*** 59士 13*** 0.5士 0.4***
(n=6)
8. 甘露醇 + 三氯蔗糖
(0.83 + 0.83 mg/kg) 试验组 244 ± 19*** 190 ±23*** 65 ± 19*** 0.7 ±0.5***
(n=4)
9. 甘露醇 + 三氯蔗糖
(0.42 + 0.42 mg/kg) 试验组 281 ± 58*** 187 ± 41*** 96 ± 14*** 1.4士 1.7*
(n=4)
10.甘露醇 + 三氯蔗糖
(0.17 + 0.17 mg/kg) 试验组 371 ± 49*** 298 ± 49* 101±24*** 2.1士 1.2*
(n=4)
2. 组织病理学
所改善的结果也反映在相对应的肝脏组织， 在经过管喂单一口服剂量 1000 mg/kg APAP的大鼠， 其体内成功的产生肝毒性， APAP肝毒性组大鼠肝 脏组织切片， 中央静脉周围肝细胞呈现碎裂、 空泡化现象明显， 细胞核少， 甚至部分肝细胞产生坏死 (necrosis)征状， 相较于正常对照组肝细胞损伤严重 (如图 2B所示）； 相对的， 在正常对照组大鼠体内的肝结构则较正常， 其肝细 胞完整， 且排列整齐， 无空泡现象 (如图 2A所示)； 而甘露醇、 薄荷醇、 三氯 蔗糖等肝保护试验组大鼠肝组织切片结果显示， 肝细胞较完整， 细胞核明显 且空泡较少 (如图 2C、 D、 F、 G、 H所示）， 显示甘露醇、 薄荷醇、 三氯蔗糖 等肝保护试验组大鼠肝组织较接近正常大鼠肝脏组织， 其中以甘露醇并用三 氯蔗糖组合保护效果最好， 且与剂量呈正相关， 剂量愈高保护效果愈佳。
3. 剩余肝功能的量测
如表 1所示， 正常对照组与 APAP肝毒性组大鼠的半乳糖单点法 (GSP)值 具有高度的显著差异 (正常对照组大鼠的 GSP值为 289±38 mg/L; APAP肝毒 性组大鼠的 GSP值为 848±123 mg/L,;? < 0.005), 此外， 碑酸氢二钙、 甘露醇、 薄荷醇与三氯蔗糖等肝保护试验组大鼠的 GSP值各为 444±60 mg/L, 253±29 mg/L, 289士 20 mg/L、 218±31 mg/L, 与 APAP肝毒性组相较， 甘露醇、 薄荷 醇与三氯蔗糖等肝保护试验组大鼠的 GSP值各与 APAP肝毒性组大鼠具有高 度的显著差异（；？ < 0.005); 单独施用 APAP产生肝毒性大鼠的 GSP值明显增 加； 然而， 在 APAP合并施用甘露醇、 薄荷醇与三氯蔗糖等赋型剂的肝保护 试验组大鼠则可 4氏抗这种改变。
实施例二
细胞色素 P450 2E1 (CYP2E1)抑制剂的筛选-鼠肝微粒体与人肝微粒体。 材料与方法
1. 试验材料
本实施例是使用大鼠与人体物种肝脏制备微粒体进行 CYP2E1抑制剂的 体外筛选， 针对 55 种常见且安全可食用的赋型剂进行细胞色素 P450 2E1 (CYP2E1)抑制剂筛选， 筛选出对大鼠或人类肝脏的 CYP2E1有效抑制剂； 该 CYP2E1抑制剂筛选原理为：是利用物种肝脏所制备微粒体中 CYP2E1与其专 一性受质 Chlorzoxazone (CZX)反应， 加入测试样品作用后， 再侦测 CYP2E1 代谢物标准品 6-OH-CZX (6_Hydroxy-Chlorzoxazone)的生成量， 并以对照组 (control)的 6-OH-CZX生成量为基准， 计算测试样品的 CYP 2E1抑制率。
各测试样品均溶于 10%曱醇 (methanol)或是二次水中， 测试不同浓度的赋 形剂（66uM, 33uM, 16.5uM; 0.167%, 0.08%, 0.042%, w/v)对 CYP2E1的抑制率， 所测试的赋型剂结果如表 2所列。
本实施例利用大鼠肝脏或人类肝脏微粒体筛选细胞色素 CYP2E1 抑制剂 所需的药剂如下：
(1) CYP2E1： 100 mM potassium phosphate ( H 7.4)含有 10 mg/mL P450 protein concentration。
(2) Control Protein： 10 mg/mL P450 Protein 溶于 100 mM Potassium Phosphate (pH 7.4)中。
(3) Buffer Solution: 0.5 M Potassium Phosphate (pH 7.4)。
(4) Stop Solution: ice-acetonitrile。
(5) Cofactors： 含有 100 mM NADP+以及 10 mM Glucose 6-Phosphate。
(6) Glucose 6-Phosphate Dehydrogenase: 2000 units/ml溶于无菌 水。
(7) Chlorzoxazone: 受质 (substrate), 16 mM Chlorzoxazone溶于 10% 曱醇 (methanol)。
(8) DDTC (Diethyldithiocarbamic acid): CYP2E1选择性抑制剂 (阳性对照组） , 20 mM DDTC溶于 10%曱醇 （methanol)。
(9) NADPH-regenerating System: 于 3.42 mL 中加入 530 uL Cofactors、 40 uL G6PDH (Glucose 6-Phosphate Dehydrogenase Solution) 以及 100 uL Control Protein。
2. 细胞色素 P450 2E1 (CYP2E1)抑制剂的筛选
使用大鼠肝脏或人类肝脏微粒体进行细胞色素 CYP2E1抑制剂筛选的实 验步骤如下所述： (1) 在 4°C水浴环境下， 0.1M磷酸緩冲液（pH 7.4) 包含 0.5 mg/mL 鼠肝或人肝微粒体、 5 mM MgCl2静置 15分钟；
(2) 此时实验组加入细胞色素 P450 2E1 反应基质药物 16 mM Chlorzoxazone 以及欲筛选化合物； 对照组以曱醇： 无菌水 =1 : 1 取代； 阳性对照组则以 DDTC取代；
(3) 最后加入辅酶 1 mM NADP+、 10 mM G6P与 2 IU G6PD。 将反 应液转移至 37°C水浴预温 （pre-incubation) 1分钟， 活性测试实验的反应 时间为 30分钟；
(4) 反应完后以 500 acetonitrile终止反应， 样品静置 1分钟后加 入内部标准品 （5 ug/mL 4-hydroxy-tobutamide) , 离心后取上层液 20 uL , 以曱醇： 无菌水作稀释十倍动作， 取 5 uL的回溶液注入 LC/MS/MS系统 进行分析；
(5) 结果分析： 将 LC/MS/MS测得的讯号数值换算成为 CYP2E1代 谢物标准品 6-Hydroxy-Chlorzoxazone生成量 (pmol)后， 以对照组为基准， 即对照组的 CYP 2E1抑制率为 0%, 以下列公式计算各阳性对照组及试验 组的 CYP 2E1抑制率： 实验組 6«OH«CZ3生成量
CYP2I1抑制率 (%) [ 1 - ,,,,,,； j 100%
对照组 6-ΟΗ- ί生成量 结果
1. 阳' )·生对照组 阳性对照组 (DDTC)所测出的 CYP 2E1抑制率如表 2所示， 由表 2可知当 DDTC的浓度为 100 μΜ时， CYP 2E1抑制率可达 89.2%。
2. 试验组 CYP 2E1抑制率
赋型剂于鼠肝微粒体所测出的 CYP 2E1抑制率如表 2所示， 由结果可知 各赋型剂于不同浓度 (66μΜ, 33μΜ, 16.5μΜ; 0.167%, 0.08%, 0.042%, w/v)的条 件下，对细胞色素 P450 2E1具有不同程度的抑制效果，其中以 0.167% Brij 58 抑制效果最佳（100.0±0.00%)
表 2、 赋形剂于鼠肝微粒体体外筛选 CYP 2E1抑制剂的抑制率 赋形剂 CYP2E1抑制率 （％)
测试浓度 66 μΜ 33 μΜ 16.5 μΜ 对照组 0
(100 μΜ) (50 μΜ) (10 μΜ) 阳性对照组 (DDTC)
89.2 ±2.2 50.4 ± 1.1 8.6 ± 1.1
100.0 ±0.0 98.6 ±0.2 96.5 ±0.3
Brij 58
(0.167%) (0.084%) (0.042%)
100.0 ±0.0 98.5 ±0.1 97.5 ±0.3
Brij 76
(0.167%) (0.084%) (0.042%)
95.9 ±0.4 92.5 ±0.7 80.6 ± 1.9
Tween 20
(0.167%) (0.084%) (0.042%)
85.1 ±0.4 79.4 ± 1.4 68.2 ± 1.3
Tween 80
(0.167%) (0.084%) (0.042%) 微晶纤维素
78.7 ±2.8 75.0 ± 5.2 73.9 ± 1.8 Microcrystalline
(0.025%) (0.013%) (0.006%) cellulose
78.1 ± 1.4 71.5 ±0.5 54.0 ±3.2
Tween 40
(0.167%) (0.084%) (0.042%) 磷酸氢二钙
Dicalcium phosphate 76.7 ±0.8 62.0 ±2.6 55.0 ±4.6 dihydrate
糖精
67.4 ±3.9 59.6 ±3.3 35.3 ±2.0 Saccharin
67.2 ± 1.4 59.3 ±2.5 45.9 ±2.6
Brij 35
(0.025%) (0.013%) (0.006%) 甘露醇
60.6 ±3.3 51.0±2.7 40.9 ±2.8 Mannitol
聚氧乙烯烷基醚
57.4 ±3.2 49.4 ±2.9 48.0 ±2.1 Cremophor RH40 赋形剂 CYP2E1抑制率 （％)
测试浓度 66 μΜ 33 μΜ 16.5 μΜ 三氯蔗糖
54.0 ±4.2 46.8 ±0.8 41.1 ±2.7
Sucralose
52.5 ±4.6 43.4 ±3.0 35.1 ±2.2
PEG 400
(0.167%) (0.084%) (0.042%) 吡 烷酮
48.7 ±0.4 43.2 ±3.6 41.1 ±2.7 Crospovidone
48.1 ±2.4 39.4 ± 1.8 32.7 ±0.8
PEG 4000
(0.167%) (0.084%) (0.042%) 羟基乙酸淀粉钠 41.2 ±4.9 37.6 ±2.5 34.1 ±0.8 Sodium starch glycolate (0.167%) (0.084%) (0.042%) 丙烯酸树脂 SI 00 39.7 ±4.9 33.5 ±4.0 12.7 ± 1.9 Eudragit SI 00 (0.167%) (0.084%) (0.042%) 羧甲基纤维素钠 38.8 ±2.4 35.9 ±2.8 10.7 ±4.0 Croscarmellose sodium (0.167%) (0.084%) (0.024%) 聚氧乙烯聚氧 ¾烯 37.3 ±3.0 18.9± 1.4 14.9 ±0.9 Pluronic F68 (0.167%) (0.084%) (0.024%) 薄荷醇
36.4 ±0.3 15.3 ±7.9 7.2 ±2.9 Menthol
低取代烃丙纤维素
36.2 ±6.0 33.8 ± 1.4 28.7 ±2.2 Low- substituted
(0.025%) (0.013%) (0.006%) hydroxypropyl cellulose
预胶化淀粉 33.6 ±2.0 26.2 ±2.8 14.0 ±2.5 Pregelatinized starch (0.167%) (0.084%) (0.024%)
32.9 ±2.0 27.0 ±3.0 13.2 ±0.6
Dextrates, NF hydrate
(0.167%) (0.084%) (0.024%)
27.6 ±3.6 12.4 ±2.2 7.5 ±2.3
Citric acid
蓖麻油聚氧乙烯醚 25.2 ±2.7 12.9 ±2.2 5.9 ±0.3 Cremophor EL (0.167%) (0.084%) (0.024%) 赋形剂 CYP2E1抑制率 （％) 测试浓度 66 μΜ 33 μΜ 16.5 μΜ 胶态二氧化硅 23.8 ±2.4 22.8 ± 1.7 4.7 ± 1.2
Aerosil 200 (0.167%) (0.084%) (0.024%) 聚乙二醇单硬脂酸酯 20.5 ±0.3 18.5 ±0.6 17.5 ± 1.5 Myrj 52 (0.167%) (0.084%) (0.024%)
19.2 ±2.0 15.1 ±0.6 9.9 ±0.3
PEG 8000
(0.167%) (0.084%) (0.024%) 山梨酸
19.0 ± 5.6 13.2 ±4.4 12.1 ± 5.7 Sorbic acid
4宁樣油 18.2 ±3.7 13.9 ±2.9 9.7 ±3.8 Lemon oil (0.167%) (0.084%) (0.024%) 羟丙基纤维素 18.0 ±2.2 12.7 ± 1.9 6.7 ±0.7 Hydroxypropyl cellulose (0.167%) (0.084%) (0.024%)
17.1 ±0.8 15.2±2.1 15.1 ± 1.4
Span 60
(0.167%) (0.084%) (0.024%) 山梨糖醇 16.1 ±0.7 5.6 ±0.5 6.4 ±0.5 Sorbitol (0.167%) (0.084%) (0.024%) 苯甲酸钠
15.8 ±0.9 7.8 ±4.1 7.1 ±2.0 Sodium benzoate
乙鲜舒泛钾
14.5 ± 1.9 7.1 ±2.3 3.9 ±2.7 Acesulfame potassium
羟丙甲纤维素酞酸酯
13.9 ±2.2 13.6 ±2.6 6.7 ±0.7 Hydroxypropyl
(0.167%) (0.084%) (0.024%) methylcellulose
羟乙甲纤维素酞酸酯
11.6±0.9 13.2 ±0.6 5.6 ±0.5
Hydroxy
(0.167%) (0.084%) (0.024%) ethylmethylcellulose
甲纤维素酞酸酯 10.3 ± 1.7 5.2 ±0.3 5.0 ± 1.1 Methylcellulose (0.167%) (0.084%) (0.024%)
9.4 ±0.6 8.5 ± 1.3 10.6 ± 1.9
Span 80
(0.167%) (0.084%) (0.024%) 赋形剂 CYP2E1抑制率 （％)
测试浓度 66 μΜ 33 μΜ 16.5 μΜ 甜蜜素
9.1 ±2.6 5.7 ±4.7 9.4 ±2.7
Sodium cyclamate
单水合乳糖
8.7 ±3.8 7.8 ±2.2 3.9 ±2.3 Lactose monohydrate
麦芽糖糊精 8.5 ±2.8 5.9±2.1 9.7 ± 5.6 Maltodextrin (0.167%) (0.084%) (0.024%) 甘油山嵛酸酯
8.2 ±2.0 3.1 ±2.5 3.1 ±0.2 Glyceryl behenate
氧化铁红
8.5 ± 5.1 10.7 ±4.1 10.3 ±2.1 Oxide red
甘油单硬脂酸酯 6.9 ± 1.8 7.4 ±2.9 8.3 ± 5.7 Glycerin monostearate (0.167%) (0.084%) (0.024%)
6.1 ±0.7 4.5 ±0.5 4.3 ±0.2
Copovidone K28
(0.167%) (0.084%) (0.024%)
/疋物 日 5.3 ±0.7 4.9 ± 1.2 5.5 ± 1.2
Starch acetate (0.167%) (0.084%) (0.024%) 硬脂酸镁
5.0 ± 1.6 3.0 ±0.7 2.0 ± 1.0 Magnesium stearate
月桂基硫酸钠
4.8 ± 1.2 6.4 ±0.9 4.6 ± 1.1 Sodium lauryl sulfate
Providone K30 3.2 ±0.2 2.2 ±0.1 4.7 ± 1.0 苯甲醇 -10.3 ±6.3 6.7 ± 1.0 8.2 ±2.0 Benzyl alcohol (0.167%) (0.084%) (0.024%) 对羟基苯甲酸甲酯钠
-21.5 ±2.0 -14.6 ±4.1 4.6 ±3.2 Methylparaben
对羟基苯甲酸丙酯
-27.3 ±3.7 -17.2 ±2.4 -4.1 ± 1.2 Propylparaben
-35.5 ±4.3 -21.0 ±4.8 -9.3 ±0.8
SolutolH15
(0.167%) (0.084%) (0.042%) 赋形剂 CYP2E1抑制率 （％)
测试浓度 66 μΜ 33 μΜ 16.5 μΜ
丁基羟基茴香醚
-85.5 ±3.9 -47.1 ± 5.3 -16.8 ±2.5
Butylated hydroxylanisol
赋型剂于人肝微粒体所测出的 CYP 2E1抑制率如表 3所示， 由结果可知 各赋型剂于不同浓度 (66μΜ, 33μΜ, 16.5μΜ; 0.167%, 0.08%, 0.042%, w/v)的条 件下，对细胞色素 P4502E1具有不同程度的抑制效果，其中以 0.167% Brij 58 抑制效果最佳 (91.2±1.3%)。
表 3、 赋形剂于人肝微粒体体外筛选 CYP 2E1抑制剂之抑制率
赋形剂 CYP2E1抑制率 （％)
测试浓度 66 μΜ 33 μΜ 16.5 μΜ
对照组 0
(100 μΜ) (50 μΜ) (10 μΜ) 阳性对照组 (DDTC)
89.6 ±0.9 49.8 ±2.9 7.3 ± 1.0
91.2± 1.3 80.5 ± 1.1 62.6 ±2.1
Brij 58
(0.167%) (0.084%) (0.042%)
86.2 ± 1.3 75.7 ± 1.6 69.0 ±3.8
Brij 76
(0.167%) (0.084%) (0.042%) 糖精
78.5 ±2.1 51.2±0.9 29.4 ±2.7
Saccharin
77.3 ± 1.0 73.0 ± 1.7 42.4 ± 1.8
Brij 35
(0.025%) (0.013%) (0.006%)
75.4 ±3.6 70.4 ±0.9 55.4 ± 1.9
Tween 20
(0.167%) (0.084%) (0.042%)
64.2 ± 1.5 54.8 ±3.5 26.4 ± 1.8
PEG 400
(0.167%) (0.084%) (0.042%) 微晶纤维素
60.2 ±4.1 54.4 ±3.8 48.8 ±0.2
Microcrystalline
(0.025%) (0.013%) (0.006%) cellulose 赋形剂 CYP2E1抑制率 （％)
测试浓度 66 μΜ 33 μΜ 16.5 μΜ 磷酸氢二钙
Dicalcium phosphate 60.1 ±0.3 56.8 ±2.2 31.2±2.9 dihydrat
三氯蔗糖
55.8 ±2.0 45.8 ±4.0 37.1 ±2.8 Sucralose
甘露醇
54.5 ±4.2 51.2±2.1 44.8 ± 1.8 Mannitol
聚氧乙烯烷基醚
50.4 ± 1.1 43.2±3.1 30.2 ±2.8 Cremophor RH40
羟基乙酸淀粉钠 49.1 ±2.9 31.4± 5.2 38.9 ± 1.3 Sodium starch glycolate (0.167%) (0.084%) (0.042%)
47.5 ± 1.5 41.4 ± 1.6 22.3 ± 1.9
PEG 2000
(0.167%) (0.084%) (0.042%)
47.1 ±0.9 23.9 ±2.9 8.7± 1.8
PEG 4000
(0.167%) (0.084%) (0.042%)
46.3 ±3.1 33.4 ±2.7 16.9 ± 1.2
Tween 40
(0.167%) (0.084%) (0.042%) 吡 烷酮 44.1 ±0.9 40.3 ±3.3 35.6± 1.8 Crospovidone (0.167%) (0.084%) (0.042%)
39.1 ±2.4 40.6 ±3.8 29.0 ± 1.7
Tween 80
(0.167%) (0.084%) (0.042%) 丙烯酸树脂 SI 00 38.3 ±0.1 35.6 ±2.4 23.2 ±3.5 Eudragit SI 00 (0.167%) (0.084%) (0.042%) 羧甲基纤维素钠 35.4 ±4.8 30.3 ± 5.4 8.1 ±2.3 Croscarmellose sodium (0.025%) (0.013%) (0.006%) 聚氧乙烯聚氧 ¾烯 31.5 ± 1.6 17.4 ±4.2 7.9 ±0.8 Pluronic F68 (0.025%) (0.013%) (0.006%) 薄荷醇 30.8 ±0.3 20.8 ±2.1 10.5 ±0.4 Menthol 赋形剂 CYP2E1抑制率 （％)
测试浓度 66 μΜ 33 μΜ 16.5 μΜ
低取代烃丙纤维素 22.1 ±3.7 20.3 ± 1.8 17.5 ±2.9
Low- substituted (0.025%) (0.013%) (0.006%) hydroxypropyl cellulose
21.1 ±4.4 14.2 ±3.6 9.4 ±0.2
PEG 8000
(0.167%) (0.084%) (0.024%) 柠檬酸 20.5 ± 1.8 15.5 ± 1.5 9.9±3.1
Citric acid
蓖麻油聚氧乙烯醚 19.2 ±0.5 15.1 ±2.2 8.1 ±0.6
Cremophor EL (0.167%) (0.084%) (0.024%)
19.2 ± 1.1 14.4 ±3.2 12.9 ±0.6
Dextrates, F hydrate
(0.167%) (0.084%) (0.024%) 预胶化淀粉 18.3 ±2.4 12.8 ±0.8 9.9 ±0.1
Pregelatinized starch (0.167%) (0.084%) (0.024%) 聚乙二醇单硬脂酸酯 18.1 ±2.6 15.7 ±2.8 14.6 ± 1.7
Myrj 52 (0.167%) (0.084%) (0.024%)
17.4 ±0.9 13.9 ±0.7 12.4 ±2.3
Span 60
(0.167%) (0.084%) (0.024%) 胶态二氧化硅 15.7±3.4 17.8±2.1 7.8 ±0.4
Aerosil 200 (0.167%) (0.084%) (0.024%)
山梨酸 14.8 ±0.1 10.9 ±2.7 8.4 ± 1.6
Sorbic acid
10.1 ±2.1 5.7 ±4.7 9.4 ±2.7
Span 80
(0.167%) (0.084%) (0.024%)
4宁樣油 7.8 ±0.3 9.8 ±0.4 8.8 ± 1.1
Lemon oil (0.167%) (0.084%) (0.024%)
用以改善对乙酰胺基酚 (Acetaminophen, APAP)药物肝毒性的无肝副作用 的新复方组合，各赋型剂于不同浓度 (66μΜ, 33μΜ, 16.5μΜ)的条件下的有效使 用剂量范围分别为： 聚氧乙烯 (20)山梨糖单月桂酸酯 (Polyethylene glycol sorbitan monolaurate； Tween 20)其中含量为 0.17~5.5 克、 微晶纤维素 (Microcrystalline cellulose)其中含量为 100~1000毫克、 磚酸氢二钙 (Dicalcium phosphate dihydrate)其中含量为 10~250毫克、 聚氧乙烯 23月桂基醚 (Brij 35) 其中含量为 100~1000毫克、 糖精 (Saccharin)其中含量为 10~40毫克、 甘露醇 (Mannitol)其中含量为 10~250毫克、聚氧乙烯烷基醚 (Cremophor RH40)其中含 量为 0.17~5.5 克、 三氯蔗糖 (Sucralose)其中含量为 10~250 毫克、 吡咯烷酮 (Crospovidone)其中含量为 0.17~5.5 克、 羟基乙酸淀粉钠（Sodium starch glycolate)其中含量为 0.17~5.5克、 丙烯酸树脂 S100 (Eudragit S100)其中含量 为 0.17~5.5克、 羧曱基纤维素钠 （Croscarmellose sodium)其中含量为 0.17~5.5 克、聚氧乙烯聚氧丙烯 （Pluronic F68) 其中含量为 1.4~5.5克、薄荷醇 (Menthol) 其中含量为 8~34 毫克、 低取代烃丙纤维素（Low-substituted hydroxypropyl cellulos)其中含量为 0.19~0.82克、 预胶化淀粉 (Pregelatinized starch)其中含量 为 1.7~5.5克、 Dextrates NF hydrated其中含量为 0.17~5.5克、柠檬酸 (Citric acid) 其中含量为 10~42毫克、蓖麻油聚氧乙烯醚 (Cremophor EL)其中含量为 1.7~5.5 克、 胶态二氧化硅 (Aerosil 200)其中含量为 0.17~5.5克、 聚乙二醇单硬脂酸酯 (Myrj 52)其中含量为 1.4~5.5克、 山梨酸 (Sorbic acid)其中含量为 6~24毫克、 柠檬油（Lemon oil)其中含量为 0.17~5.5 克、 羟丙基纤维素（Hydroxypropyl cellulose)其中含量为 0.17~5.5克、 山梨糖醇 (Sorbitol)其中含量为 0.17~5.5克、 乙鲜舒泛钾 (Acesulfame potassium)其中含量为 1.4~5.5克、 羟丙曱纤维素酞酸 酉^ Hydroxypropyl methylcellulose)其中含量为 0.17~5.5克、单水合乳糖 (Lactose monohydrate)其中含量为 6~24 毫克、 麦芽糖糊精 (Maltodextrin)其中含量为 0.17-5.5克、 Brij 58其中含量为 0.17~5.5克、 Brij 76其中含量为 0.17~5.5克、 Tween 80其中含量为 0.17~5.5克、 Tween 40其中含量为 1.4~5.5克、 PEG 400 其中含量为 1.4-5.5克、 PEG 4000其中含量为 1.4-5.5克、 PEG 8000其中含量 为 1.4~5.5克、 Span 60其中含量为 1.4~5.5克、 苯曱酸钠 (Sodium benzoate)其 中含量为 2.9~11.9 毫克、 羟乙曱纤维素酞酸酯 (Hydroxy ethylmethylcellulose) 其中含量为 0.17~5.5克、曱纤维素酞酸酯 (Methylcellulose)其中含量为 0.17~5.5 克、 Span 80 其中含量为 1.4~5.5 克、 甜蜜素 (Sodium cyclamate)其中含量为 3.3~13.2毫克、 甘油山嵛酸酯 (Glyceryl behenate)其中含量为 17.4~69.9毫克、 氧化铁红 (Oxide red)其中含量为 11.3~45.2 毫克、 甘油单硬脂酸酯 (Glycerin monostearate)其中含量为 1.4~5.5克、 Copovidone K28其中含量为 0.17~5.5克、 淀粉醋酸酯（Starch acetate)其中含量为 0.17~5.5 克、 硬脂酸镁 (Magnesium stearate)其中含量为 9.7~39.0毫克、月桂基硫酸钠 (Sodium lauryl sulfate)其中含 量为 4.7-19.0毫克、 Providone K30其中含量为 0.18-0.73毫克、 及 PEG 2000 其中含量为 1.4~5.5克。
本发明所提供的无肝副作用的对乙酰胺基酚新复方， 与单独使用对乙酰 胺基酚的试验结果相互比较时， 在生化分析 (ALT、 AST值)、 病理学分析及剩 余肝功能的量测 (GSP值)等各方面的分析结果，都有明显减少使用对乙酰胺基 酚所造成的肝毒性副作用的功效。
上列详细说明是针对本发明的一可行实施例的具体说明， 但该实施例并 非用以限制本发明的保护范围， 凡未脱离本发明技艺精神所作出的等效实施 或变更，例如：对乙酰胺基酚、细胞色素 P450 2E1抑制剂、细胞色素 P450 2E1 抑制剂选用的种类、 施用浓度及比例， 以及等变化的等效性实施例， 均应包 含于本案的保护范围中。
综上所述， 本案不但在对乙酰胺基酚的应用上确属创新， 并以并用常见 且安全的常用赋型剂能来确实改善因使用对乙酰胺基酚所造成的肝毒性副作 用。

Claims

权 利 要 求
1.一种用以改善对乙酰胺基酚 (Acetaminophen, APAP)药物肝毒性的无肝 副作用的新复方组合， 包含：
(a)—药学有效量的对乙酰胺基酚； 及
(b)—或两种以上可降低经肝脏酵素 CYP2E1代谢药物所产生肝毒性的化 合物。
2.如权利要求 1 所述的用以改善对乙酰胺基酚药物肝毒性的无肝副作用 的新复方组合， 其中该化合物是选自下列群组中的至少一种或其任意组合： 聚氧乙烯 (20)山梨糖单月桂酸酯 (Polyethylene glycol sorbitan monolaurate； Tween 20)、 微晶纤维素（Microcrystalline cellulose) , 磚酸氢二钙（Dicalcium phosphate dihydrate), 聚氧乙烯 23月桂基醚 (Brij 35)、 糖精 (Saccharin)、 甘露 醇 (Mannitol)、 聚氧乙烯烷基醚 (Cremophor RH40)、 三氯蔗糖 (Sucralose)、 吡咯 烷酮 (Crospovidone)、 羟基乙酸淀粉钠（Sodium starch glycolate), 丙烯酸树脂 S100(Eudragit S100), 羧曱基纤维素钠 (Croscarmellose sodium)、 聚氧乙烯聚氧 丙婦 (Pluronic F68)、 薄荷醇 (Menthol)、 低取代烃丙纤维素（Low-substituted hydroxypropyl cellulos)、 予贞股化淀粉 (Pregelatinized starch)、 Dextrates NF hydrated, 柠檬酸 (Citric acid), 蓖麻油聚氧乙烯醚 (Cremophor EL)、 胶态二氧 化硅 (Aerosil 200)、 聚乙二醇单硬脂酸酯 (Myrj 52)、 山梨酸 (Sorbic acid)、 柠檬 油 (Lemon oil), 羟丙基纤维素 (Hydroxypropyl cellulose), 山梨糖醇（Sorbitol), 乙鲜舒泛钾 (Acesulfame potassium)、 幾丙曱纤维素 酸酯 (Hydroxypropyl methylcellulose)、单水合乳糖 (Lactose monohydrate)、麦芽糖糊精 (Maltodextrin)、 Brij 58、 Brij 76 , Tween 80、 Tween 40、 PEG 400、 PEG 4000、 PEG 8000、 Span 60、 苯曱酸钠（Sodium benzoate)、 羟 乙 曱纤维素酞酸酯（Hydroxy ethylmethylcellulose) , 曱纤维素酞酸酯 (Methylcellulose)、 Span 80、 甜蜜素 (Sodium cyclamate) . 甘油山备酸醋 (Glyceryl behenate)、 氧化铁红 (Oxide red)、 甘油单硬脂酸酯 (Glycerin monostearate)、 Copovidone K28、 淀粉醋酸酯 (Starch acetate)、 硬月旨酸镁 (Magnesium stearate) . 月桂基石克酸 ] (Sodium lauryl sulfate)、 Providone K30、 及 PEG 2000。
3.如权利要求 2所述的用以改善对乙酰胺基酚 (Acetaminophen, APAP)药 物肝毒性的无肝副作用的新复方组合， 其中该化合物组成是选自下列群组中 的至少一种或其任意组合， 并限定其组合物的有效使用剂量： 聚氧乙烯 (20) 山梨糖单月桂酸酯 (Polyethylene glycol sorbitan monolaurate; Tween 20)其中含 量为 0.17~5.5克、 微晶纤维素 (Microcrystalline cellulose)其中含量为 100~1000 毫克、磚酸氢二钙 (Dicalcium phosphate dihydrate)其中含量为 10~250毫克、 聚 氧乙烯 23月桂基醚 (Brij 35)其中含量为 100~1000毫克、 糖精 (Saccharin)其中 含量为 10~40毫克、 甘露醇 (Mannitol)其中含量为 10~250毫克、 聚氧乙烯烷 基醚 (Cremophor RH40)其中含量为 0.17~5.5克、 三氯蔗糖 (Sucralose)其中含量 为 10~250毫克、吡咯烷酮 (Crospovidone)其中含量为 0.17~5.5克、羟基乙酸淀 粉钠（Sodium starch glycolate)其中含量为 0.17~5.5 克、 丙烯酸树脂 S100 (Eudragit S100)其中含量为 0.17~5.5 克、 羧曱基纤维素钠 （Croscarmellose sodium)其中含量为 0.17~5.5克、 聚氧乙烯聚氧丙烯 （Pluronic F68) 其中含量 为 1.4~5.5 克、 薄荷醇 (Menthol)其中含量为 8~34 毫克、 低取代烃丙纤维素 (Low-substituted hydroxypropyl cellulos)其中含量为 0.19~0.82克、 预胶化淀粉 (Pregelatinized starch)其中含量为 1.7 5.5克、 Dextrates NF hydrated其中含量 为 0.17~5.5克、 柠檬酸 (Citric acid)其中含量为 10~42毫克、 蓖麻油聚氧乙烯 醚 (Cremophor EL)其中含量为 1.7~5.5克、胶态二氧化硅 (Aerosil 200)其中含量 为 0.17~5.5克、 聚乙二醇单硬脂酸酯 (Myrj 52)其中含量为 1.4~5.5克、 山梨酸 (Sorbic acid)其中含量为 6~24毫克、柠檬油 (Lemon oil)其中含量为 0.17~5.5克、 羟丙基纤维素 (Hydroxypropyl cellulose)其中含量为 0.17~5.5 克、 山梨糖醇 (Sorbitol)其中含量为 0.17~5.5克、 乙鲜舒泛钾 (Acesulfame potassium)其中含量 为 1.4~5.5克、 羟丙曱纤维素酞酸酯 (Hydroxypropyl methylcellulose)其中含量 为 0.17~5.5克、单水合乳糖 (Lactose monohydrate)其中含量为 6~24毫克、麦芽 糖糊精 (Maltodextrin)其中含量为 0.17~5.5克、 Brij 58其中含量为 0.17~5.5克、 Brij 76其中含量为 0.17-5.5克、 Tween 80其中含量为 0.17-5.5克、 Tween 40 其中含量为 1.4~5.5克、 PEG 400其中含量为 1.4~5.5克、 PEG 4000其中含量 为 1.4~5.5克、 PEG 8000其中含量为 1.4~5.5克、 Span 60其中含量为 1.4~5.5 克、 苯曱酸钠 (Sodium benzoate)其中含量为 2.9~11.9毫克、 羟乙曱纤维素酞酸 酯 (Hydroxy ethylmethylcellulose)其中含量为 0.17~5.5 克、 曱纤维素酞酸酯 (Methylcellulose)其中含量为 0.17~5.5克、 Span 80其中含量为 1.4~5.5克、 甜 蜜素（Sodium cyclamate)其中含量为 3.3~13.2 毫克、 甘油山嵛酸酯 (Glyceryl behenate)其中含量为 17.4~69.9 毫克、 氧化铁红（Oxide red)其中含量为 11.3-45.2毫克、甘油单硬脂酸酯 (Glycerin monostearate)其中含量为 1.4~5.5克、 Copovidone K28其中含量为 0.17~5.5克、 淀粉醋酸酯 (Starch acetate)其中含量 为 0.17~5.5克、硬脂酸镁 (Magnesium stearate)其中含量为 9.7~39.0毫克、 月桂 基硫酸钠 (Sodium lauryl sulfate)其中含量为 4.7~19.0毫克、 Providone K30其中 含量为 0.18-0.73毫克、 及 PEG 2000其中含量为 1.4-5.5克。
4.如权利要求 2所述的用以改善对乙酰胺基酚 (Acetaminophen, APAP)药 物肝毒性的无肝副作用的化合物组合， 其中该化合物是选自甘露醇 (Mannitol) 并用三氯蔗糖 (Sucalose)组合为最佳。
5.如权利要求 1 所述的用以改善对乙酰胺基酚药物肝毒性的无肝副作用 的新复方组合， 其中该组合是经分开、 同时或依序地使用。
6.如权利要求 1 所述的用以改善对乙酰胺基酚药物肝毒性的无肝副作用 的新复方组合， 其中该对乙酰胺基酚和 /或可降低经肝脏酵素 CYP2E1代谢药 物所产生肝毒性的化合物是以胶、 喷剂、 软锭剂、 锭剂或可分散性片剂的形 式投予。
7.如权利要求 1 所述的用以改善对乙酰胺基酚药物肝毒性的无肝副作用 的新复方组合， 其中该组合被包含于医药包、 套组或病患包。
8.—种如权利要求 1 所述的组合在制造治疗改善对乙酰胺基酚药物肝毒 性的无肝副作用的药剂上的用途。
PCT/CN2013/087049 2013-11-13 2013-11-13 无肝副作用的对乙酰胺基酚新复方组合 WO2015070396A1 (zh)

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