CN102488884B - 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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- CN102488884B CN102488884B CN201110417354.2A CN201110417354A CN102488884B CN 102488884 B CN102488884 B CN 102488884B CN 201110417354 A CN201110417354 A CN 201110417354A CN 102488884 B CN102488884 B CN 102488884B
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- 238000002347 injection Methods 0.000 title abstract description 45
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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 for the treatment of severe hepatitis.
Background technology
Thymopentin, Full Name in English is Thymopoietin or Timunox, and english abbreviation is TP-5, and it is comprised of arginine, lysine, aspartic acid, valine and tyrosine five seed amino acids, and chemical structural formula is
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 Thymic hormone.Thymosin can be induced differentiation and the maturation of T-cell subsets, also can strengthen the reactivity worth of all kinds of T-cells, and then regulates whole immune function.
Several single polypeptide compounds have now been isolated from thymosin, as thymopoietin II (Thymopoietin II), by 49 aminoacid, formed, other are also just like thymosin α1 (Thymosin α 1), serum thymic factor (FTS), thymic humoral factors (THF) etc., wherein to the most study of thymopoietin II.Find afterwards the amino acid residue fragment (being essence-Lai-Radix Asparagi-figured silk fabrics-tyrosine) of thymopoietin 32-36 position, the whole physiological functions identical with thymopoietin were arranged, be referred to as Thymopentin (Thymopentin, TP-5).
On clinical liver disease, Thymopentin is usually used in treating hepatitis B infected low with Immune Function.Hepatitis B patient is often with the low problem of Immune Function, Thymopentin is by improving Immune Function, induce endogenous interferon, improve level and the expression of receptor level of interleukin-2, improve the phagocytic function of activity of natural killer cell and macrophage, to improve the treatment level of difficult chronic hepatitis.Normal drug combination is used for the treatment of hepatitis B clinically.
Thymopentin is the earliest by Johnson & The exploitation of Johnson company, went on the market as immunostimulant and immunomodulator in Italy, Germany in 1985, 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 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.Current national Bureau of Drugs Supervision accepts again, ratifies the application for registration of many unit Thymopentin and thymopentin for injection (tp-5), and product rule are 1mg and 10mg, and the domestic 50mg product that there is no are at present advised.
On clinical liver disease, the shortage of 50mg product rule, restricted the application of this product at clinical liver disease.Hepatopathy patients is the general single administration 50mg of liver failure patient particularly, and the specification that hospital is used is propped up for 10mg/, and 5ml, by subcutaneous or drug administration by injection, needs injection 5 times, and patient is very painful, and compliance is poor, is badly in need of clinically the product rule that 50mg/ props up.
Summary of the invention
Owing to only having at present 10mg/ to prop up the Thymopentin of specification, therefore critically ill patient need to 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 for the treatment of 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 as follows:
A kind of heavy dose of Thymopentin that is used for the treatment of the serious symptom hepatitis B patient, wherein, the specification of described heavy dose of Thymopentin is 50mg.
The application of the heavy dose of Thymopentin that is used for the treatment of the serious symptom hepatitis B patient described in technique scheme in preparation treatment serious symptom hepatitis B patient medicine, wherein, the specification of described heavy dose of Thymopentin is 50mg.
The specification of mentioning in the present invention is identical with the specification definition in 10mg Thymopentin product description.
Large bolus injection provided by the invention is comprised of Thymopentin 50000mg, mannitol 50000mg and water for injection 1000ml with the Thymopentin prescription.
Its preparation technology is as follows: take Thymopentin 50000mg, mannitol 50000mg by above-mentioned recipe quantity and add water for injection to dissolve, mix, be settled to 1000 milliliters, 0.2 μ M membrane filtration degerming, being sub-packed in specification is in the 2ml cillin bottle, in every cillin bottle, packing 1ml, jump a queue, lyophilization, gland, labeling, packing, obtain.
Its concrete operation step is:
1), solution preparation:
In ten thousand grades of clean rooms, get the recipe quantity Thymopentin, mannitol adds in about 900ml water for injection, shakes up, and is settled to 1000 milliliters, obtain.
2), endotoxin detection
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 this product fill, jump a queue.1 milliliter of every loading amount, 2 milliliters of cillin bottles and plug thereof all according to GMP require to be cleaned, sterilizing and depyrogenation, all in preparation preparation, pouring process utensil used all according to GMP require to be cleaned, sterilizing and depyrogenation, lyophilization, the jewelling lid, label, packing, obtain.
Described cryodesiccated step is as follows:
1, pre-freeze: the drain Temperature Setting is-46--50 ℃ that drain reaches-46 ℃ and keeps starting to fall cold-trap after 3-5 hour.
Start evacuation when 2, condenser temperature is lower than-55 ℃, primary drying, the drain Temperature Setting is-20 ℃, the drain temperature keeps 1-2 hour to-20 ℃, then 10 ℃ of every risings of drain temperature keep 1-2 hour, vacuum is set as 0.16 ± 0.01mbar, the vacuum degree control scope is≤0.23mbar or≤5.20V.
3, redrying, the drain Temperature Setting is 38-40 ℃ and keeps 5-8 hour after temperature, vacuum is set as 0.09 ± 0.02mbar, the vacuum degree control scope is≤0.14mbar or≤4.80V.
Another object of the present invention is to provide the large bolus injection application of Thymopentin aspect the treatment severe hepatitis.
According to " the guideline (2010 editions) ", treatment of chronic mainly comprises antiviral, immunomodulating, antiinflammatory and antioxidation, fibrosis and symptomatic treatment.Current all kinds of antiviral agents is the inhibition virus replication, can not thoroughly remove virus, and treatment is very long the course for the treatment of, the withdrawal time that can't estimate, and hepatopathy doctor and patient are still being perplexed in the drug resistance of period in a medicine and the virus after drug withdrawal and biochemical bounce-back.Virus sweep may be by immunization therapy thoroughly, improves the immunologic function of body and obtains.Thymopentin can stimulate Cellular Immunity, be conducive to the hepatitis B virus of Low-level Replication is removed fully, thereby make up the shortcoming that antiviral drugs can not directly be removed hepatitis B virus, not only the more alone medicine of curative effect is good, and can reduce the rebound phenomenon after drug resistance and drug withdrawal.
The positive severe hepatitis of Thymopentin (50mg/ time) associating adefovir ester treatment HBeAg for large bolus injection of the present invention, and its antiviral effect and safety have been carried out to clinical observation.Show that by clinical observation heavy dose of Thymopentin can significantly strengthen the Anti-viral Treatment of adefovir ester, and safety is better, it is a kind of medicine of effective, safe treatment severe hepatitis, belong to domestic and international reported first, be worth the antiviral therapy in patients with severe hepatitis B at clinical application.
Large bolus injection of the present invention adopts the 50mg specification with Thymopentin, facilitates the administration of serious symptom hepatitis B patient, improves the compliance of this patient colony, meets the specific demand of serious symptom hepatitis B patient, is the important supplement of current clinical use specification.
The present invention has following beneficial effect:
1, the Thymopentin of 50mg specification of the present invention is combined the Anti-viral Treatment that can significantly strengthen adefovir ester while using with antiviral agents nucleotide analog adefovir ester, and safety is better, it is a kind of medicine of effective, safe treatment severe hepatitis;
2, large bolus injection of the present invention adopts the 50mg specification with Thymopentin, facilitates the administration of serious symptom hepatitis B patient, improves the compliance of this patient colony, meets the specific demand of serious symptom hepatitis B patient, is the important supplement of current clinical use specification;
3, because human body is 4ml, is 3ml by hypodermic maximum amount of liquid medicine by the maximum amount of liquid medicine of intramuscular injection at every turn, 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 current 10mg specification, if make to inject the injection volume that total amount reaches 50mg, need to carry out spaced injection repeatedly.
The specific embodiment:
For making technical scheme of the present invention be convenient to understand, below in conjunction with the specific embodiment, the present invention is further illustrated.
embodiment 1: the preparation of Thymopentin for large bolus injection (50mg):
1), solution preparation:
In ten thousand grades of clean rooms, get recipe quantity Thymopentin 50000mg, mannitol 50000mg and add in about 900ml water for injection, shake up, be settled to 1000 milliliters, obtain.
2), endotoxin detection
Limulus test is done in sampling, and every milliliter of endotoxin content of result is less than 2.5EU.
3), content monitoring
With high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), sampling detects the content of Thymopentin, result show that the content of Thymopentin in sample is labelled amount 90%～110%., 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 this product fill, jump a queue.1 milliliter of every loading amount, 2 milliliters of cillin bottles and plug thereof all according to GMP require to be cleaned, sterilizing and depyrogenation, all in preparation preparation, pouring process utensil used all according to GMP require to be cleaned, sterilizing and depyrogenation.
6), lyophilization
1. pre-freeze: the drain Temperature Setting is-46 ℃, and drain reaches-46 ℃ and keeps starting to fall cold-trap after 5 hours.
Start evacuation when 2. condenser temperature is lower than-55 ℃, primary drying, the drain Temperature Setting is-20 ℃, the drain temperature keeps 2 hours to-20 ℃, then 10 ℃ of every risings of drain temperature keep 1.5 hours, and vacuum is set as 0.16mbar, the vacuum degree control scope is≤0.23mbar or≤5.20V.
3. redrying, the drain Temperature Setting is 38 ℃ and keeps 8 hours after temperature, vacuum is set as 0.09mbar, the vacuum degree control scope is≤0.14mbar or≤4.80V.
7), freezing after, jewelling lid, label, packing obtains the Thymopentin of 50mg specification of the present invention.
embodiment 2, the effect detection of Thymopentin (50mg) for large bolus injection:
One, check
1, acid-base value
Test method: pH value algoscopy (2010 editions two appendix VI H of Chinese Pharmacopoeia)
The mensuration process: get at random 3 batches of the Thymopentin that embodiment 1 prepares the 50mg specification of gained, by its lot number called after 20090102,20090103 and 20090104, every adds water 5ml and makes it to dissolve, and measures pH in accordance with the law.
Result: three batches of test sample pH value are all between 6.0～8.0.Determination data is in Table 1.
Table 1 thymopentin for injection (tp-5) Basicity Determination result
2, clarity of solution and color
Test method: get 5 of this product, add respectively water 1ml and dissolve, solution is answered achromaticity and clarification; As aobvious muddy, with No. 1 turbidity standard solution (two appendix IX B of Chinese Pharmacopoeia version in 2010), relatively, all must not be denseer.
Conclusion: three batches of equal achromaticity and clarifications of need testing solution.
3, determination of water
This product, with reference to two appendix appendix VIII M first methods of Chinese Pharmacopoeia (2010 editions), is carried out determination of water to three batches of test samples.
Three batches of test sample moisture all are no more than 5.0%, and measurement result is in Table 2.
Table 2 thymopentin for injection (tp-5) determination of water result
Result: the water content of three batches of test samples all meets a lower limit and requires (being no more than 5.0%).
4, related substance
The inspection of thymopentin for injection (tp-5) quality standard related substance adopts high performance liquid chromatography (2010 editions two appendix V D of Chinese Pharmacopoeia), and this product adopts with the Thymopentin related substance and checks same procedure.Determining instrument, chromatographic program are with under the assay item.
Algoscopy: get this product, add mobile phase and dissolve and be diluted in every 1ml solution containing Thymopentin 5mg as test solution, it is appropriate that precision measures test solution, adds mobile phase and make in every 1ml containing the solution of Thymopentin 0.05mg solution in contrast.Precision measures contrast solution 20 μ l injection liquid chromatographies, adjusts instrumental sensitivity, and making the main constituent peak height is 10%～20% of monitor full scale, and precision measures test solution 20 μ l sample introductions, records to main constituent peak retention time 2.5 times of chromatogram.
Result: the single maximum contaminant peak area in the three batches of test sample chromatograms except main peak, solvent peak all is not more than 1.5 times (1.5%) of contrast solution main peak area, impurity peak area and be not more than 2.5 times (2.5%) of contrast solution main peak area.
Three batches of test sample testing results are in 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 and (%) |
| 20090102 | 0.053 | 0.10 |
| 20090103 | 0.058 | 0.11 |
| 20090104 | 0.057 | 0.11 |
Simultaneously, also adopted the dual wavelength detection under the related substance detection, further with end absorption, investigated related substance, checking two, three, tetrapeptide and aminoacid, wavelength is respectively 275nm, 203nm, and testing result is as follows:
Test sample related substance testing result under the different detection of table 4 wavelength
Result shows, the unimodal area of 203nm end wavelength place sample impurity and assorted peak area and lower than the 275nm place, in formulated limit, therefore still adopt 275nm to investigate related substance as detecting wavelength.
Two, assay
According to high performance liquid chromatography (2010 editions two appendix V D of Chinese Pharmacopoeia), measure.
Analytical tool: HP1100 high performance liquid chromatograph.
The anti-phase C of chromatographic column: ZORBAX
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 measures Thymopentin reference substance solution 20 μ l injecting chromatographs, and continuous sample introduction three times, record chromatogram, and the theoretical cam curve of computer chromatography post must not be less than 2% for testing effectively lower than 1200, three main peak area standard deviations.Precision measures this product 20 μ l, is measured in the same method, and by external standard method, with calculated by peak area this product content, containing Thymopentin, should be 90.0%～110.0% of labelled amount.
According to above-mentioned definite content assaying method, the sample of trial production in three batches has been carried out to assay, the results are shown in Table 5.
The assay result of test agent in three batches, table 5
| Lot number | 20090102 | 20090103 | 20090104 |
| Content (%) | 99.89 | 99.96 | 100.32 |
Conclusion: in three batches, the assay of the sample of trial production is all up to specification.
Three, preparation stability test
1, accelerated test:
48 of sample thiefs, (exsiccator is put a beaker that fills the supersaturation sodium chloride solution to be placed in 40 ℃, 75% humidity lucifuge environment, sample is put in exsiccator, add a cover, exsiccator is put in 40 ℃ of light tight constant temperature ovens) in, investigate respectively at sampling in the 1st, 2,3,6 months after placing, and within 0 month, investigate data and trace analysis, log.
Three batch samples are tested by accelerated test (40 ℃, 75% humidity lucifuge environment) investigation method respectively, detected at the appointed time on time, three batches of test samples are investigated six months outward appearances without significant change, and related substance, content are all in the limit of regulation.Result shows that this product is stable under accelerated test (40 ℃, 75% humidity) condition.(result of the test is in 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, Preserving time is investigated test
48 of sample thiefs (outsourcing aluminium-foil paper), put in lucifuge, cool dark place environment, respectively at after placing the 0th, 3,6,9,12,18,24 months the time for sampling said method investigate, and within 0 month, investigate data and trace analysis, log.
Three batch samples are tested by Preserving time test investigation method regulation respectively, in official hour, are detected.Result shows: this product is observed 24 months in lucifuge, cool dark place environment, and outward appearance, related substance, content are without significant change.Result of the test is in Table 9,10,11.
20090102 batches of thymopentin for injection (tp-5) long-term investigation result of the tests of table 9
20090103 batches of thymopentin for injection (tp-5) long-term investigation result of the tests of table 10
20090104 batches of thymopentin for injection (tp-5) long-term investigation result of the tests of table 11
Conclusion: these product outward appearance 6 months under accelerated test (40 ℃, 75% humidity) condition is unchanged, content, related substance passed examination.These product have been 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, illustrates that these product 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 present 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: KeYu animal cultivation center, Beijing.The animal quality certification number: SCXK (capital) 20070003.
2, experimental technique and index testing 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: Rabbit Heart is got blood, puts in dry vessel except defibrinating.Add 0.9% sodium chloride injection and shake up gently rear centrifugal (1500 turn/mim, 10mim), abandoning supernatant, repeatedly several times, colourless to clear liquid till.Add 0.9% sodium chloride injection to be diluted to 2% blood cell suspension standby.
Get test tube, according to following order, add various solution:
3 concentration of thymopentin for injection (tp-5) all add various solution according to upper table, and each series is made 2 parallel pipes.The test tube that has added liquid is mixed gently, put 37 ℃ of constant temperature and place, observed respectively at 0.5,1.0,2.0,3.0,4.0 hour.
2.2, criterion
2.2.1 as solution becomes clear, and be peony, mean haemolysis.Be designated as "+
2.2.2 if solution appearance is identical with the negative control pipe, show not occur haemolysis, be designated as "-"
If be 0.3ml 2.2.3 medicinal liquid adds volume, do not cause haemolysis in 3 hours, show that this concentration can be used as intravenous concentration.
2.2.4, when medicinal liquid adds volume to be 0.3ml, as in 0.5 hour, caused haemolysis, should not make injection.
3, experimental result: the thymopentin for injection (tp-5) hemolytic test the results are shown in 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
From in 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
From in 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
From in 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 Anti-viral Treatment and the safety clinical observation of severe hepatitis with Thymopentin:
One, object and method
1, physical data
Observe altogether the positive patients with severe hepatitis B of 195 routine HBeAg year June from 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.When all patients are selected, HBeAg is all positive, HBV DNA level>1 * 10
5iU/ml.
2, Therapeutic Method
The patient is divided into two groups, applies respectively heavy dose of Thymopentin (50mg/ time) associating adefovir ester and the treatment of routine dose Thymopentin (10mg/ time) associating adefovir ester, 24 weeks courses for the treatment of.
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: dosing adefovir dipivoxil tablets (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.Before above index is all treated, the treatment after 12 weeks, the treatment after within 24 weeks, respectively observe 1 time.
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 be calculated.All statistical test all adopt two-sided test, and the P value is less than or equal to 0.05 and will be considered to checked difference statistical significance is arranged.
Measurement data will adopt mean ± standard deviation to carry out descriptive statistics.Compare difference before and after the employing paired t-test compares after treating with before treatment; Relatively adopt variance analysis between group.
Enumeration data adopts frequency (constituent ratio) to carry out descriptive statistics.Variation before and after treatment adopts χ
2check.
Two, result
1, baseline case
Observe altogether 195 routine patients, heavy dose of Thymopentin group 130 examples, conventional group 65 examples.The aspects such as demography data during baseline, the severe hepatitis 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, the 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
Treat serum HBV DNA (logarithm value) drop-out value after 12 weeks, heavy dose of group is 4.24, and conventional group is to compare before and after 3.36, two groups of group internal therapies, and difference has statistical significance (p<0.0001), points out two groups of treatments all can obviously reduce the HBVDNA level.Between two groups of groups, relatively, difference has statistical significance (p<0.0001), and the heavy dose of group of prompting curative effect is better than conventional group (in Table 1).
Treat serum HBV DNA (logarithm value) drop-out value after 24 weeks, heavy dose of group is 4.33, and conventional group is to compare before and after 3.61, two groups of group internal therapies, difference has statistical significance (p<0.0001), points out two groups of treatments still to have the effect that reduces significantly the HBVDNA level.Between two groups of groups, relatively, difference has statistical significance (p=0.0009), and the heavy dose of group of prompting curative effect is better than conventional group (in Table 15).
Before and after table 15 treatment, the HBVDNA logarithm value changes
Annotate: in the * group, compare p<0.0001; & Compare p<0.0001 in group;
2.2, the secondary efficacy index
2.2.1, serum HBV DNA suppresses situation fully
After treating 12 weeks, heavy dose of group has 42.86% (54/126 example) case serum HBV DNA to suppress (<1 * 10 fully
2), conventional group is 27.42% (17/62 example), and two groups are relatively, and difference has statistical significance (p=0.0401); After treating 24 weeks, heavy dose of group has 62.10% (77/124 example) case serum HBV DNA to suppress fully, and conventional group is 38.46% (25/65 example), and two groups relatively, and difference has statistical significance (p=0.0020).Show that, aspect the complete suppression ratio of HBVDNA, heavy dose of Thymopentin group curative effect is better than conventional group (in Table 16).
After table 16 treatment, HBVDNA suppresses situation fully
2.2.2, the ratio of serum HBV DNA levels decline >=2log10
Treat 12 weeks, the ratio aspect of serum HBV DNA levels 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); Treat 24 weeks, the ratio of serum HBV DNA levels 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 levels decline >=2log10, and heavy dose of Thymopentin group curative effect is better than conventional group (in Table 17).
The variation that after table 17 treatment, the decline of HBVDNA logarithm value is greater than 2
2.2.3, serum HBeAg negative conversion rate
Treat 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); Treat 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).Prompting is after treating 24 weeks aspect serum HBeAg negative conversion rate, and heavy dose of Thymopentin group curative effect is better than conventional group (in Table 18).
Serum HBeAg negative conversion rate situation after table 18 treatment
2.2.4, serum HBeAg/HBeAb conversion ratio
Treat 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); Treat 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 is organized curative effect without significant difference (in Table 19) with routine.
Serum HBeAg/HBeAb conversion ratio situation after table 19 treatment
2.2.5, the ALT normalization rate
After treating 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 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 better than conventional group (in Table 20).
ALT normalization rate situation after table 20 treatment
2.2.6, the ALT drop-out value
After treating 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 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 better than conventional group (in Table 21) aspect reduction ALT.
ALT (IU/L) situation of change before and after table 21 treatment
Annotate: in the * group, compare p<0.0001; & Compare p<0.0001 in group;
3, safety analysis
Treat heavy dose of Thymopentin group leukocyte after 24 weeks 1 example (1/130 example) is arranged, 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 showed no the variation of clinical meaning.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 showed no the variation of clinical meaning.Without other adverse drug reactions, occur.
Conclusion: result shows, applies heavy dose of Thymopentin 50mg associating adefovir ester treatment 12 and 24 weeks, and the content that can make serum HBV DNA descends respectively 4.24 and 4.33log10IU/ml during than baseline; While treating 12 and 24 weeks, there is 27.42% and 62.10% patients serum HBVDNA to suppress (<1 * 10 fully
2), the content that 95.24% and 90.32% patients serum HBVDNA arranged decline>=2log10 during than baseline; After treatment 24 weeks, serum HBeAg negative conversion rate is 39.67%; Treat ALT normalization rate after 12 and 24 weeks and be respectively 83.08% and 89.08%, these aspects all significantly are better than conventional Thymopentin group, show that heavy dose of Thymopentin associating adefovir ester curative effect is better than routine dose associating adefovir ester, and strengthen the Anti-viral Treatment of adefovir ester.
Treating after 24 weeks heavy dose of group has 1 routine leukocyte and 1 routine BUN to have clinical meaning to descend, and all the other erythrocyte, hemoglobin, renal function, routine urinalysis and Electrocardioscopy are showed no the variation of clinical meaning, with routine group zero difference relatively.Without other adverse drug reactions, occur.Point out heavy dose of Thymopentin clinical practice safety better.
The above, it is only preferred embodiment of the present invention, not the present invention is done to any formal and substantial restriction, all those skilled in the art, within not breaking away from the technical solution of the present invention scope, when utilizing the disclosed above technology contents, and the equivalent variations of a little change of making, modification and differentiation is equivalent embodiment of the present invention; Simultaneously, the change of any equivalent variations that all foundations essence technology of the present invention is done above embodiment, modification and differentiation, all still belong in the scope of technical scheme of the present invention.
Claims (1)
1. heavy dose of Thymopentin and the adefovir ester application in preparation treatment severe hepatitis medicine, it is characterized in that: described heavy dose of Thymopentin specification is 50mg, by Thymopentin 50000mg, mannitol 50000mg and water for injection 1000ml, by following preparation technology, is made:
1), solution preparation:
In ten thousand grades of clean rooms, get the recipe quantity Thymopentin, mannitol adds in about 900ml water for injection, shakes up, and is settled to 1000 milliliters, obtain;
2), endotoxin detection
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 this product fill, jump a queue, 1 milliliter of every loading amount, 2 milliliters of cillin bottles and plug thereof all according to GMP require to be cleaned, sterilizing and depyrogenation, all in preparation preparation, pouring process utensil used all according to GMP require to be cleaned, sterilizing and depyrogenation, lyophilization, the jewelling lid, label, packing, obtain; Described cryodesiccated step is as follows:
1, pre-freeze: the drain Temperature Setting is-46--50 ℃ that drain reaches-46 ℃ and keeps starting to fall cold-trap after 3-5 hour;
Start evacuation when 2, condenser temperature is lower than-55 ℃, primary drying: the drain Temperature Setting is-20 ℃, the drain temperature keeps 1-2 hour to-20 ℃, then 10 ℃ of every risings of drain temperature keep 1-2 hour, vacuum is set as 0.16 ± 0.01mbar, the vacuum degree control scope is≤0.23mbar or≤5.20V;
3, redrying: the drain Temperature Setting is 38-40 ℃, after temperature, keeps 5-8 hour, and vacuum is set as 0.09 ± 0.02mbar, the vacuum degree control scope is≤0.14mbar or≤4.80V.
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| CN100337684C (en) * | 2005-05-11 | 2007-09-19 | 北京双鹭药业股份有限公司 | Thymic pentapeptide aqua prepn and its prepn process and application |
| CN101244255B (en) * | 2007-02-14 | 2011-08-03 | 成都地奥九泓制药厂 | Thymus gland pentapeptide injection and uses thereof |
| CN101683519B (en) * | 2008-08-25 | 2012-01-25 | 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 |
| CN101411864B (en) * | 2008-12-02 | 2011-08-10 | 上海华源药业（宁夏）沙赛制药有限公司 | Thymopentin dry powder formulation and preparation method thereof |
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2011
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