CN102488884A - Thymopoietin for large dosage injection and application thereof for treating severe hepatitis - Google Patents
Thymopoietin for large dosage injection and application thereof for treating severe hepatitis Download PDFInfo
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- CN102488884A CN102488884A CN2011104173542A CN201110417354A CN102488884A CN 102488884 A CN102488884 A CN 102488884A CN 2011104173542 A CN2011104173542 A CN 2011104173542A CN 201110417354 A CN201110417354 A CN 201110417354A CN 102488884 A CN102488884 A CN 102488884A
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- thymopentin
- thymopoietin
- injection
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- heavy dose
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- Granted
Links
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- 238000002347 injection Methods 0.000 title abstract description 45
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- 231100000283 hepatitis Toxicity 0.000 title abstract 7
- 238000011282 treatment Methods 0.000 claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 17
- PSWFFKRAVBDQEG-YGQNSOCVSA-N thymopentin Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-YGQNSOCVSA-N 0.000 claims description 100
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses thymopoietin for large dosage injection and an application thereof for treating severe hepatitis, belonging to the technical field of medicine. The specification of the large dosage thymopoietin is 50 mg, and the large dosage thymopoietin used for treating severe hepatitis patients is applied in the preparation of medicine for treating severe hepatitis patients, wherein the specification of the large dosage thymopoietin is 50 mg, and 1 ml is injected each time. The thymopoietin with large dosage of 50 mg of the invention is cooperatively used with adefovir dipivoxil to greatly improve the antiviral treatment effect of adefovir dipivoxil, and the security of the thymopoietin is good, so that the thymopoietin is a medicine for effectively and safely treating severe hepatitis; besides, the medicine is convenient to be delivered to the severe hepatitis patients to improve the compliance of the patient crowd and to satisfy the special demands of the severe hepatitis patients.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of large bolus injection with Thymopentin and in the application of treating the serious symptom hepatitis B.
Background technology
Thymopentin, Full Name in English are Thymopoietin or Timunox, and english abbreviation is TP-5, and it is made up of arginine, lysine, aspartic acid, valine and tyrosine five seed amino acids, and chemical structural formula does
Thymus is one-level lympho-epithelial tissue, is the primary central immune organ of human body, is the cytocerastic center of T-organ, except the required microenvironment of T-cell development is provided, also can produce multiple thymosin parahormone.Thymosin can be induced the differentiation and the maturation of T-cell subsets, also can strengthen the reactivity worth of all kinds of T-cells, and then regulates whole functions of immune system.
Several single polypeptide compounds from thymosin, have been isolated at present; Like thymopoietin II (Thymopoietin II); Be made up of 49 aminoacid, other are also just like thymosin (Thymosin α 1), FTS (FTS); Thymic humoral factors (THF) etc. are wherein maximum to the research of thymopoietin II.Found the amino acid residue fragment (being essence-Lai-Radix Asparagi-figured silk fabrics-tyrosine) of thymopoietin 32-36 position afterwards, the whole physiological functions identical with thymopoietin arranged, be referred to as Thymopentin (Thymopentin, TP-5).
On the clinical liver disease, Thymopentin is usually used in treating hepatitis B infected with the body cell immunologic hypofunction.Hepatitis B patient is often with body cell immunologic hypofunction problem; Thymopentin is through improving the body cell immunologic function; Induce endogenous interferon; Improve the level and the expression of receptor level of interleukin-2, improve the phagocytic function of natural killer cell vigor and macrophage, to improve the treatment level of difficult chronic hepatitis.Normal clinically drug combination is used to treat hepatitis B.
Thymopentin goes on the market as immunostimulant and immunomodulator in Italy, Germany in 1985 the earliest by the exploitation of Johnson Johnson company, and commodity are called Timunox, and specification is 50mg.China adopts polypeptide solid-state reaction method to produce the Thymopentin raw material by Hainan Zhonghe Medicine Co., Ltd at first; Raw material and preparation thymopentin for injection (tp-5) obtained Ministry of Public Health four kind new medicine certificate and list marketings in 1997, raw material and preparation that Chengdu Diao 9 Wang pharmaceutical factory obtains this kind in calendar year 2001 are produced certificate of approval.Present national Bureau of Drugs Supervision accepts, ratifies the application for registration of how tame unit Thymopentin and thymopentin for injection (tp-5) again, and article rule are 1mg and 10mg, and domestic still do not have 50mg article at present and advise.
The shortage of 50mg article rule has restricted the application of these article at clinical liver disease on the clinical liver disease.Hepatopathy patients is the general single administration 50mg of liver failure patient particularly, and the specification that hospital uses is propped up as 10mg/, and 5ml needs injection 5 times through subcutaneous or drug administration by injection, and patient is very painful, and compliance is poor, is badly in need of the article rule that 50mg/ props up clinically.
Summary of the invention
Owing to have only 10mg/ to prop up the Thymopentin of specification at present; Therefore critically ill patient need be injected 5 times when injection; Make patient very painful when treatment; And 10mg/ to prop up the Thymopentin compliance of specification poor, in order to solve this situation, the invention provides a kind of Thymopentin that is used to treat the heavy dose of specification of serious symptom hepatitis B patient.
Another object of the present invention has been to disclose the application of Thymopentin in preparation treatment serious symptom hepatitis B patient medicine of this heavy dose of specification.
Technical scheme of the present invention is following:
A kind of heavy dose of Thymopentin that is used to treat the serious symptom hepatitis B patient, wherein, the specification of said heavy dose of Thymopentin is 50mg.
Being used for described in the technique scheme treated the application of heavy dose of Thymopentin of serious symptom hepatitis B patient at preparation treatment serious symptom hepatitis B patient medicine, and wherein, the specification of said heavy dose of Thymopentin is 50mg.
The specification of being mentioned among the present invention is identical with the specification definition in the 10mg Thymopentin product description.
Large bolus injection provided by the invention is made up of Thymopentin 50000mg, mannitol 50000mg and water for injection 1000ml with the Thymopentin prescription.
Its preparation technology is following: take by weighing Thymopentin 50000mg, the dissolving of mannitol 50000mg adding water for injection by above-mentioned recipe quantity, mixing is settled to 1000 milliliters; 0.2 the degerming of μ M membrane filtration, being sub-packed in specification is in the 2ml cillin bottle, packing 1ml in every cillin bottle; Jump a queue lyophilization, gland; Labeling, packing promptly gets.
Its concrete operations step is:
1), solution preparation:
In ten thousand grades of clean rooms, get in recipe quantity Thymopentin, the about 900ml water for injection of mannitol adding, shake up, be settled to 1000 milliliters, promptly get.
2), endotoxin monitoring
Limulus test is done in sampling, and every milliliter of endotoxin content should be less than 2.5EU.
3), content monitoring
The sampling detection level should be 90%～110% of labelled amount.
4), filtration sterilization
Under hundred grades of cleaning conditions, with 0.2 μ M membrane filtration degerming.
5), fill and lyophilization
Under the condition of hundred grades of cleanliness factors, carry out these article fill, jump a queue.1 milliliter of every loading amount, 2 milliliters of cillin bottles and plug thereof all according to GMP require to clean, sterilization and depyrogenation, all in preparation preparation, pouring process used utensil all according to GMP require to clean, sterilization and depyrogenation; Lyophilization, the jewelling lid is labelled; Packing promptly gets.
Said cryodesiccated step is following:
1, pre-freeze: the drain temperature is set at-46--50 ℃, drain reaches-46 ℃ and keeps beginning to fall cold-trap after 3-5 hour.
Begin evacuation when 2, condenser temperature is lower than-55 ℃; Primary drying; The drain temperature is set at-20 ℃, and the drain temperature was to-20 ℃ of maintenances 1-2 hour, and the every rising of drain temperature kept 1-2 hour for 10 ℃ then; Vacuum is set at 0.16 ± 0.01mbar, the vacuum degree control scope is≤0.23mbar or≤5.20V.
3, redrying, drain temperature are set at 38-40 ℃ and kept 5-8 hour to temperature back, and vacuum is set at 0.09 ± 0.02mbar, the vacuum degree control scope is≤0.14mbar or≤4.80V.
Another object of the present invention be to provide large bolus injection with Thymopentin in the application aspect the treatment serious symptom hepatitis B.
According to " prevention and treatment for chronic hepatitis B guide (2010 editions) ", the chronic hepatitis B treatment mainly comprises antiviral, immunomodulating, antiinflammatory and antioxidation, fibrosis and symptomatic treatment.Present all kinds of antiviral agents is the inhibition virus replication, can not thoroughly remove virus, and treatment is very long the course of treatment, the withdrawal time that can't estimate, and the drug resistance of period in a medicine and the virus after the drug withdrawal are still perplexing hepatopathy doctor and patient with biochemical bounce-back.Virus sweep then maybe be through immunization therapy completely, improves body's immunological function and obtains.Thymopentin can stimulate the body cell immunity; Help the low-level hepatitis B virus that duplicates is removed fully; Thereby remedy the shortcoming that antiviral drugs can not directly be removed hepatitis B virus, not only the more single medication of curative effect is good, and can reduce the rebound phenomenon after drug resistance and the drug withdrawal.
Large bolus injection of the present invention is treated the positive serious symptom hepatitis B of HBeAg with Thymopentin (50mg/ time) associating adefovir ester, and its antiviral effect and safety have been carried out clinical observation.Show that through clinical observation heavy dose of Thymopentin can significantly strengthen the antiviral curative effect of adefovir ester; And safety is better; It is a kind of medicine of effective, safe treatment serious symptom hepatitis B; Belong to domestic and international reported first, be worth at the antiviral therapy of clinical application in the serious symptom hepatitis B patient.
Large bolus injection of the present invention adopts the 50mg specification with Thymopentin, makes things convenient for the administration of serious symptom hepatitis B patient, improves the compliance of this patient colony, satisfies the specific demand of serious symptom hepatitis B patient, is the important supplement of present clinical use specification.
The present invention has following beneficial effect:
1, the Thymopentin of 50mg specification of the present invention and antiviral agents nucleotide analog adefovir ester are united the antiviral curative effect that can significantly strengthen adefovir ester when using; And safety is better, is a kind of medicine of effective, safe treatment serious symptom hepatitis B;
2, large bolus injection of the present invention adopts the 50mg specification with Thymopentin, makes things convenient for the administration of serious symptom hepatitis B patient, improves the compliance of this patient colony, satisfies the specific demand of serious symptom hepatitis B patient, is the important supplement of present clinical use specification;
3, since human body be 4ml, be 3ml through the maximum amount of liquid medicine of intramuscular injection at every turn through hypodermic maximum amount of liquid medicine; If injection surpasses maximum amount of liquid medicine; Patient can obviously feel uncomfortable or produce other inadaptations, therefore when the Thymopentin treatment of using 50mg specification of the present invention, can disposablely inject, and the Thymopentin of present 10mg specification; If make the injection total amount reach the injection volume of 50mg, need carry out spaced injection repeatedly.
The specific embodiment:
For making technical scheme of the present invention be convenient to understand, the present invention is further described below in conjunction with the specific embodiment.
Embodiment 1: large bolus injection is with the preparation of Thymopentin (50mg):
1), solution preparation:
In ten thousand grades of clean rooms, get in recipe quantity Thymopentin 50000mg, the about 900ml water for injection of mannitol 50000mg adding, shake up, be settled to 1000 milliliters, promptly get.
2), endotoxin monitoring
Limulus test is done in sampling, and every milliliter of endotoxin content of result is less than 2.5EU.
3), content monitoring
With HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D), sampling detects the content of Thymopentin, and the result shows that the content of Thymopentin in the sample is 90%～110% of labelled amount., show to meet quality standard.
4), filtration sterilization
Under hundred grades of cleaning conditions, with 0.2 μ M membrane filtration degerming.
5), fill
Under the condition of hundred grades of cleanliness factors, carry out these article fill, jump a queue.1 milliliter of every loading amount, 2 milliliters of cillin bottles and plug thereof all according to GMP require to clean, sterilization and depyrogenation, all in preparation preparation, pouring process used utensil all according to GMP require to clean, sterilization and depyrogenation.
6), lyophilization
1. pre-freeze: the drain temperature is set at-46 ℃, and drain reaches-46 ℃ and keeps beginning to fall cold-trap after 5 hours.
Begin evacuation when 2. condenser temperature is lower than-55 ℃, primary drying, the drain temperature is set at-20 ℃; The drain temperature kept 2 hours to-20 ℃; 10 ℃ of every risings of drain temperature kept 1.5 hours then, and vacuum is set at 0.16mbar, the vacuum degree control scope is≤0.23mbar or≤5.20V.
3. redrying, drain temperature are set at 38 ℃ and kept 8 hours to the temperature back, and vacuum is set at 0.09mbar, the vacuum degree control scope is≤0.14mbar or≤4.80V.
7), behind freezing the finishing, the jewelling lid is labelled, packing promptly gets the Thymopentin of 50mg specification of the present invention.
Embodiment 2, large bolus injection are with the effect detection of Thymopentin (50mg):
One, inspection
1, PH
Test method: pH value algoscopy (2010 editions two appendix VI H of Chinese Pharmacopoeia)
The mensuration process: get 3 batches of the Thymopentin of the 50mg specification of embodiment 1 preparation gained at random, with its lot number called after 20090102,20090103 and 20090104, every adds water 5ml and makes it dissolving, measures the solution pH value in accordance with the law.
The result: three batches of test sample pH value are all between 6.0～8.0.Determination data is seen table 1.
Table 1 thymopentin for injection (tp-5) basicity is measured the result
2, clarity of solution and color
Test method: get 5 of these article, add water 1ml dissolving respectively, solution is answered achromaticity and clarification; As showing muddy, with No. 1 turbidity standard solution (two appendix IX of Chinese Pharmacopoeia version in 2010 B), relatively, all must not be denseer.
Conclusion: three batches of equal achromaticity and clarifications of need testing solution.
3, determination of water
These article carry out determination of water with reference to two appendix appendix VIII of Chinese Pharmacopoeia (2010 editions) M, first method to three batches of test samples.
Three batches of test sample moisture all are no more than 5.0%, measure the result and see table 2.
Table 2 thymopentin for injection (tp-5) determination of water result
The result: the water content of three batches of test samples all meets a following limit and requires (being no more than 5.0%).
4, related substance
HPLC (2010 editions two appendix V D of Chinese Pharmacopoeia) is adopted in the inspection of thymopentin for injection (tp-5) quality standard related substance, and these article adopt and Thymopentin related substance inspection same procedure.Determining instrument, chromatographic program are with under the assay item.
Algoscopy: get these article, add mobile phase dissolving and be diluted to contain Thymopentin 5mg among every 1ml solution as supplying examination solution, precision is measured and is supplied examination solution an amount of, add mobile phase process contain Thymopentin 0.05mg among every 1ml solution as contrast solution.Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, the adjustment instrumental sensitivity, and making the main constituent peak height is 10%～20% of monitor full scale, precision is measured and is supplied examination solution 20 μ l sample introductions, 2.5 times of writing down chromatogram to main constituent peak retention time.
Result: all be not more than 1.5 times (1.5%) of contrast solution main peak area in the three batches of test sample chromatograms except that main peak, single maximum contaminant peak area the solvent peak, impurity peak area and 2.5 times (2.5%) being not more than contrast solution main peak area.
Three batches of test sample testing results are seen table 3.
Table 3 test sample related substance testing result
| The sample lot number | The unimodal area of sample impurity (%) | The assorted peak area of sample with (%) |
| 20090102 | 0.053 | 0.10 |
| 20090103 | 0.058 | 0.11 |
| 20090104 | 0.057 | 0.11 |
Simultaneously, under the related substance detection, also adopted the dual wavelength detection, further investigated related substance with end absorption, with check two, three, tetrapeptide and aminoacid, wavelength is respectively 275nm, 203nm, testing result is following:
Test sample related substance testing result under the different detection of table 4 wavelength
The result shows, terminal wavelength unimodal area of sample impurity of 203nm and assorted peak area be lower than 275nm place, in the limit of being formulated, so still adopt 275nm as detection wavelength investigation related substance.
Two, assay
Measure according to HPLC (2010 editions two appendix V D of Chinese Pharmacopoeia).
Analytical tool: HP1100 high performance liquid chromatograph.
Chromatographic column: ZORBAX anti-phase C
18Chromatographic column 2.1 * 150mm.
Mobile phase: 0.05mol/L phosphate buffer (pH7.0)-methanol (90: 10)
Flow velocity: 1.0ml/min.
Detect wavelength: 275nm.
Algoscopy: precision is measured Thymopentin reference substance solution 20 μ l injecting chromatographs, continuous sample introduction three times, and the record chromatogram, the theoretical cam curve of calculating chromatographic column, it is effective for testing less than 2% to be lower than 1200, three main peak area standard deviations.Precision is measured these article 20 μ l, measures with method,, contains Thymopentin and should be 90.0%～110.0% of labelled amount with these article of calculated by peak area content by external standard method.
According to above-mentioned definite content assaying method, the sample of trial production in three batches has been carried out assay, the result sees table 5.
The assay result of test agent in three batches in the table 5
| Lot number | 20090102 | 20090103 | 20090104 |
| Content (%) | 99.89 | 99.96 | 100.32 |
Conclusion: the assay of the sample of trial production is all up to specification in three batches.
Three, preparation stability test
1, accelerated test:
48 of sample thiefs; Place 40 ℃, 75% humidity lucifuge environment (exsiccator put one fill the supersaturation sodium chloride solution beaker, sample is put in the exsiccator, adds a cover; Exsiccator is put in 40 ℃ of light tight constant temperature ovens) in; Investigate respectively at placing back sampling in the 1st, 2,3,6 month, and investigated data and collection of illustrative plates in 0 month relatively, log.
Three lot sample article make an experiment by accelerated test (40 ℃, 75% humidity lucifuge environment) investigation method respectively, detect at the appointed time on time, and three batches of test samples are investigated six months outward appearances is not had significant change, and related substance, content are all in the limit of regulation.The result shows that these article are stable under accelerated test (40 ℃, 75% humidity) condition.(result of the test is seen table 6,7,8).
40 ℃ of 20090102 batches of thymopentin for injection (tp-5) of table 6,75% humidity accelerated test result
40 ℃ of 20090103 batches of thymopentin for injection (tp-5) of table 7,75% humidity accelerated test result
40 ℃ of 20090104 batches of injections of table 8,75% humidity Thymopentin accelerated test result
2, the long-term indwelling investigated test
48 of sample thiefs (outsourcing aluminium-foil paper) are put in lucifuge, the cool dark place environment, respectively at place the back in the time of the 0th, 3,6,9,12,18,24 month sampling investigate with said method, and investigated data and collection of illustrative plates in 0 month relatively, log.
Three lot sample article make an experiment by long-term indwelling test investigation method regulation respectively, in official hour, detect.The result shows: these article were observed 24 months in lucifuge, cool dark place environment, and outward appearance, related substance, content do not have significant change.Result of the test is seen table 9,10,11.
20090102 batches of thymopentin for injection (tp-5) long-term investigation of table 9 result of the test
20090103 batches of thymopentin for injection (tp-5) long-term investigation of table 10 result of the test
20090104 batches of thymopentin for injection (tp-5) long-term investigation of table 11 result of the test
Conclusion: these article are 6 months no changes of outward appearance under accelerated test (40 ℃, 75% humidity) condition, content, related substance passed examination.These article were observed 24 months in cool dark place, lucifuge environment, and outward appearance and content do not have significant change, and the related substance passed examination does not have impurity peaks to occur, and explains that these article have good stability with this understanding.
The hemolytic test of experimental example 3, thymopentin for injection (tp-5):
1, experiment material
1.1, test sample
Title: the thymopentin for injection (tp-5) (Thymopentin for Iniection) of the embodiment of the invention 1 preparation.Lot number: 20090102.Specification: 50mg/ props up.Physicochemical property: white powder.Stability and keeping: airtight, preserve cool dark place.
1.2, experimental animal
Kind: rabbit.System: large ear rabbit.Sex and quantity: female, 1.Animal age: 16 weeks.The weight of animals: 2.5kg.Animal origin: Beijing section space animal cultivation center.The animal quality certification number: SCXK (capital) 20070003.
2, experimental technique and index detect requirement
2.1, experimental technique
Thymopentin for injection (tp-5): be mixed with 0.1mg/ml with 0.9% sodium chloride injection during test, 1.0mg/ml, 3.3mg/ml3 concentration.
The preparation of blood cell suspension: the rabbit heart extracting blood, put to remove in the dry vessel and defibrinate.Add 0.9% sodium chloride injection shake up gently the back centrifugal (1500 commentaries on classics/mim, 10mim), abandoning supernatant, repeatedly several times, to clear liquid colourless till.Adding 0.9% sodium chloride injection, to be diluted to 2% blood cell suspension subsequent use.
Get test tube, add various solution according to following order:
3 concentration of thymopentin for injection (tp-5) all add various solution according to last table, and each series is made 2 parallel pipes.The test tube that will add liquid is mixing gently, puts 37 ℃ of constant temperature and places, respectively at 0.5,1.0,2.0,3.0,4.0 h observation.
2.2, criterion
2.2.1 clear like solution becomes, and be peony, haemolysis promptly represented.Be designated as "+
2.2.2 if solution appearance is identical with the negative control pipe, then show haemolysis does not take place, be designated as "-"
If 2.2.3 medicinal liquid adds volume is 0.3ml, in 3 hours, do not cause haemolysis, show that then this concentration can be used as intravenous concentration.
2.2.4 when medicinal liquid adding volume is 0.3ml,, then should not make injection as in 0.5 hour, causing haemolysis.
3, experimental result: thymopentin for injection (tp-5) hemolytic test result sees table 12～table 14.
Table 12 thymopentin for injection (tp-5) 0.1mg/ml concentration haemolysis, agglutination result
Annotate: "-" not under this concentration of haemolysis "+" haemolysis each dosing volume test tube be and haemolysis and agglutination occur
By visible in the table 12, thymopentin for injection (tp-5) hemolytic reaction do not occur under 0.1mg/ml concentration.
Table 13 thymopentin for injection (tp-5) 1.0mg/ml concentration haemolysis, agglutination result
Annotate: "-" not under this concentration of haemolysis "+" haemolysis each dosing volume test tube be and haemolysis and agglutination occur
By visible in the table 13, thymopentin for injection (tp-5) hemolytic reaction do not occur under 1.0mg/ml concentration.
Table 14 thymopentin for injection (tp-5) 3.3mg/ml concentration haemolysis, agglutination result
Annotate: "-" not under this concentration of haemolysis "+" haemolysis each dosing volume test tube be and haemolysis and agglutination occur
By visible in the table 14, thymopentin for injection (tp-5) hemolytic reaction do not occur under 3.3mg/ml concentration.
Conclusion: thymopentin for injection (tp-5) 0.1,1.0,3.3mg/ml solution 0.3ml reaction tube haemolysis do not occur in 3 hours.
Embodiment 4, large bolus injection are treated the antiviral curative effect and the safety clinical observation of serious symptom hepatitis B with Thymopentin:
One, object and method
1, physical data
Observe the positive serious symptom hepatitis B patient of 195 routine HBeAg altogether from year June in JIUYUE, 2007 to 2011, diagnosis meets " viral hepatitis is prevented and treated scheme " of the whole nation, Xi'an in 2000 viral hepatitis academic conference revision.Male's 133 examples wherein, women's 62 examples, age 18～68, average 37.4 years old.HBeAg was all positive when all patients were selected, HBV dna level＞1 * 10
5IU/ml.
2, Therapeutic Method
The patient is divided into two groups, uses heavy dose of Thymopentin (50mg/ time) associating adefovir ester and the treatment of routine dose Thymopentin (10mg/ time) associating adefovir ester respectively, 24 weeks of the course of treatment.
Medication: heavy dose of Thymopentin: thymopentin for injection (tp-5) (50mg/ props up), 50mg/ time, the next day 1 time, subcutaneous injection; The routine dose Thymopentin: thymus gland pentapeptide injection (10mg/ props up), 10mg/ time, the next day 1 time, subcutaneous injection; Adefovir ester: adefovir ester sheet (10mg/ sheet), 10mg/ time, 1 time on the one, oral.
3, observation index
Leading indicator: HBVDNA drop-out value.Less important index: HBVDNA suppression ratio, HBVDNA decline 2log ratio, HBeAg negative conversion rate, HBeAg/HBeAb conversion ratio, ALT normalization rate.Safety indexes: routine blood test, routine urinalysis and renal function.That above index is all treated is preceding, respectively observed in 24 weeks 1 time in treatment 12 weeks of back, treatment back.
4, detection method
HBVDNA adopts the PCR detection by quantitative; The hepatitis B serum markers adopts enzyme linked immunosorbent assay to detect; Liver function adopts the AU5400 automatic clinical chemistry analyzer to detect.
5, statistical analysis
Data statistic analysis adopts SAS 9.2 statistical analysis softwares to calculate.All statistical test all adopt two-sided test, and the P value is less than or equal to 0.05 difference that will be considered to checked has statistical significance.
Measurement data will adopt mean ± standard deviation to carry out descriptive statistics.Compare after the treatment with before the treatment, adopt relatively front and back difference of paired t-test; Relatively adopt variance analysis between group.
Enumeration data adopts frequency (constituent ratio) to carry out descriptive statistics.χ is adopted in variation before and after the treatment
2Check.
Two, result
1, baseline case
Observe 195 routine patients altogether, heavy dose of Thymopentin group 130 examples, conventional group 65 examples.Aspects such as the demography data during baseline, the serious symptom hepatitis B course of disease, HBVDNA logarithm value, ALT, two groups are compared zero difference, show that two groups have comparability.
2, clinical curative effect analysis
2.1, main curative effect index
When carrying out efficacy analysis, for reaching the case that can't detect, its HBVDNA level is by lower limit.
HBVDNA decline logarithm value
Serum HBV DNA (logarithm value) drop-out value after 12 weeks of treatment, the heavy dose group is 4.24, and conventional group is that compare 3.36, two groups of group internal therapies front and back, and difference has statistical significance (p＜0.0001), points out two groups of treatments all can obviously reduce the HBVDNA level.Relatively, difference has statistical significance (p＜0.0001) between two groups of groups, and the heavy dose of group of prompting curative effect is superior to conventional group (seeing table 1).
Serum HBV DNA (logarithm value) drop-out value after 24 weeks of treatment, the heavy dose group is 4.33, and conventional group is that compare 3.61, two groups of group internal therapies front and back, and difference has statistical significance (p＜0.0001), points out two groups of treatments still to have the effect that reduces the HBVDNA level significantly.Relatively, difference has statistical significance (p=0.0009) between two groups of groups, and the heavy dose of group of prompting curative effect is superior to conventional group (seeing table 15).
The HBVDNA logarithm value changes before and after table 15 treatment
Annotate: compare p＜0.0001 in the * group; Compare p＜0.0001 in the & group;
2.2, the secondary efficacy index
2.2.1, serum HBV DNA suppresses situation fully
After treating for 12 weeks, heavy dose of group has 42.86% (54/126 example) case serum HBV DNA to suppress (＜1 * 10 fully
2), conventional group then is 27.42% (17/62 example), and two groups are relatively, and difference has statistical significance (p=0.0401); After treating for 24 weeks, heavy dose of group has 62.10% (77/124 example) case serum HBV DNA to suppress fully, and conventional group then is 38.46% (25/65 example), and two groups relatively, and difference has statistical significance (p=0.0020).Be illustrated in the complete suppression ratio of HBVDNA aspect, heavy dose of Thymopentin group curative effect is superior to conventional group (seeing table 16).
Table 16 treatment back HBVDNA suppresses situation fully
2.2.2, the ratio of serum HBV DNA level decline >=2log10
Treated for 12 weeks, the ratio aspect of serum HBV DNA level decline >=2log10, heavy dose of group is 95.24% (120/126 example), and conventional group is 83.87% (52/62 example), and two groups are relatively, and difference has statistical significance (p=0.0086); Treated for 24 weeks, the ratio of serum HBV DNA level decline >=2log10, heavy dose of group is 90.32% (112/124 example), and conventional group is 78.46% (51/65 example), and two groups are relatively, and difference has statistical significance (p=0.0245).Prompting is aspect the ratio of serum HBV DNA level decline >=2log10, and heavy dose of Thymopentin group curative effect is superior to conventional group (seeing table 17).
Table 17 treatment back HBVDNA logarithm value descends greater than 2 variation
2.2.3, serum HBeAg negative conversion rate
Treated for 12 weeks, aspect serum HBeAg negative conversion rate, heavy dose of group is 8.59% (11/128 example), and conventional group is 6.15% (4/65 example), and two groups relatively, difference not statistically significant (p=0.5496); Treated for 24 weeks, heavy dose of group serum HBeAg negative conversion rate is 39.67% (48/121 example), and conventional group is 23.44% (15/64 example), and two groups relatively, and difference has statistical significance (p=0.0267).Aspect the serum HBeAg negative conversion rate, heavy dose of Thymopentin group curative effect is superior to conventional group (seeing table 18) after 24 weeks of treatment in prompting.
Table 18 treatment back serum HBeAg negative conversion rate situation
2.2.4, serum HBeAg/HBeAb conversion ratio
Treated for 12 weeks, aspect serum HBeAg/HBeAb conversion ratio, heavy dose of group is 3.85% (5/130 example), and conventional group is 0.00% (0/65 example), and two groups relatively, difference not statistically significant (p=0.1092); Treated for 24 weeks, heavy dose of group serum HBeAg/HBeAb conversion ratio is 27.05% (33/122 example), and conventional group is 15.63% (10/64 example), and two groups relatively, difference not statistically significant (p=0.0791).Prompting is aspect serum HBeAg/HBeAb conversion ratio, and heavy dose of Thymopentin group does not have significant difference (seeing table 19) with conventional group curative effect.
Table 19 treatment back serum HBeAg/HBeAb conversion ratio situation
2.2.5, the ALT normalization rate
After treating for 12 weeks, the ALT normalization rate of heavy dose of Thymopentin group is 83.08% (108/130 example), and conventional group is 53.13% (34/64 example), and two groups of comparing differences have statistical significance (p＜0.0001); After treating for 24 weeks, the ALT normalization rate of heavy dose of Thymopentin group is 89.08% (106/119 example), and conventional group is 71.43% (45/63 example), and two groups of comparing differences have statistical significance (p=0.0101).Prompting is aspect the ALT normalization rate, and heavy dose of Thymopentin group curative effect is superior to conventional group (seeing table 20).
Table 20 treatment back ALT normalization rate situation
2.2.6, the ALT drop-out value
After treating for 12 weeks, heavy dose of Thymopentin group ALT decline 147.71 (IU/L), conventional group ALT decline 102.66 (IU/L), two groups of comparing differences have statistical significance (p＜0.0001); After treating for 24 weeks, heavy dose of Thymopentin group ALT decline 149.13 (IU/L), conventional group ALT decline 118.37 (IU/L), two groups of comparing differences have statistical significance (p=0.0019).Point out heavy dose of Thymopentin group being superior to conventional group (seeing table 21) aspect the reduction ALT.
ALT (IU/L) situation of change before and after table 21 treatment
Annotate: compare p＜0.0001 in the * group; Compare p＜0.0001 in the & group;
3, safety analysis
The heavy dose of Thymopentin group leukocyte in treatment 24 week back has 1 example (1/130 example); Blood urea nitrogen (BUN) has 1 example (1/130 example) to have clinical meaning decline, and all the other erythrocyte, platelet, hemoglobin, serum creatinine (Cr), electrocardiogram are not all seen the variation that clinical meaning is arranged.Conventional Thymopentin group leukocyte has 1 example (1/65 example), and platelet has 1 example (1/65 example) to have clinical meaning decline, and all the other erythrocyte, hemoglobin, renal function, electrocardiogram are not all seen the variation that clinical meaning is arranged.Not having other adverse drug reactions takes place.
Conclusion: the result shows, uses heavy dose of Thymopentin 50mg associating adefovir ester 12 and 24 weeks of treatment, and the content that can make serum HBV DNA descends 4.24 and 4.33log10IU/ml during than baseline respectively; Treatment has 27.42% and 62.10% patients serum HBVDNA to suppress (＜1 * 10 fully during 12 and 24 weeks
2), the content that 95.24% and 90.32% patients serum HBVDNA arranged decline>=2log10 during than baseline; After 24 weeks of treatment, serum HBeAg negative conversion rate is 39.67%; The ALT normalization rate is respectively 83.08% and 89.08% after 12 and 24 weeks of treatment; These aspects all significantly are superior to conventional Thymopentin group; Show that heavy dose of Thymopentin associating adefovir ester curative effect is superior to routine dose associating adefovir ester, and strengthen the antiviral curative effect of adefovir ester.
Treating the heavy dose of group in 24 all backs has 1 routine leukocyte and 1 routine BUN to have clinical meaning decline, and the variation that clinical meaning is arranged is not all seen in all the other erythrocyte, hemoglobin, renal function, routine urinalysis and Electrocardioscopy, compares zero difference with the routine group.Not having other adverse drug reactions takes place.Point out heavy dose of Thymopentin clinical practice safety better.
The above; Being merely preferred embodiment of the present invention, is not that the present invention is done any formal and substantial restriction, allly is familiar with the professional and technical personnel; In not breaking away from technical scheme scope of the present invention; The technology contents that is disclosed more than capable of using, and a little change of making, modify the equivalent variations with differentiation, be equivalent embodiment of the present invention; Simultaneously, all foundations essence technology of the present invention all still belongs in the scope of technical scheme of the present invention change, modification and the differentiation of any equivalent variations that above embodiment did.
Claims (2)
1. heavy dose of Thymopentin that is used to treat the serious symptom hepatitis B patient, it is characterized in that: the specification of said heavy dose of Thymopentin is 50mg.
2. the described heavy dose of Thymopentin that is used for treating the serious symptom hepatitis B patient of claim 1 is in the application for preparing treatment serious symptom hepatitis B patient medicine, and it is characterized in that: the specification of said heavy dose of Thymopentin is 50mg.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660407A (en) * | 2005-01-21 | 2005-08-31 | 北京维信开泰医药科技发展有限公司 | Liquid preparation containing penta peptide of thymus and preparing method |
| CN1676162A (en) * | 2004-03-30 | 2005-10-05 | 北京中科亚光生物科技有限公司 | Thymic penta peptide injection liquid |
| CN1739786A (en) * | 2005-05-11 | 2006-03-01 | 北京双鹭药业股份有限公司 | Thymic pentapeptide aqua prepn and its prepn process and application |
| CN101244255A (en) * | 2007-02-14 | 2008-08-20 | 成都地奥九泓制药厂 | Thymus gland pentapeptide injection and uses thereof |
| CN101411864A (en) * | 2008-12-02 | 2009-04-22 | 上海华源药业（宁夏）沙赛制药有限公司 | Thymopentin dry powder formulation and preparation method thereof |
| CN101683519A (en) * | 2008-08-25 | 2010-03-31 | 海南中和多肽药物研发有限公司 | Composition of thymic peptide alpha 1 and thymopeptide-5 and preparation method thereof |
-
2011
- 2011-12-14 CN CN201110417354.2A patent/CN102488884B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1676162A (en) * | 2004-03-30 | 2005-10-05 | 北京中科亚光生物科技有限公司 | Thymic penta peptide injection liquid |
| CN1660407A (en) * | 2005-01-21 | 2005-08-31 | 北京维信开泰医药科技发展有限公司 | Liquid preparation containing penta peptide of thymus and preparing method |
| CN1739786A (en) * | 2005-05-11 | 2006-03-01 | 北京双鹭药业股份有限公司 | Thymic pentapeptide aqua prepn and its prepn process and application |
| CN101244255A (en) * | 2007-02-14 | 2008-08-20 | 成都地奥九泓制药厂 | Thymus gland pentapeptide injection and uses thereof |
| CN101683519A (en) * | 2008-08-25 | 2010-03-31 | 海南中和多肽药物研发有限公司 | Composition of thymic peptide alpha 1 and thymopeptide-5 and preparation method thereof |
| CN101411864A (en) * | 2008-12-02 | 2009-04-22 | 上海华源药业（宁夏）沙赛制药有限公司 | Thymopentin dry powder formulation and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| GIOVANNA FATTOVICH ET AL: "A randomized controlled trial of thymopentin therapy in patients with chronic hepatitis B", 《JOURNAL OF HEPATOLOGY》 * |
| 张绪清等: "胸腺五肽治疗慢性重型乙型病毒性肝炎的疗效评价", 《第三军医大学学报》 * |
| 袁喆等: "胸腺五肽治疗重型肝炎临床疗效观察", 《现代医药卫生》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536898A (en) * | 2013-10-31 | 2014-01-29 | 成都天台山制药有限公司 | Thymopentin (TP-5) drug composition |
| CN103536898B (en) * | 2013-10-31 | 2015-06-17 | 成都天台山制药有限公司 | Thymopentin (TP-5) drug composition |
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