CN102755350A - Refined seal oil and application thereof to preparation of medicament for treating non-alcoholic fatty liver - Google Patents
Refined seal oil and application thereof to preparation of medicament for treating non-alcoholic fatty liver Download PDFInfo
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Abstract
The invention discloses refined seal oil, which is characterized in that: an omega-3 polyunsaturated fatty acid in the refined seal oil consists of the following components in percentage by weight: 4.64-5.03 percent of eicosapentaenoic acid (EPA) C20H30O2, 3.86-4.18 percent of docosapentaenoic acid (DPA) C22H34O2 and 9.5-10.29 percent of docosahexenoic acid (DHA) C22H32O2. The invention further discloses an application of the refined seal oil to preparation of a medicament for treating non-alcoholic fatty liver. The refined seal oil disclosed by the invention can be used for treating non-alcoholic fatty liver, and can also be used for effectively reducing total cholesterol and triglyceride in blood serum.
Description
Technical field
The present invention relates to a kind of refined fur seal and the application in the medicine of preparation treatment non-alcoholic fatty liver disease thereof.The present invention also relates to this refined fur seal and reduce the application in the medicine of T-CHOL in the serum or triglyceride in preparation.
Background technology
Adeps Phocae vitulinae (harp seal oil) is commonly called as seal oil, is that the fat deposit of the mammal fur seal from waters, deep-sea high and cold (50 ℃) refines the oil of processing.Fur seal is with famous and precious morrhua; Salmon fish etc. are food; The thick fat deposit of enrichment in the body; Be rich in omega-3 polyunsaturated fatty acids (EPA, DPA, DHA) in the Adeps Phocae vitulinae, the natural ecological environment of the pollution-free cleaning in the arctic in addition, Adeps Phocae vitulinae becomes the important source of optimal omega-3 unsaturated fatty acid in the Nature.It has the liver protecting, blood lipid regulation etc. and acts on existing report in some documents, has caused the great attention of domestic and international field of medicaments.
Unsaturated fatty acid is one type of extremely important fatty acid, and it comprises ω-3 and ω-6 series, but human body can not synthesize, must be through the biological approach picked-up, and the former is from marine animal (fish, fur seal etc.), and the latter is from vegetable oil (like Semen arachidis hypogaeae, Oleum Glycines etc.).Find that after deliberation ω-3 and ω-6 series must keep suitable ratio just can keep the normal physiological activity of human body.WHO thinks that the optimal proportion of ω-3 and ω-6 is 1:4, and the modern diet structure often causes people's omega-3 unsaturated fatty acid Deficiency of Intake, and the large-scale statistical data shows that interior this ratio substantial deviation of present human body is to 1:25, even 1:30.In view of the above, WHO and FAO (Food and Agriculture Organization of the United Nation) issue a statement: in view of the importance and the human general lacking of product itself, need promote the serial unsaturated fatty acid of ω-3 at world wide.Because the fur seal and the mankind belong to mammal together; The ω that fur seal provides-3 is identical with the chemical molecular structure of human body; Can be absorption of human body and utilization directly, and Fish are rudimentary cold blooded animals, its available ω-3 must transform the rear through liver can be absorption of human body and utilization.
Fatty liver is meant the pathological changes of fatty overheap in the hepatocyte that causes owing to a variety of causes.The positive serious threat compatriots' of fatty liver disease health becomes the second largest hepatopathy that is only second to viral hepatitis, has been acknowledged as the common cause of disguised liver cirrhosis.Fatty liver is a kind of common clinical picture, but not a kind of independently disease.If the untimely treatment of fatty liver probably causes fat hepatitis, liver cirrhosis, even hepatocarcinoma.
The detection means of fatty liver is numerous at present, but can accurately judge what fatty liver degree and reverse changed, is " liver/spleen CT value ", belongs to the association in " flat the sweeping of the conventional CT of epigastrium " />.Data show: 0.7 < liver/>spleen CT value≤1 is slight fatty liver, and 0.5 < liverspleen CT value≤0.7 is the moderate fatty liver, and liver/spleen CT value≤0.5 is severe fatty liver liver/spleen, and the CT value is the most accurately to detect the scientific method of fatty liver at present.
Authorized disclosed application number to disclose the application of Adeps Phocae vitulinae as preparation treatment fatty liver medicine for the Chinese invention patent application of " 01135517.4 " on April 12nd, 2006, but the needed dosage of this Adeps Phocae vitulinae is big, this medicine is too expensive for the patient.
Therefore, develop for the patient having of relatively economical as soon as possible and treat fatty liver effectively, non-alcoholic fatty liver disease especially, particularly the medicine of severe non-alcoholic fatty liver disease is very important.
Summary of the invention
The object of the present invention is to provide a kind of refined fur seal of low omega-3 unsaturated fatty acid content, it can treat non-alcoholic fatty liver disease effectively with lower dosage, especially the severe non-alcoholic fatty liver disease.
In order to achieve the above object, the invention provides a kind of refined fur seal, it is characterized in that: the weight percent content of omega-3 polyunsaturated fatty acids is respectively in this refined fur seal:
Eicosapentaenoic acid (C
20H
30O
2, EPA): 4.64%-5.03%;
DPA DOCOSA-PENTENOIC ACID (C
22H
34O
2, DPA): 3.86%-4.18%;
Docosahexenoic acid (C
22H
32O
2, DHA): 9.5%-10.29%.
Further, the present invention also provides the application of this refined fur seal in the medicine of preparation treatment non-alcoholic fatty liver disease.
Further; Non-alcoholic fatty liver disease described in the application of this refined fur seal of the present invention in the medicine of preparation treatment non-alcoholic fatty liver disease is slight, moderate or severe non-alcoholic fatty liver disease; Wherein 0.7 < liver/>spleen CT value≤1 is slight non-alcoholic fatty liver disease; 0.5 < liver/>spleen CT value≤0.7 is the moderate non-alcoholic fatty liver disease, and liver/spleen CT value≤0.5 is the severe non-alcoholic fatty liver disease.
Further, the day taking dose of the refined fur seal described in the application of this refined fur seal of the present invention in the medicine of preparation treatment non-alcoholic fatty liver disease is 33mg/kg-111mg/kg.
Further, the day taking dose of the refined fur seal described in the application of this refined fur seal of the present invention in the medicine of preparation treatment non-alcoholic fatty liver disease is 0.036ml/kg-0.121ml/kg.
The present invention also provides this refined fur seal to reduce the application in the medicine of T-CHOL in the serum or triglyceride in preparation.
Further, this refined fur seal is 33mg/kg-111mg/kg at the day taking dose that preparation reduces the refined fur seal described in the application in the medicine of T-CHOL in the serum or triglyceride.
Further, this refined fur seal is 0.036ml/kg-0.121ml/kg at the day taking dose that preparation reduces the refined fur seal described in the application in the medicine of T-CHOL in the serum or triglyceride.
Refined fur seal of the present invention just can reach the treatment non-alcoholic fatty liver disease with lower omega-3 polyunsaturated fatty acids content and lower day taking dose; Especially the effect of severe non-alcoholic fatty liver disease also can reduce T-CHOL and triglyceride in the serum effectively.The raw material of the range of choice for to(for) enterprise is wider, can reduce the production of medicine cost, reduces the price of medicine, and then alleviates patient's financial burden.
The specific embodiment
No. 201110263392.7 patent applications of application number that the method for preparing of Adeps Phocae vitulinae of the present invention is submitted on JIUYUE 7th, 2011 with reference to this case applicant, this public announcement of a patent application day is on February 8th, 2012.Can certainly use other method for preparing known in the art and carry out the preparation of Adeps Phocae vitulinae of the present invention.
Embodiment 1: the preparation of refined fur seal
Equipment: adopt the EA250/KD200 single-stage short-range molecular distillation of German UIC manufactured to extract equipment.
I. preparation flow is following:
1. 100kg fur seal Animal fat is shredded;
2. the warm water of the fur seal Animal fat that shreds with 40 ℃ of temperature is cleaned;
3. put into the oil water separator centrifugalize after the fur seal Animal fat cleaning with chopping and obtain isolating water and fatty raw material;
4. isolated water in the step 3 is filtered the fatty raw material that obtains water and centrifugalize omission, the fatty raw material that centrifugalize is omitted adds in the fatty raw material;
5. unlatching molecular still, when system vacuum reached 0.001mbar, setting the primary heater temperature was 310 ℃, setting the feed heater temperature is 200 ℃, and fatty raw material is outgased;
6. the primary heater temperature reaches 200 ℃, beginning charging, charging rate 80L/h; The primary heater temperature reaches 310 ℃, charging rate 140L/h;
7. the refined fur seal finished product that distills is collected in cooling.
II. eicosapentaenoic acid (EPA), docosahexenoic acid (DHA) and DPA DOCOSA-PENTENOIC ACID (DPA) content detection
1. detection principle
For the eicosapentaenoic acid (EPA) in the embodiment 1 prepared refining seal oil, docosahexenoic acid (DHA) and DPA DOCOSA-PENTENOIC ACID (DPA) assay; Our company adopts HPLC external standard algoscopy: the unsaturated fatty acid in the sample is carried out esterification; Become methyl eicosapentaenoic acid (EPAM), Methyl docosahexaenoate (DHAM) and DPA DOCOSA-PENTENOIC ACID methyl ester (DPAM); Adopt HPLC external standard algoscopy to measure the content of three kinds of unsaturated fatty acid methyl ester, converse the content of corresponding unsaturated fatty acid.
2. chromatographic condition
Instrument: the high performance liquid chromatograph that Agilent company dispatches from the factory: comprise the intelligent column oven of G1316A, G1314F variable wavelength UV-detector, G1311C1260 quaternary pump (containing built-in degasser), G2170BA chromatographic work station, the full-automatic injector of G1329B (600bar); Excellent spectrum ultra-pure water draft machine.
Reagent: DBPC 2,6 ditertiary butyl p cresol (BHT), sodium metal, glacial acetic acid, isopropyl alcohol are homemade analytical pure; Methanol, acetonitrile are homemade chromatographically pure.EPA methyl ester (EPAM) titer (10mg/ml), DHA methyl ester (DHAM) titer (10mg/ml), DPA methyl ester (DPAM) titer (10mg/ml) are Supelco Company products under the Sigma house flag.
Sample: embodiment 1 prepared refining seal oil.
Chromatographic column: Lichrospher RP-18; 5um,
4mm * 250mm.
Mobile phase:
Acetonitrile: methanol: water=7:1:2
A pump: methanol: water=1:2 (0.3ml/min)
B pump: acetonitrile (0.7ml/min)
Constant gradient eluting: flow velocity 1.0ml/min
Column temperature: 45 ℃
Detect wavelength: 210nm
Sample size: 20ul
Theoretical cam curve: should be not less than 5000 by the calculating of EPAM peak
Separating degree: the separating degree of three main constituent peaks and adjacent impurity peaks should be greater than 1.0
Analysis time: 45min
3. detection method is specific as follows:
3.1 analyte derivativeization: the about 100mg of sample thief refining seal oil (120ul), the accurate title, decide, and puts in the brown volumetric flask of 100ml; Add the 0.5mol/l Feldalat NM 4ml of new system, place 30 ℃ of continuous joltings of 120r/min of constant-temperature shaking shaking table, react about 30 minutes after; Check and whether also have oil droplet; If still exist, continue jolting, be not as the criterion with little oil droplet.To wherein adding 0.2ml glacial acetic acid cessation reaction, with the methanol constant volume that contains 0.005%BHT.4 ℃ of placements must not be above 24 hours.
3.2 the preparation of standard solution: precision is measured EPAM titer 0.1ml, and DHAM titer 0.1ml, DPAM titer 0.1ml place the brown volumetric flask of 10ml, and the isopropyl alcohol standardize solution is as mixing mark solution.
3.3 sample introduction: get the derivatization sample that step 3.1 is processed, use the 0.45um membrane filtration, precision is measured the 20ul sample introduction, the record chromatogram; Other gets standard solution, measures with method.The RRT of EPAM, DHAM, three kinds of methyl ester of DPAM is respectively about 21min, 28min, 38min.
4. the result calculates
According to external standard method with calculated by peak area.
Accurately take by weighing 3 parts of embodiment 1 prepared refining seal oils, record takes by weighing quality m (every part of about 100mg) respectively, operates according to the method described above, and external standard method is with the content of three kinds of fatty acid methyl esters of peak area mensuration, and computing formula is following:
Above-mentioned formula also is suitable for DHAM, DPAM.
To the methyl ester content that calculates, still need and carry out following conversion:
III. iodine number
1. test method foundation
GB/T5532-2008 State Standard of the People's Republic of China " mensuration of animal and plant fat iodine number ".
2. test method
Get the prepared refining seal oil 1.0g of embodiment, put in the dry iodine flask of 500ml, add cyclohexane extraction and glacial acetic acid equal-volume mixed liquor 20ml; After the dissolving, accurate Webster (Wijs) the reagent 25ml that adds, close plug shakes up; In the dark placed 1 hour, and added liquor kalii iodide 20ml and water 150ml, shake up; With the remaining iodine of sodium thiosulfate volumetric solution (0.1mol/L) titration, shake well during titration, liquid to be mixed brown becomes when faint yellow; Add starch indicator solution 1ml, continue titration and disappear to blue.Do blank experiment simultaneously.Volume (ml) with consume sulfur sodium thiosulfate volumetric solution (0.1mol/L) is V
2, the volume (ml) that blank assay consumes is V
1, example weight (g) is M, the concentration of sodium thiosulfate volumetric solution (0.1mol/L) is c (mol/l), shines the iodine number of computes sample refining seal oil:
3. measure result's value:
| Iodine number (g/100g) | Value arrives as a result |
| ＜20 | 0.1 |
| 20-60 | 0.5 |
| ＞60 | 1 |
4. related reagent requires:
4.1 liquor kalii iodide (KI): 100g/L does not contain iodate or free-iodine.
4.2 starch solution: the 5g soluble starch is mixed in 30ml water, add 1000ml boiling water, and boiled 3 minutes, then cooling.
4.3 sodium thiosulfate standard solution: c (Na
2S
2O
35H
2O)=and 0.1mol/L, demarcate in back 7 days and use.
4.4 cyclohexane extraction and glacial acetic acid equal-volume mixed liquor.
4.5 Webster (Wijs) reagent: take by weighing iodine monochloride 25g and be dissolved in the 1500ml glacial acetic acid.The glacial acetic acid of preparation Webster (Wijs) reagent should contain reducing substances, and this reagent also should be done the blank determination of blank.
Identify whether glacial acetic acid contains the method for reducing substances:
Get glacial acetic acid 2ml, add the 10ml distilled water diluting, add 1mol/L potassium permanganate 0.1ml, the color that is appeared should remain unchanged in 2 hours.If redness is taken off, explained that reducing substances exists.
Can adopt commercially available Webster (Wijs) reagent.
IV. acid number
1. test method foundation
Hot ethanol algoscopy among the GB/T5530-2005 State Standard of the People's Republic of China " animal and plant fat acid number and acidity assaying ".
2. test method
Take by weighing 5.0g embodiment 1 prepared refining seal oil sample M (degree of accuracy that sample is weighed: 0.02g), in the conical flask of packing into.To contain 0.5ml phenolphthalein indicator (10g/L; The phenolphthalein of 10g is dissolved in 95% alcoholic solution of 1L) the 50ml alcoholic solution insert in the conical flask; Be heated to boiling, when alcoholic acid temperature is higher than 70 ℃, with the sodium hydroxide of 0.1mol/L or potassium hydroxide solution titration to solution changes color; And keep solution 15s colour-fast, be terminal point.
Neutralization back ethanol is transferred in the conical flask that specimen is housed, fully mixes, boil.With sodium hydroxide or potassium hydroxide standard solution titration, titration process is wanted continuous jolting, changes to solution colour, and keeps 15s colour-fast, is titration end-point.
3. the result calculates
Acid number (S) (mg/g) is calculated as follows:
In the formula:
V: the volume of used potassium hydroxide standard solution, ml;
C: the accurate concentration of used potassium hydroxide standard solution, mol/L;
M: the quality of sample, g.
V. peroxide value
1. test method foundation
GB/T5538-2005 State Standard of the People's Republic of China " animal and plant fat peroxide value mensuration ".
2. test method
Carbon dioxide or nitrogen wash iodine flask with clean, dry; Precision take by weighing embodiment 1 prepared seal oil sample (M) 5.0g (the weighing degree of accuracy: ± 0.01g); Place above-mentioned iodine flask, add 50ml acetic acid-isooctane solution, cover stopper and shake to sample dissolution.Add the 0.5ml saturated solution of potassium iodide, cover stopper and make its reaction, the time is 1min ± 1s, shakes iodine flask during this period at least 3 times, adds the 30ml distilled water then immediately.With the above-mentioned solution of hypo solution (C:0.01mol/L) titration, almost disappear up to yellow, add about 0.5ml starch solution, continue titration, disappear to blue, be terminal point.The hypo solution volume V2 that record consumes.Do blank simultaneously, the hypo solution volume V1 that record consumes.
Surpass 0.1ml when blank experiment consumes hypo solution (0.01mol/L), should change hypo solution (0.01mol/L), again sample is measured.
3. the result calculates
Peroxide value P is calculated as follows:
V1: be used for barren hypo solution and consume volume, ml;
V2: the hypo solution that is used for sample determination consumes volume, ml;
C: the concentration of hypo solution, mol/L;
M: the quality of sample, g;
P: peroxide value, with every kilogram of expression of mM, mmol/kg.
4. required reagent requirement
4.1 glacial acetic acid and isobutyltrimethylmethane. mixed liquor (6:4): glacial acetic acid and isobutyltrimethylmethane. all use pure, exsiccant noble gas (carbon dioxide or nitrogen) air-flow to remove oxygen.
4.2 saturated solution of potassium iodide: newly the preparation and must not contain free-iodine and iodate.Guarantee to have in the solution crystallization to exist, deposit in the lucifuge place.If in 30ml acetic acid-isooctane solution, add 0.5ml saturated solution of potassium iodide and 2 starch solutions, blueness occurs, and need hypo solution (0.01mol/L) could eliminate more than 1, then prepare this solution again.
4.3 hypo solution (0.01mol/L): prepare hypo solution (0.1mol/L) earlier.Take by weighing 21.9g five water sodium thiosulfate (Na2S2O35H2O) and be dissolved in the distilled water, be diluted to 1L.Face and use preceding demarcation, dilution 10 makes hypo solution (0.01mol/L).
4.4 starch solution (5g/L): the 1g soluble starch is mixed with the small amount of cold distilled water, under condition of stirring, be dissolved in the 200ml boiling water, add the 250ml salicylic acid as antiseptic and boil 3min, take off and cool off from thermal source immediately.This solution can be stored 2-3 week at 4 ℃ of refrigerators, when titration end-point when not obvious, needs preparation again to colourless from blueness.
Sensitivity verification method: with adding in the 5ml starch solution in the 100ml water; Add 0.05% liquor kalii iodide and 1 0.05% liquor natrii hypochloritis; When splashing into hypo solution (0.1mol/L) when 0.05ml is above, navy blue disappears, and promptly representes insufficient sensitivity.
Embodiment 1 prepared refined fur seal test result of samples is:
Embodiment 2: the preparation of refined fur seal
Equipment: adopt the EA250/KD200 single-stage short-range molecular distillation of German UIC manufactured to extract equipment.
Preparation flow is following:
1. 100kg fur seal Animal fat is shredded;
2. the warm water of the fur seal Animal fat that shreds with 45 ℃ of temperature is cleaned;
3. put into the oil water separator centrifugalize after the fur seal Animal fat cleaning with chopping and obtain isolating water and fatty raw material;
4. isolated water in the step 3 is filtered the fatty raw material that obtains water and centrifugalize omission, the fatty raw material that centrifugalize is omitted adds in the fatty raw material;
5. unlatching molecular still, when system vacuum reached 0.003mbar, setting the primary heater temperature was 320 ℃, setting the feed heater temperature is 220 ℃, and fatty raw material is outgased;
6. the primary heater temperature reaches 200 ℃, beginning charging, charging rate 90L/h; The primary heater temperature reaches 320 ℃, charging rate 160L/h;
7. the refined fur seal finished product that distills is collected in cooling.
As embodiment 1 is said embodiment 2 prepared refined fur seal samples are carried out content detection, iodine number and acid value measuring.
Embodiment 2 prepared refined fur seal test result of samples are:
Embodiment 3: the preparation of refined fur seal
Equipment: adopt the EA250/KD200 single-stage short-range molecular distillation of German UIC manufactured to extract equipment.
Preparation flow is following:
8. 100kg fur seal Animal fat is shredded;
9. the warm water of the fur seal Animal fat that shreds with 45 ℃ of temperature is cleaned;
10. put into the oil water separator centrifugalize after the fur seal Animal fat cleaning with chopping and obtain isolating water and fatty raw material;
11. isolated water in the step 3 is filtered the fatty raw material that obtains water and centrifugalize omission, and the fatty raw material that centrifugalize is omitted adds in the fatty raw material;
12. the unlatching molecular still, when system vacuum reached 0.002mbar, setting the primary heater temperature was 315 ℃, and setting the feed heater temperature is 210 ℃, and fatty raw material is outgased;
13. the primary heater temperature reaches 200 ℃, beginning charging, charging rate 85L/h; The primary heater temperature reaches 315 ℃, charging rate 150L/h;
14. the refined fur seal finished product that distills is collected in cooling.
As embodiment 1 is said embodiment 3 prepared refined fur seal samples are carried out content detection, iodine number and acid value measuring.
Embodiment 3 prepared refined fur seal test result of samples are:
Experiment 1: the clinical trial of embodiment 1 prepared refined fur seal is following:
1, test objective
Checking the present invention treats the effectiveness of non-alcoholic fatty liver disease.
2, EXPERIMENTAL DESIGN
2.1 the description of test master-plan and scheme
Follow the GCP principle, adopt at random, double blinding, multicenter, Adeps Phocae vitulinae study with the parallel control of placebo.Object of study is the non-alcoholic fatty liver disease patient, can estimate case and add up to 400 examples.The experimenter will assign to fur seal line of oils and placebo group at random according to the ratio of 3:1.
2.2 the consideration that EXPERIMENTAL DESIGN and matched group are selected
Do not treat at present the medicine listing of fatty liver, therefore adopt placebo to compare.
2.3 the selection of object of study
2.3.1 diagnostic criteria
Non-alcohol fatty liver practice guidelines with reference in February, 2006 China's hepatology meeting fatty liver and the revision of alcoholic liver disease group:
All possess that any one person can be diagnosed as non-alcoholic fatty liver disease in following the 1st ~ 5 and the 6th or the 7th.
1) no history of drinking history or drink amount to the amount of alcohol male weekly 140g, the women is < 70g weekly;
2) viral hepatitis, drug-induced liver disease, total parenteral nutrition, hepatolenticular degeneration etc. can cause the specified disease of fatty liver except;
3) except that the primary disease clinical manifestation, nonspecific symptom and signs such as weak, dyspepsia, dull pain in liver, hepatosplenomegaly can be arranged;
4) can have overweight with (or) metabolism syndrome related components such as internal organs property is fat, fasting glucose increases, blood fat disorder, hypertension;
5) serum transaminase and gamma glutamyl transpeptidase level can have mild to moderate increasing (less than 5 times of normal value upper limits), and it is main increasing with alanine aminotransferase (ALT) usually;
6) the liver Radiologic imaging meets the imaging diagnosis standard of diffusivity fatty liver;
7) the liver biological tissue is learned and is changed the pathological diagnosis standard that meets fatty liver.
2.3.2 inclusion criteria
1) signature Informed Consent Form person;
2) sex at 18 ~ 65 years old age;
3) clinical diagnosis meets the diagnostic criteria of non-alcoholic fatty property;
4) liver/spleen CT ratio≤1;
5) TG＞ULN;
6) use the medicine (medicine that comprises the liver protecting and ALT lowering or effect for reducing fat) of treating fatty liver in nearly 4 weeks;
7) the child-bearing period women must have effective contraceptives.
2.3.3 exclusion standard
1) diabetics and fasting glucose are greater than 7.0;
2) hepatopathy due to the factors such as viral hepatitis, medicine, ethanol, autoimmune, Wilson disease, total parenteral nutrition;
3) merging the heart, kidney, lung, endocrine, blood, metabolism and digestion is serious protopathy person, or the psychotic;
4) glutamate pyruvate transaminase (ALT) >=10 times;
5) GGT＞5 times ULN;
6) serum total bilirubin (TBIL)＞1.5 times ULN;
7) serum albumin (ALB)＜33g/L;
8) creatinine (Cr)＞130umol/L;
9) platelet count (PLT)＜80109/L;
10) carry out any way slimmer in 3 months;
11) participate in other clinical trial person in 3 months;
12) anemia of pregnant woman, women breast-feeding their children or application estrogen contraception person;
13) alcoholic or drug-addict;
14) known to the test drug allergy sufferers.
2.3.4 rejecting standard
1) do not meet case selected, exclusion standard;
2) experimenter's compliance is poor, not by scheme requirement pill taker (greater than 120% or less than 80%);
3) duration of test has been used the other drug person that possibly influence this research therapeutic evaluation.
2.4 process of the test
2.4.1 investigational agent
Embodiment 1 prepared Adeps Phocae vitulinae omega-3 polyunsaturated fatty acids contains 18% omega-3 polyunsaturated fatty acids.
2.4.2 placebo
Olive oil, commercial obtaining.Contain oleic acid 53%, meet placebo and prepare requirement.
2.4.3 administrated method
Every day twice, each 0.018ml/kg, diet be to not influence of investigational agent, so the time of taking medicine is not required.
3, the analysis of curative effect/effect
3.1 main curative effect index
Liver/spleen CT ratio:
FAS crowd, test group 324 examples, matched group 104 examples.Test group: baseline period liver/spleen CT ratio median is 0.802 (0.110 ~ 1.000), and meansigma methods is 0.748 ± 0.194; Liver/spleen CT ratio median is 0.832 (0.016 ~ 1.287) when treating for 24 weeks, and meansigma methods is 0.794 ± 0.220; Changing value before and after the treatment (back-preceding) meansigma methods is 0.046 ± 0.167, and 95%CI is 0.028 ~ 0.064.Matched group: baseline period liver/spleen CT ratio median is 0.795 (0.162 ~ 0.985), and meansigma methods is 0.750 ± 0.194; Liver/spleen CT ratio median is 0.810 (0.029 ~ 1.212) when treating for 24 weeks, and meansigma methods is 0.772 ± 0.237; Changing value before and after the treatment (back-preceding) meansigma methods is 0.023 ± 0.188, and 95%CI is-0.014 ~ 0.059.Treatment back test group liver/spleen CT ratio obviously raises, and has the statistical significance of highly significant, and P=0.0000 (＜0.01; Table 2; And covariance analysis 95% credibility interval is that 95%CI is 0.028～0.064 (table 1), does not comprise 0, and further the embodiment of the invention 1 prepared Adeps Phocae vitulinae liver/spleen CT ratio that can raise is taken in prompting; And there is 95% power of a test to promote amplitude between 0.028～0.064, has the clinical practice meaning.Explain and take the embodiment of the invention 1 prepared Adeps Phocae vitulinae liver/spleen CT ratio that can obviously raise clinically, alleviate the liver fat deposition.Relatively has statistical significance in the matched group group; P=0.0399 (＜0.05; But covariance analysis 95%CI is-0.014～0.059 (table 1), comprises 0 table 2); Power of a test liver/spleen CT that placebo 95% is taken in prompting can drop between-0.014～0.059 than changing value, does not have practical significance for promoting liver/spleen CT ratio clinically.Liver/spleen CT ratio rising meansigma methods test group is higher than matched group before and after two groups of treatments, but compares P=0.9415 (table 2) between group, and difference does not have statistical significance.
PPS crowd, test group 294 examples, matched group 92 examples.Test group baseline period liver/spleen CT ratio median is 0.804 (0.110 ~ 1.000), and meansigma methods is 0.749 ± 0.193; Liver/spleen CT ratio median is 0.835 (0.016 ~ 1.287) when treating for 24 weeks, and meansigma methods is 0.798 ± 0.220; Changing value before and after the treatment (back-preceding) meansigma methods is 0.049 ± 0.171, and 95%CI is 0.029 ~ 0.068.Matched group baseline period liver/spleen CT ratio median is 0.812 (0.162 ~ 0.985), and meansigma methods is 0.757 ± 0.194; Liver/spleen CT ratio median is 0.816 (0.029 ~ 1.212) when treating for 24 weeks, and meansigma methods is 0.781 ± 0.242; Changing value before and after the treatment (back-preceding) meansigma methods is 0.024 ± 0.200, and 95%CI is-0.017 ~ 0.066.Experimenter liver/spleen CT ratio test group has obvious rising before and after the treatment; Compare P=0.0000 (＜0.01 in the group; Statistical significance with highly significant, and covariance analysis 95% credibility interval is that 95%CI is 0.029～0.068, do not comprise 0; Further confirm to take the embodiment of the invention 1 prepared Adeps Phocae vitulinae liver/spleen CT ratio that can obviously raise clinically, alleviate the liver fat deposition.It is not obvious that matched group raises, P=0.0542 relatively in the group, and not statistically significant, and 95%CI is-0.017～0.066, comprises 0, do not have clinical meaning.Two groups are relatively, and the meansigma methods test group of liver/spleen CT ratio lift-off value is a little more than matched group, but P=0.9454, difference does not have statistical significance.
Subfraction is analysed:
This research has been carried out subfraction to the case liver/spleen CT ratio that is diagnosed as the severe non-alcoholic fatty liver disease before treating and has been analysed severe fatty liver test group 42 examples in the FAS analytic set, matched group 15 examples.Test group baseline period liver/spleen CT ratio median is 0.406 (0.110 ~ 0.500), and meansigma methods is 0.376 ± 0.111; Liver/spleen CT ratio median is 0.475 (0.016 ~ 1.283) when treating for 24 weeks, and meansigma methods is 0.504 ± 0.247; Changing value before and after the treatment (back-preceding) meansigma methods is 0.128 ± 0.226, and 95%CI is 0.058～0.199.Matched group baseline period liver/spleen CT ratio median is 0.406 (0.162 ~ 0.498), and meansigma methods is 0.391 ± 0.094; Liver/spleen CT ratio median is 0.477 (0.029 ~ 0.842) when treating for 24 weeks, and meansigma methods is 0.474 ± 0.231; Changing value before and after the treatment (back-preceding) meansigma methods is 0.083 ± 0.196, and 95%CI is-0.025 ~ 0.192.Treatment back test group obviously raises, and has the statistical significance of highly significant, and p=0.0004 (＜0.01; Table 4; And covariance analysis 95% credibility interval is that 95%CI is 0.058～0.199 (table 3), does not comprise 0, shows that further this rising has clinical meaning; Can obviously raise clinically liver/spleen CT ratio of severe non-alcoholic fatty liver disease patient of the embodiment of the invention 1 prepared Adeps Phocae vitulinae is taken in prompting, alleviates the liver fat deposition.Compare P=0.2439 (table 4) before and after the treatment of control group, covariance analysis 95%CI is-0.025～0.192 (table 3), comprises 0, and prompting is taken placebo and neither had statistical significance, also do not have the clinical practice meaning for rising liver/spleen CT ratio.Liver/spleen CT ratio rising meansigma methods test group is higher than matched group before and after two groups of treatments, but compares P=0.6562 (table 4) between group, and difference does not have statistical significance.PPS analyzes and analyzes consistent with FAS.
The situation of change of experimenter liver/spleen CT ratio before and after table 1 treatment
The comparison of experimenter liver/spleen CT ratio situation of change before and after table 2 treatment
Relatively adopt in the group of changing value to meet rank test, statistic is S; Relatively use the Wilcoxon rank test between group, statistic is Z.
The situation of change of experimenter liver/spleen CT ratio before and after the case treatment of severe fatty liver before table 3 treatment
The comparison of experimenter liver/spleen CT ratio situation of change before and after the case treatment of severe fatty liver before table 4 treatment
Relatively adopt in the group of changing value to meet rank test, statistic is S; Relatively use the Wilcoxon rank test between group, statistic is Z.
4. blood fat:
T-CHOL:
In the FAS analytic set, test group: baseline period TC content median is 5.35 (2.70 ~ 11.07) mmol/L, average out to 5.40 ± 1.12mmol/L.Treatment back the 12nd all TC content medians are 5.10 (2.45 ~ 12.50) mmol/L; Average out to 5.16 ± 1.07mmol/L; Difference (anterior-posterior) TC content median is 0.19 (2.46 ~ 4.80) mmol/L, and average out to 0.22 ± 0.97mmol/L, 95%CI are 0.110 ~ 0.333.Treatment back the 24th all TC content medians are 5.20 (2.40 ~ 12.15) mmol/L; Average out to 5.27 ± 1.18mmol/L; Difference (anterior-posterior) TC content median is 0.03 (6.47 ~ 5.58) mmol/L, and average out to 0.13 ± 1.11mmol/L, 95%CI are 0.002 ~ 0.257.Referring to table 5..
Matched group: baseline period TC content median is 5.33 (2.84～11.49) mmol/L, average out to 5.35 ± 1.09mmol/L.Treatment back the 12nd all TC content medians are 5.00 (2.91 ~ 7.90) mmol/L; Average out to 5.16 ± 1.12mmol/L; Difference (anterior-posterior) TC content median is 0.20 (2.41 ~ 4.02) mmol/L, and average out to 0.20 ± 0.98mmol/L, 95%CI are-0.006～0.409.Treatment back the 24th all TC content medians are 5.20 (2.99 ~ 8.03) mmol/L; Average out to 5.27 ± 1.09mmol/L, difference (anterior-posterior) TC content median is-0.08 (1.62 ~ 3.76) mmol/L, average out to 0.07 ± 0.94mmol/L; 95%CI is-0.126 ~ 0.268, table 5.
Compare in the group; Test group: TC content obviously descends than baseline when treating for 12 weeks, and has the highly significant statistical significance, P=0.0006 (less than 0.01); In addition; The 95%CI of TC content front and back difference is 0.110～0.333 during 12 weeks, does not comprise 0, shows that equally the decline of clinical meaning appears having in test group TC.Treatment is TC content meansigma methods and baseline during 24 weeks; Still have by a relatively large margin and descend; Do not change (P=0.0515) though present statistical significance; But the 95%CI of difference is 0.002～0.257 before and after the 24 when week TC content, does not comprise 0, show equally test group during 24 weeks TC the decline of clinical meaning appears having.Matched group: treatment 12 when week TC content descends than baseline to some extent, and has statistical significance (P=0.0269), but during 12 weeks before and after the TC content 95%CI of difference be-0.006～0.409, comprise 0, so this decline does not have clinical meaning.TC content meansigma methods and baseline do not have significant change when treating for 24 weeks, and do not have statistical significance (P=0.8807), and the 95%CI of TC content front and back difference is-0.126～0.268 during 24 weeks, comprises 0, does not equally also have clinical meaning.See table 7 for details.
Relatively, treated for the 12nd week and the 24th week between group, TC meansigma methods fall test group is all greater than matched group, but group difference does not all demonstrate statistical significance.See table 7 for details.
The PPS analytic set is consistent with the FAS analysis result, sees table 5 and table 6. for details.
Triglyceride TG:
Among the FAS crowd; Test group: baseline period TG content median is 2.50 (0.86 ~ 28.54) mmol/L, and meansigma methods is 3.41 ± 2.79mmol/L, and treatment back the 12nd all TG content medians are 2.15 (0.30 ~ 25.33) mmol/L; Meansigma methods is 2.81 ± 2.40mmol/L; Difference (anterior-posterior) median is 0.40 (8.62 ~ 24.31) mmol/L, and meansigma methods is 0.60 ± 2.49mmol/L, and 95%CI is 0.317～0.890.Treating the 24th all TG content medians is 2.23 (0.49 ~ 27.77) mmol/L; Meansigma methods is 2.72 ± 2.16mmol/L; Difference (anterior-posterior) median is 0.34 (9.44 ~ 23.19) mmol/L, and meansigma methods is 0.69 ± 2.49mmol/L, and 95%CI is 0.400～0.973 (table 8).
Matched group: baseline period TG content median is 2.53 (1.64 ~ 25.37) mmol/L; Meansigma methods is 3.26 ± 2.89mmol/L; Treatment back the 12nd all TG content medians are 2.38 (0.80～18.28) mmol/L, and meansigma methods is 3.48 ± 3.39mmol/L, and difference (anterior-posterior) median is 0.17 (16.54 ~ 8.43) mmol/L; Meansigma methods is-0.30 ± 2.57mmol/L, and 95%CI is-0.840～0.242.Treating the 24th all TG content medians is 2.19 (0.98 ~ 18.39) mmol/L; Meansigma methods is 2.92 ± 2.45mmol/L; Difference (anterior-posterior) median is 0.19 (4.45 ~ 8.95) mmol/L, and meansigma methods is 0.24 ± 1.63mmol/L, and 95%CI is-0.105～0.577 (table 8).
Compare in the group, tangible reduction all appearred in TG content before test group was treated when 12 weeks of treatment and 24 weeks, and had the statistical significance of highly significant; P=0.0000 (＜0.01; And the 95%CI of TG content front and back difference was 0.400 ~ 0.973 when the 95%CI of difference was 0.317 ~ 0.890,24 weeks before and after the TG content during 12 weeks, did not all comprise 0; Explain that taking behind the Adeps Phocae vitulinae TG descends and not only have statistical significance, and have practical significance clinically; Compare when 12 weeks of treatment of control group are all with 24 with before the treatment; All there is not significant change; And do not have statistical significance P＞0.05 (table 10), the 95%CI of TG content front and back difference was-0.105 ~ 0.577 when the 95%CI of difference was-0.840 ~ 0.242,24 weeks before and after the TG content during 12 weeks; All comprise 0, explain that taking behind the placebo TG descends and do not have practical significance clinically.(table 10)
Relatively, when treating for the 12nd week, test group TG drop-out value is apparently higher than matched group, and has remarkable statistical significance between group, and P=0.0081 (＜0.01.Treatment is during 24 weeks, and test group TG drop-out value still is higher than matched group, but does not demonstrate the difference with statistical significance, P=0.0517 (＞0.05).(table 10)
The PPS analysis result is consistent with FAS, sees table 8 and table 9 for details.
The situation of change (FAS) of T-CHOL TC (mmol/L) before and after each group treatment of table 5
The situation of change (PPS) of T-CHOL TC (mmol/L) before and after each group treatment of table 6
The comparison of T-CHOL TC (mmol/L) situation of change before and after each group treatment of table 7
Relatively adopt paired t-test in the group of difference, relatively adopt the t of group check between group, statistic is t.
The situation of change (FAS) of triglyceride TG (mmol/L) before and after each group treatment of table 8
The situation of change (PPS) of triglyceride TG (mmol/L) before and after each group treatment of table 9
The comparison of triglyceride TG (mmol/L) situation of change before and after each group treatment of table 10
Relatively adopt paired t-test in the group of difference, relatively adopt the t of group check between group, statistic is t.
5. the effectiveness brief summary of clinical experiment
This research FAS is all consistent with the PPS analysis result.
Liver/spleen CT ratio: FAS crowd is during 24 weeks; Test group and matched group liver/spleen CT average of relatives value is respectively 0.794 ± 0.220 and 0.750 ± 0.194; Changing value before and after the treatment (back-preceding) meansigma methods is respectively 0.046 ± 0.167 and 0.023 ± 0.188, and test group rising amplitude is greater than placebo group.The statistical significance that relatively has highly significant before and after the test group treatment; P=0.0000 (＜0.01); And difference 95%CI is 0.028～0.064, does not comprise 0, and further the Adeps Phocae vitulinae liver/spleen CT ratio that can raise is taken in prompting; And there is 95% power of a test to promote amplitude between 0.028～0.064, has the clinical practice meaning.Compare P=0.0399 (＜0.05) before and after the treatment of control group; Has statistical significance; But 95%CI is-0.014 ~ 0.059; Comprise 0, power of a test liver/spleen CT that placebo 95% is taken in prompting can drop between-0.014 ~ 0.059 than changing value, does not have practical significance for promoting liver/spleen CT ratio clinically.
The inferior group of severe fatty liver analysis of cases: severe fatty liver test group 42 examples in the FAS analytic set, matched group 15 examples.Test group and matched group liver/spleen CT average of relatives value are respectively 0.504 ± 0.247 and 0.474 ± 0.231 when treating for 24 weeks; Poor before and after the treatment (back-preceding) meansigma methods is respectively 0.128 ± 0.226 and 0.083 ± 0.196, and test group rising amplitude is greater than placebo group.Compare P=0.0004 (＜0.01) before and after the test group treatment; Statistical significance with highly significant; 95%CI is 0.058～0.199, does not comprise 0, and the Adeps Phocae vitulinae severe fatty liver patients with hepatic/spleen CT ratio that can raise is taken in prompting; And there is 95% power of a test to promote amplitude between 0.058 ~ 0.199, has the clinical practice meaning.The treatment of control group front and back are than P=0.2439; Do not have statistical significance, 95%CI is-0.025～0.192, comprises 0; Power of a test liver/spleen CT that placebo 95% is taken in prompting can drop between-0.025～0.192 than changing value, does not have practical significance for promoting liver/spleen CT ratio clinically.
Total cholesterol level: TC content obviously descended than baseline when test group treated for 12 weeks; And have the highly significant statistical significance, P=0.0006 (less than 0.01), the 95%CI of difference are 0.110～0.333; Do not comprise 0, show that equally the decline of clinical meaning appears having in test group TC.24 when week TC content continue to descend by a relatively large margin, change (P=0.0515) though present statistical significance, the 95%CI of difference is 0.002～0.257, does not comprise 0, show equally test group during 24 weeks TC descend and have clinical meaning.Matched group, the 95%CI of difference is-0.006～0.409 before and after 12 all TC content, comprises 0, changes not have clinical meaning.24 all 95%CI are-0.126～0.268, comprise 0, do not have clinical meaning equally.
Tangible reduction all appearred when 12 weeks of content of triglyceride: test group TG treatment and 24 weeks; P=0.0000 (＜0.01; And the 95%CI of difference is respectively 0.317～0.890 and 0.400 ~ 0.973; All do not comprise 0, explain that taking behind the Adeps Phocae vitulinae TG descends and not only have the statistical significance of highly significant, and have practical significance clinically; TG does not all have significant change when 12 weeks of treatment of control group and 24 weeks; P＞0.05, the 95%CI of difference is respectively-0.840～0.242 and-0.105 ~ 0.577, all comprises 0; Prompting is taken placebo TG decline and is not promptly had statistical significance, does not also have practical significance clinically.Relatively, during the 12nd week, TG drop-out value test group is apparently higher than matched group, and has the highly significant statistical significance between group.
In sum:
The present invention has significant clinical meaning to liver/spleen CT ratio and the blood fat reducing that improves non-alcoholic fatty liver disease, especially the serious symptom Patients with Fatty Liver is demonstrated clinical efficacy preferably.
The present invention has clinical meaning to T-CHOL and content of triglyceride in the reduction serum.
Experiment 2: the clinical trial of embodiment 1 prepared refined fur seal is following:
Enforcement 2 is identical with experiment 1 clinical trial, and different is following one: the 2.4.3 administrated method
Every day twice, each 0.0605ml/kg, diet be to not influence of investigational agent, so the time of taking medicine is not required.
The clinical effectiveness that experiment 2 is obtained is similar with the result that experiment 1 is obtained.
Experiment 3: the clinical trial of embodiment 1 prepared refined fur seal is following:
Enforcement 3 is identical with experiment 1 clinical trial, and different is following one:
2.4.3 administrated method
Every day twice, each 16.5mg/kg, diet be to not influence of investigational agent, so the time of taking medicine is not required.
The clinical effectiveness that experiment 3 is obtained is similar with the result that experiment 1 is obtained.
Experiment 4: the clinical trial of embodiment 1 prepared refined fur seal is following:
Enforcement 4 is identical with experiment 1 clinical trial, and different is following one:
2.4.3 administrated method
Every day twice, each 55.5mg/kg, diet be to not influence of investigational agent, so the time of taking medicine is not required.
The clinical effectiveness that experiment 4 is obtained is similar with the result that experiment 1 is obtained.
Experiment 5: the clinical trial of embodiment 2 prepared refined fur seals is following:
Enforcement 5 is identical with experiment 1 clinical trial, and different is following one:
2.4.1 investigational agent
Embodiment 2 prepared refined fur seals contain 19.5% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 5 is obtained is similar with the result that experiment 1 is obtained.
Experiment 6: the clinical trial of embodiment 2 prepared refined fur seals is following:
Enforcement 6 is identical with experiment 2 clinical trials, and different is following one:
2.4.1 investigational agent
Embodiment 2 prepared refined fur seals contain 19.5% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 6 is obtained is similar with the result that experiment 1 is obtained.
Experiment 7: the clinical trial of embodiment 2 prepared refined fur seals is following:
Enforcement 7 is identical with experiment 3 clinical trials, and different is following one:
2.4.1 investigational agent
Embodiment 2 prepared refined fur seals contain 19.5% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 7 is obtained is similar with the result that experiment 1 is obtained.
Experiment 8: the clinical trial of embodiment 2 prepared refined fur seals is following:
Enforcement 8 is identical with experiment 4 clinical trials, and different is following one:
2.4.1 investigational agent
Embodiment 2 prepared refined fur seals contain 19.5% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 8 is obtained is similar with the result that experiment 1 is obtained.
Experiment 9: the clinical trial of embodiment 3 prepared refined fur seals is following:
Enforcement 9 is identical with experiment 1 clinical trial, and different is following one:
2.4.1 investigational agent
Embodiment 3 prepared refined fur seals contain 18.76% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 9 is obtained is similar with the result that experiment 1 is obtained.
Experiment 10: the clinical trial of embodiment 3 prepared refined fur seals is following:
Enforcement 10 is identical with experiment 2 clinical trials, and different is following one:
2.4.1 investigational agent
Embodiment 3 prepared refined fur seals contain 18.76% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 10 is obtained is similar with the result that experiment 1 is obtained.
Experiment 11: the clinical trial of embodiment 3 prepared refined fur seals is following:
Enforcement 11 is identical with experiment 3 clinical trials, and different is following one:
2.4.1 investigational agent
Embodiment 3 prepared refined fur seals contain 18.76% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 11 is obtained is similar with the result that experiment 1 is obtained.
Experiment 12: the clinical trial of embodiment 3 prepared refined fur seals is following:
Enforcement 12 is identical with experiment 4 clinical trials, and different is following one:
2.4.1 investigational agent
Embodiment 3 prepared refined fur seals contain 18.76% omega-3 polyunsaturated fatty acids.
The clinical effectiveness that experiment 12 is obtained is similar with the result that experiment 1 is obtained.
Claims (8)
1. refined fur seal, it is characterized in that: the weight percent content of omega-3 polyunsaturated fatty acids is respectively in this refined fur seal:
Eicosapentaenoic acid: 4.64%-5.03%;
DPA DOCOSA-PENTENOIC ACID: 3.86%-4.18%;
Docosahexenoic acid: 9.5%-10.29%.
2. the application of the described refined fur seal of claim 1 in the medicine of preparation treatment non-alcoholic fatty liver disease.
3. application according to claim 2; It is characterized in that: described non-alcoholic fatty liver disease is slight, moderate or severe non-alcoholic fatty liver disease; Wherein 0.7 < liver/>spleen CT value≤1 is slight non-alcoholic fatty liver disease; 0.5 < liver/>spleen CT value≤0.7 is the moderate non-alcoholic fatty liver disease, and liver/spleen CT value≤0.5 is the severe non-alcoholic fatty liver disease.
4. according to the described application of arbitrary claim in the claim 1 to 3, it is characterized in that: the day taking dose of described refined fur seal is 33mg/kg-111mg/kg.
5. according to the described application of arbitrary claim in the claim 1 to 3, it is characterized in that: the day taking dose of described refined fur seal is 0.036ml/kg-0.121ml/kg.
6. the described refined fur seal of claim 1 reduces the application in the medicine of T-CHOL in the serum or triglyceride in preparation.
7. application according to claim 6 is characterized in that: the day taking dose of described refined fur seal is 33mg/kg-111mg/kg.
8. application according to claim 6 is characterized in that: the day taking dose of described refined fur seal is 0.036ml/kg-0.121ml/kg.
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| US20140100273A1 (en) * | 2012-06-17 | 2014-04-10 | Matinas Biopharma, Inc. | Methods of administering compositions comprising docosapentaenoic acid |
| US9757404B2 (en) | 2014-09-25 | 2017-09-12 | Astrazeneca Ab | Combination comprising an omega-3 fatty acid composition and an SGLT2 inhibitor |
| CN109613176A (en) * | 2018-12-28 | 2019-04-12 | 上海邦成生物工程有限公司 | A kind of detection method and its detection combination reagent of feed fat peroxide value |
| WO2021028737A1 (en) | 2019-08-13 | 2021-02-18 | Team Foods Colombia S.A. | Lipid composition comprising antioxidants and natural polyphenols as a non-pharmacological alternative for the treatment and prevention of non-alcoholic fatty liver disease (nafld) |
| WO2021143912A1 (en) * | 2020-01-16 | 2021-07-22 | 上海萨美细胞技术有限公司 | Therapeutic action of cell-free fat extract on fatty liver and complications thereof |
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| CN101255379A (en) * | 2007-08-16 | 2008-09-03 | 张义兴 | Purified fur seal oil and method for preparing the same |
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| CN1951399A (en) * | 2005-10-18 | 2007-04-25 | 天津贝特药业有限公司 | A refined fur seal enriched in OMEGA-3 polyunsaturated fatty acid and preparation thereof |
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| WO2021028737A1 (en) | 2019-08-13 | 2021-02-18 | Team Foods Colombia S.A. | Lipid composition comprising antioxidants and natural polyphenols as a non-pharmacological alternative for the treatment and prevention of non-alcoholic fatty liver disease (nafld) |
| WO2021143912A1 (en) * | 2020-01-16 | 2021-07-22 | 上海萨美细胞技术有限公司 | Therapeutic action of cell-free fat extract on fatty liver and complications thereof |
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