CN1488343A - Tiopronin freeze-dried powder injection - Google Patents

Tiopronin freeze-dried powder injection Download PDF

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Publication number
CN1488343A
CN1488343A CNA021594139A CN02159413A CN1488343A CN 1488343 A CN1488343 A CN 1488343A CN A021594139 A CNA021594139 A CN A021594139A CN 02159413 A CN02159413 A CN 02159413A CN 1488343 A CN1488343 A CN 1488343A
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injection
tiopronin
dextran
chemical compound
dried powder
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CN1194678C (en
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穆来安
杨波
刘晨江
邵长青
宋祥林
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Henan Xinyi Pharmaceutical Co ltd
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XINYI PHARMACEUTICAL CO Ltd HENAN PROV
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Abstract

The invention refers to a Tiopronin freeze-dried powder-form injection for treating chronic liver diseases. It comprises active Tiopronin compound 1-1000mg, like 50mg, 100mg or 200mg, and the receivable carrier of drug is selected from one or multiple of low-molecular dextran, mannite, cyclodextrin, soluble amylum, glucide, NaCl, benzoic acid, cellulose or water. It also refers to the making method including the steps of preparing medical liquid, eliminating heat source, sterilizing, canning and freeze-drying.

Description

Thiopronine freeze dried powder injection agent
Technical field
The present invention relates to medicine and formulation art thereof, particularly, the present invention relates to hepatic tiopronin and freezing-dried powder injection thereof and preparation method thereof.
Background technology
Tiopronin (English name: Tiopronin) be a kind of metabolism improving antidote, its molecular formula: C 5H 9NO 3S, molecular weight: 163.20, structural formula is as follows:
Figure A0215941300041
Its liver function that is mainly used in chronic hepatopathy is improved.Oral and the water needle injection of this product goes on the market at present.Existing injection is the aqueous pharmaceutical of tiopronin sodium salt of 2ml or 5ml concentration 5% of packing in per 1 ampoule, because tiopronin is poor at water stability, oxidation reaction easily takes place, so there is short drawback of storage time in aqueous solution injection, use effect duration short, influenced the safety of this product and effectively use.Powder injection formulation can address the above problem, but because the fusing point lower (96-99 ℃) of tiopronin and the poor stability of tiopronin, so should not adopt high temperature sterilization to make the Injectable sterile powder.
The present invention finds to adopt cryodesiccated method that tiopronin is made the sterile injection powder preparation through research, not only can address the aforementioned drawbacks, and the freezing-dried powder injection of the inventive method preparation has good stability.
Goal of the invention
Therefore, the purpose of this invention is to provide a kind of Thiopronine freeze dried powder injection agent;
Another object of the present invention has provided a kind of method for preparing Thiopronine freeze dried powder injection agent;
Another object of the present invention has provided a kind of purposes with Thiopronine freeze dried powder injection agent preparation treatment hepatitis medicament.
Summary of the invention
Thiopronine freeze dried powder injection agent of the present invention is become to be grouped into the medicine acceptable carrier by the active component tiopronin, wherein said medicine acceptable carrier can be selected from one or more in low molecular dextran, mannitol, cyclodextrin, soluble starch, glucide, sodium chloride, benzoic acid or the cellulose substances, preferred low molecular dextran, especially preferred Dextran 40.Wherein, the weight ratio between tiopronin and the medicine acceptable carrier can be 1-10: 1, and preferred 1-2: 1.
Injection preferred group of the present invention becomes active component tiopronin and Dextran 40 (low molecular dextran), and wherein the weight ratio of tiopronin and Dextran 40 is 1-3: 1, and preferred 2: 1.The specification of injection of the present invention preferably contains reactive compound tiopronin 50mg, 100mg or 200mg for containing reactive compound tiopronin 1-1000mg.
Freezing-dried powder injection of the present invention prepares in order to the below method:
The preparation method of Thiopronine freeze dried powder injection agent of the present invention comprises the following steps:
A. preparating liquid: be about to the active component tiopronin and add the dissolving of injection water, add medicine acceptable carrier mixing, add the injection water to ormal weight;
B. depyrogenation: in the medicinal liquid of step a, add injection and filtered in 30 minutes in 60-80 ℃ of heating with active carbon;
C. degerming: the filtrate of step b is carried out the malleation degerming with germ tight filter filter;
D. canned: as to carry out sterile filling with the control cillin bottle;
E. lyophilizing: under cryogenic vacuum, carry out lyophilization.
To use 1000 Thiopronine freeze dried powder injection agents of 1000ml water for injection preparation to be example, the weight of material scope that the preparation Thiopronine freeze dried powder injection agent uses is:
Tiopronin 5-500g
Dextran 40 (or other pharmaceutically suitable carrier) 50-250g
Water for injection 1000ml
Make 1000 of dried frozen aquatic productses altogether
Concrete steps are as follows:
Preparating liquid:
Take by weighing injection tiopronin raw material (tiopronin content must not be less than 98.5%, contains heavy metal and must not cross 15/1000000ths), add the injection water, make its dissolving, concentration is 0.2g/ml.The 20% low molecular dextran solution mixing of handling through the degerming depyrogenation in advance that adds ormal weight then.Add the injection water again to prescribed volume such as 1000ml, making tiopronin content is 0.1g/ml, and dextran content is 0.05/ml.
Depyrogenation:
Add injection in the above-mentioned medicinal liquid with active carbon (activated carbon dosage is the 0.3-0.5% of tiopronin raw material weight),, filter, collect filtrate 60-80 ℃ of heating 30 minutes.
Degerming:
Above-mentioned filtrate is carried out the malleation degerming by aseptic manipulation with germ tight filter filter, pressure with 0.22 μ microporous filter membrane, should carry out the bubbling point test earlier before filtering below 0.1Mpa, and the filtrate sample presentation carries out pyrogen test and semi-finished product content is checked packing then.
Canned:
(1) processing of control cillin bottle: control cillin bottle specification is 5ml, with 0.5-1.0HCl liquid the control cillin bottle is filled during pretreatment, heat-treated in following 30 minutes for 100 ℃, industrial water is washed control cillin bottle (slightly washing), and----pure water is washed control cillin bottle (fine purifiation), and------injection is washed control cillin bottle (washing eventually), the control cillin bottle of cleaning is thoroughly removed pyrogen through 220 ℃ of bakings in following 2 hours. and it is standby to move sterilizing room after reducing to 60 ℃.
(2) fill: carry out fill, the false add plug 100 grades of cleanliness factor ultra-clean workplaces.
Lyophilizing:
In special-purpose freeze drying box, at pre-freeze 1.5-2 below-40 ℃ hour, under-25 ℃, 1.33Pa (0.01 holder) vacuum, distil then, remove after 90% at free moisture, heat drying (maximum temperature must not above 35 ℃) treats that temperature curve overlaps respectively with vacuum curve, promptly can be considered lyophilizing and finish, jump a queue entirely automatically in the freeze drying box.
Seal: the control cillin bottle takes out from freeze drying box in batches, adds aluminium lid and gets final product.
Illustrate: the pH of this product is 1.5-2.5, and acidity is stronger, so the control cillin bottle will be through peracid treatment, to improve the stability and the acidproof ability of control cillin bottle.
Injection of the present invention is used 2ml 5%NaHCO during use 3Injection (special solvent) dissolving joins the injection of transfusion device medium-sized vein, and also medicine or the infusion solution with the other treatment hepatopathy uses simultaneously, together injection, and this injection can use every day, and every day 1-3 time, be 7-10 days a course of treatment.
Injection of the present invention has good stability, and curative effect is good, characteristics easy to use, and relatively liquid drugs injection has better stability, below beneficial effect of the present invention is described by experiment.
One. the preliminarily stabilised experimental study of tiopronin freeze-dried powder injection and tiopronin liquid drugs injection, sodium thio pronine liquid drugs injection
I, test objective:
Tiopronin is as the active drug of treatment chronic persistent hepatitis, and the domestic and international market mainly contains two kinds of dosage forms.A) aqueous injection tablet: 100 of the Zhi Er pleasures of Japanese Santen Pharmaceutical Co. Ltd. and the tiopronin tablets sheet of Henan new friendship Pharmaceutical limited company etc., i.e. tiopronin sheet (specification 100mg) .B): the general sieve sodium of the 5% sulfur aqueous injection (specification 2ml, 5ml) of Japanese Santen Pharmaceutical Co. Ltd..The intravenous injection aqueous injection has rapid-action than oral tablet, bioavailability height, advantages such as good effect.But because of tiopronin (CH 3-CHSH-CONHCH 2COOH) contain active-SH sulfydryl in the structure, easy oxidation deterioration is a dithio thing [structural formula: (CH in the aqueous solution 3CH) 2SS (CONHCH 2COOH) 2] affect the treatment, so tiopronin aqueous injection less stable.With special process tiopronin is made lyophilized injectable powder, solved the stability of injection tiopronin preferably, guaranteed product quality, clinical practice simultaneously has easy to use, rapid-action, bioavailability height, eutherapeutic advantage.With reference to " medical medicine Japan pharmaceuticals collection " the 9th edition (1985) P558＜sodium thio pronine 5% aqueous injection〉method prepared " 5% tiopronin aqueous injection ", " the 5% sodium thio pronine aqueous injection " of specification 2ml.And these preparations have been finished influence factor's stability test of 0-10 days under 40 ℃, 60 ℃ temperature conditions, strong illumination influence factor stability test and the room temperature stability test that keeps sample; Finished under 40 ℃, the 60 ℃ temperature conditions of the present invention " tiopronin freeze-dried powder injection " influence factor's stability test of 0-10 days simultaneously, strong illumination influence factor stability test and the room temperature stability test that keeps sample.Compare then, investigate the product stability of " 5% tiopronin aqueous injection ", " 5% sodium thio pronine aqueous injection ", " tiopronin freeze-dried powder injection ".
The preparation of II, sample
A, 5% tiopronin liquid drugs injection (2ml): get 50g pin tiopronin crude drug, quantitatively be diluted to 1000ml with water for injection, become the 2ml injection with the 2ml ampoule filling, seal, sterilization, lamp inspection promptly get 500 products.
B, 5% sodium thio pronine aqueous injection
Take by weighing 50g injection tiopronin crude drug, earlier with the dissolving of 100ml water for injection, reuse 10%NaHCO 3Transfer pH6-7, and then quantitatively be diluted to 1000ml with injection water and become the 2ml injection with the 2ml ampoule filling, seal, the lamp inspection of sterilizing promptly gets 500 products.
C, 100mg tiopronin freeze-dried powder injection
Get 50g injection tiopronin crude drug, the 25g dextran-40 is with the water for injection dissolving and be diluted to 1000ml, add 1.5g injection active carbon,, filter at 60-80 ℃ of following 0.5 hour depyrogenation, filtrate is used the filtration sterilization of 0.22ul filter membrane malleation, collect bacteria-free filtrate in the sterilizing room, get 2ml and be filled in the cillin bottle, the freeze drying box vacuum freeze-drying, gland is checked promptly to get 500 products.
III, test method:
The main temperature of investigating, tiopronin oxidation product disulphide HPLC method mensuration changes of contents situation in the changes of contents situation of 0-10 days samples and the sample under influence factor's experimental conditions such as strong illumination.
A, Determination on content method:
Precision takes by weighing after content an amount of (being equivalent to tiopronin 300mg approximately) adds water 30ml dissolving, adds starch indicator solution 1ml, with iodine liquid (0.1mol/L) rapidly titration to solution show shallow blue purple, and colour-fast in 30 seconds.Every 1ml iodine liquid (0.1mol/L) is equivalent to the C of 16.32mg 5H 9NO 3S.
B, impurity (dithio thing) HPLC method assay
It is a small amount of to get content, becomes the test liquid of 1mg/ml with distilled water diluting.The HPLC chromatographic condition is as follows:
Pillar: C18 post 250 * 4.6mm 5um
Mobile phase: methanol: water=usefulness phosphoric acid was transferred pH2.5 in 3: 7
Detect wavelength: 205nm
Flow velocity: 1ml/ minute
Sample size: 5ul
Tiopronin retention time: 4 minutes.Two fluidisation thing retention times 6 minutes, return-the change method surveys the content of dithio thing impurity.
IV, measurement result:
A, tiopronin freeze-dried powder injection stability test
A, the room temperature stability test that keeps sample: (seeing Table 1)
Table 1
Lot number Detection time Period of storage (moon) Assay %
????970601 ???????97.6.6 ????0 ????99.28
???????97.9.6 ????3 ????99.35
???????97.12.6 ????6 ????99.26
???????98.3.6 ????9 ????99.19
???????98.5.28 ????12 ????99.20
Illustrate that keep sample 1 year tiopronin freeze-dried powder injection product content of room temperature is stable.
B, 40 ℃, 60 ℃ influence factor's tests
Freeze dried tiopronin powder for injection (100mg) is investigated 10 days under 40 ℃, the 60 ℃ conditions, now gathers the assay result as follows: (seeing Table 2)
Table 2
Time (my god) ??0 ??1 ???3 ???5 ??10
Content % 40℃ 99.80 99.70 ?99.80 ?99.65 ?99.50
60℃ 99.70 99.65 ?99.60 ?99.63 ?99.55
Impurity % 40℃ 0.3％ 0.3％ ?0.4％ ?0.3％ ?0.4％
60℃ 0.3％ 0.3％ ?0.4％ ?0.3％ ?0.4％
Brief summary: 40 ℃, 60 ℃ this product are investigated 10 days, and content's index is stable, and product quality is stable under this investigation condition.
C, strong illumination influence factor stability test
It is an amount of to get tiopronin freeze-dried powder injection, puts under the injection clarity analyzer, with 3000LX illuminance irradiation 10 days, in 0,1,3,5,10 day difference sampling and measuring content, with 0 day measurement result relatively.Measurement result sees the following form 3:
Table 3
Time (my god) ??????0 ??????1 ?????3 ?????5 ?????10
Content % ????99.80 ????99.80 ????99.10 ????98.50 ????98.40
Impurity % ????0.2 ????0.2 ????0.8 ????1.4 ????1.5
The HPLC method
This product was through 10 days strong illuminations, and assay does not have too big variation, met the quality standard regulation, but had seen progressively downward trend from measured value, and this product should keep in Dark Place during storage.
D, high humidity influence factor stability test
This product is a lyophilized formulations, sternly is encapsulated in the control cillin bottle, and humidity is little to its influence, so do not do this test.
The study on the stability test of B, 5% tiopronin aqueous injection (2ml):
A, the room temperature long-time stability that keep sample are investigated test
5% tiopronin aqueous injection room temperature kept sample 1 year, existing with 0,3,6,9, the result such as the following table 4 of December sample assay:
Table 4
Lot number Detection time Period of storage (moon) Assay (%)
????970601 ????97.6.6 ????97.9.6 ????97.12.6 ????98.3.6 ????98.5.28 ????0 ????3 ????6 ????9 ????12 ????99.60 ????89.50 ????81.30 ????73.40 ????68.90
The 5% tiopronin liquid drugs injection room temperature long-time stability extreme difference that keeps sample is described, kept somewhere 1 year that content drops to 68.90% by first timing 99.60%, loses medical value fully.Do not add antioxidant, 5% tiopronin liquid drugs injection is room temperature storage for a long time.
B.40 ℃, 5% tiopronin aqueous injection (2ml) is investigated under 40 ℃, 60 ℃ conditions of test 5% tiopronin aqueous injection (2ml) and investigated 10 days under 60 ℃ of conditions, now gather the assay result as follows: (seeing Table 5)
Table 5
Time (my god) ??0 ???1 ??2 ??3 ??4 ??5 ??10
Content % ?40℃ 99.60 ?98.8 ?98.8 ?97.7 ?96.5 ?95.0 ?91.5
?60℃ 99.60 ?97.8 ?97.8 ?96.8 ?95.6 ?94.3 ?89.4
Impurity % ?40℃ 0.4 ?1.2 ?1.6 ?2.4 ?3.5 ?5.0 ?8.5
?60℃ 0.4 ?2.2 ?3.9 ?3.4 ?4.4 ?5.7 ?10.5
5% tiopronin aqueous solution is very unstable under 40 ℃ as can be seen, 60 ℃ influence factor's conditions, 0 day with 10 days mutually ratio content drop to 91.50%, 89.4 impurity disulphide by 99.60% and rise to 8.5%, 10.5% by 0.4%, lost medical value.
C, strong illumination influence factor stability test
It is an amount of to get 5% tiopronin aqueous injection, puts under the injection clarity analyzer, and with 3000LX illuminance irradiation 10 days, in 0,1,3,5,10 day difference sampling and measuring, with 0 day measurement result relatively: measurement result saw the following form 6:
Table 6
Time (my god) ??????0 ??????1 ??????3 ??????5 ?????10
Content % ????99.60 ????97.90 ????96.00 ????94.20 ????89.10
Impurity % ????0.4 ????2.0 ????4.1 ????5.9 ????10.9
(HPLC method)
This product was through 10 days strong illuminations, and content drops to 89.10% by 99.60%, and impurity dithio thing is raised to 10.90% by 0.4%, has lost medical value, so unstable under the 5% tiopronin aqueous injection high light condition.
This product is described through 10 days strong illuminations, content descends obviously, has lost medical value.
D, high humidity influence factor stability test
Because of this product is the ampoule packing, humidity is little to its influence, so do not do this test.
The stability test of C, 5% sodium thio pronine aqueous injection (2ml)
A, the room temperature long-term stable experiment that keeps sample
5% sodium thio pronine aqueous injection room temperature kept sample 1 year, existing with 0,3,6,9, the result such as the following table 7 of December sample assay:
Table 7
Lot number Detection time Period of storage (moon) Assay (%)
?970601 ????97.6.6 ????97.9.6 ????97.12.6 ????98.3.6 ????98.5.28 ????0 ????3 ????6 ????9 ????12 ????99.80 ????87.50 ????80.10 ????71.50 ????64.70
The 5% sodium thio pronine liquid drugs injection room temperature long-time stability extreme difference that keeps sample is described, kept somewhere 1 year that content drops to 64.70% by initial 99.80%, lose medical value fully, do not add antioxidant, specific process is stored, and 5% sodium thio pronine liquid drugs injection can not long term store.
B.40 ℃, the stability test of 60 ℃ of influence factor's condition 5% sodium thio pronine aqueous injection (2ml)
The stability test of 0-10 days 5% sodium thio pronine aqueous injection (2ml) under 40 ℃, 60 ℃ influence factor's conditions, the assay result is as follows: (seeing Table 8)
Table 8
Time (my god) ????0 ???1 ???2 ???3 ???4 ???5 ???10
Content % ?40℃ 99.80 ?98.80 ?97.40 ?96.5 ?95.50 ?94.30 ?90.80
?60℃ 99.80 ?98.30 ?97.70 ?96.40 ?95.20 ?94.0 ?89.00
Impurity % ?40℃ 0.2 ?1.2 ?1.6 ?3.5 ?4.5 ?5.8 ?9.1
?60℃ 0.2 ?1.5 ?2.6 ?3.5 ?4.8 ?6.0 ?11
Under 40 ℃ as can be seen, 60 ℃ influence factor's conditions, 5% sodium thio pronine aqueous injection is very unstable, 0 day with 10 days mutually ratio content drop to 90.80% and 89.0% by 99.80%; Impurity disulphide rises to 9.1%, 11.% by 0.2%.Lost medical value.
C, strong illumination influence factor stability test
It is an amount of to get 5% sodium thio pronine aqueous injection, puts under the injection clarity analyzer, and with 3000LX illuminance irradiation 10 days, in 0,1,3,5,10 day difference sampling and measuring content, with 0 day measurement result relatively: measurement result saw the following form 9:
Table 9
Time (my god) ??????0 ??????1 ??????3 ??????5 ?????10
Content % ????99.80 ????97.00 ????95.30 ????92.80 ????87.30
Impurity % ????0.2 ????3.0 ????4.7 ????7.1 ????12.8
(HPLC method)
This product was through 10 days strong illuminations, and content drops to 87.30% by 99.80%, and impurity dithio thing is raised to 12.80% by 0.2%, has lost medical value, so unstable under the 5% sodium thio pronine aqueous injection high light condition.
D, high humidity influence factor stability test
Because of this product is the ampoule packing, humidity is little to its influence, so do not do this test.
V, conclusion:
A. keep sample 1 year assay of tiopronin freeze-dried powder injection room temperature is stable, and 5% tiopronin aqueous injection, the 5% sodium thio pronine aqueous injection room temperature 1 year assay that keeps sample is extremely unstable, has lost medical value.
B.40 ℃, the tiopronin freeze-dried powder injection assay is stable under 60 ℃ of influence factor's conditions, and 5% tiopronin aqueous injection, 5% sodium thio pronine aqueous injection content dropped to 90% by initial 0 day 99.60% and 99.80% to 10 days, impurity dithio thing then is elevated to 10% by 0.4% and 0.2%, product content is seriously unstable, has lost medical value.
C.3000LX freeze dried tiopronin powder for injection was through 10 days strong illuminations, and assay does not have too big variation, met the quality standard regulation, but had seen progressively downward trend from measured value, and this product should keep in Dark Place during storage.5% tiopronin aqueous injection, extremely unstable under the 5% sodium thio pronine aqueous injection 3000LX strong illumination condition, lost medical value.
Therefore, freeze dried tiopronin powder for injection obviously than 5% tiopronin aqueous injection, 5% sodium thio pronine aqueous injection steady quality, has tangible stability advantage.
Two. to the efficacy experiment of viral chronic hepatic injury
Be subjected to the reagent thing: the tiopronin injection: 100mg/ props up lyophilized preparation, presses method preparation among the embodiment 1
Contrast medicine: vitamin K 1Injection: 100mg/ props up liquid drugs injection, and Wuxi the 7th pharmaceutical factory produces.Authentication code: the accurate word of Su Wei medicine (82) 2689-2 number, product batch number: 930417.Preserve shading, cool dark place.
Dosage regimen: treatment group: press 200mg/ daily dose dead point tiopronin injection, in 4 weeks of successive administration, follow-up observation is 6 months after the drug withdrawal.
Matched group: press 40mg/ daily dose dead point vitamin k 1Pin, in 4 weeks of successive administration, follow-up observation is 6 months after the drug withdrawal.
Observation index:
1. symptom: weak, poor appetite, detest that oil, nausea and vomiting, abdominal distention, yellowish urine, heating, hepatic region are painful, nose knob or gingiva bleeding gingival hemorrhage etc.Before the treatment with+,-the expression symptom has or not, in the treatment and treatment back with-, ± ,+, ++ the expression transference cure, alleviate, constant and increase the weight of, finished the difference observed and recorded 6 months by being responsible for doctor per 2 weeks, treatment before treatment, during the treatment;
2. sign: yellow sclera, spider angioma (quantity), liver palm, ascites, abdominal wall varicosis, liver circle (under the upper bound, the right rib), liver quality and touch and kowtow pain, spleen circle (under the left rib), edema of lower limbs, and body temperature, pulse, blood pressure, cardiopulmonary etc., finished the difference observed and recorded 6 months by being responsible for doctor per 2 weeks, treatment before treatment, during the treatment;
3. biochemical analysis: SB (standard bicarbonate), T (total serum protein), A/G (Archon albumen ratio), ALT (serum glutamic pyruvic transminase), AST (glutamic oxaloacetic transaminase, GOT), Y-GT (glutamine transpeptidase), AKP (alkali phosphatase), cholesterol, BuN (blood urea nitrogen) etc., before the treatment, during the treatment per 2 weeks, treatment finish detected respectively in 6 months, record;
Serum-virus learn sign: HbsAg (hepatitis B virus surface antigen) HbeAg (hepatitis B virus e antigen), HbeAb (antihepatitis b e antibody), HbcAb (anti-HBc), before and after the treatment, treatment finish detected respectively in 6 months, record;
5.B super: observation liver spleen, portal vein, splenic vein morphology situation, each is checked, writes down once before and after the treatment;
6. electrocardiogram, hematuria routine, urine three gallbladders: before and after the treatment each detect, record once;
7.CT, other inspections such as MRI, gastroscope: according to circumstances determine by being responsible for the doctor;
8. untoward reaction: by being responsible for the doctor according to practical situation, per 2 weeks are concluded record once;
9. record patient history of drinking history, alcohol drinking patterns and drinking amount etc.
10. curative effect judging standard: " viral hepatitis curative effect of medication evaluation criterion " by Ministry of Health of the People's Republic of China's promulgation carried out.
The results are shown in Table 10 and table 11.
Table 10: two groups of patient's doing well,improving situations compare (%) after the medication
Group example number transference cure alleviates the total improvement rate of portion (%) P value
Treatment organizes 107 51 34 79.4
Weak＜0.05
Matched group 48 13 15 58.3
Treatment organizes 98 35 33 69.4
Poor appetite＜0.01
Matched group 46 8 13 45.7
Treatment group 96 is detested oil 33 31 67.4
Matched group 39 feels sick 7 16 59.0
Treatment organizes 77 22 29 66.2
Abdominal distention＜0.05
Matched group 33 4 12 48.5
Treatment organizes 79 26 30 70.9
Jaundice
Matched group 37 10 15 67.6
Treatment organizes 56 11 19 53.6
Liver pain
Matched group 28 4 10 50.0
Treatment organizes 38 7 15 57.9
Hepatomegaly＜0.01
Matched group 20 15 30.0
Annotate: routine number refer to respectively organize before the medication the male patient of corresponding symptom count transference cure alleviate with drug withdrawal in the time of 6 months the doing well,improving situation be standard
Table 11: two groups of liver function index improvement situations (X ± SD) relatively after the medication
P value drug withdrawal P half a year value during drug withdrawal before the medication of group example number liver function
Treatment organizes 107 140 ± 48.3 58 ± 28.1＜0.005 81 ± 37.4＜0.01
ALT(u)
Matched group 48 123 ± 50.9 64 ± 31.4＜0.05 86 ± 36.7＜0.05
* the P value--
Treatment organizes 66 94 ± 27.9 49 ± 18.6＜0.01 60 ± 22.4＜0.05
AST(u)
Matched group 30 96 ± 28.4 54 ± 22.2＜0.01 86 ± 31.4-
* P value＜0.05
Treatment organizes 71 109 ± 37.2 53 ± 21.6＜0.01 67 ± 24.8＜0.05
r-GT(u)
Matched group 32 108 ± 96.4 64 ± 23.5＜0.05 80 ± 30.8＜0.05
* the P value---
Treatment organizes 56 50 ± 6.9 88 ± 7.9＜0.05 84 ± 8.6＜0.05
T(g/L)
Matched group 25 48 ± 7.1 47 ± 6.1-48 ± 6.8-
* P value-＜0.05＜0.05
Treatment organizes 67 1.2 ± 0.21 1.5 ± 0.23＜0.05 1.5 ± 0.27＜0.05
A/G
Matched group 32 1.2 ± 0.19 1.2 ± 0.17-1.2 ± 0.19-
* P value-＜0.05＜0.05
Treatment organizes 75 63 ± 23.4 27 ± 14.4＜0.01 31 ± 16.4＜0.05
SB(umol/L)
Matched group 36 57 ± 18.9 28 ± 15.6＜0.05 33 ± 19.7＜0.05
* the P value---
Annotate: routine number refers to the preceding abnormal liver function case load of medication
The P value is respectively drug withdrawal and drug withdrawal liver function indexes and preceding comparison of medication during half a year
* the P value is that liver function indexes compares between two groups
Three. the characteristics and the comparison of pharmacology, drug effect and the pharmacokinetics of tiopronin freeze-dried powder injection and tiopronin aqueous injection and tiopronin tablet
(1). the pharmacology of freeze dried tiopronin powder for injection and pharmacodynamic study experiment
Animal experiment shows that freeze dried tiopronin powder for injection of the present invention is to TAA (thioacetamide), CCL 4(carbon tetrachloride) causes in the animal acute liver damage model serum AST, ALT to raise the reduction effect, and the accumulating of triglyceride that the chronic hepatic injury model is caused has inhibitory action.Can promote liver glycogen synthetic, suppress cholesterol and increase, help serum albumin/globulin ratio and go up.
Following description of test freeze dried tiopronin powder for injection of the present invention is to the protective effect of hepatic injury
1, experiment purpose
The main MPG that observes of this test is to CCL 4The therapeutical effect of induced mice acute liver damage.For clinical practice provides scientific basis.
2, test material
(1) is subjected to reagent: tiopronin (MPG)
(2) positive control drug: reduced glutathion (GSH)
(3) make model drug: carbon tetrachloride (CCL 4)
(4) solvent control: sodium bicarbonate (NaHCO 3)
(5) experimental animal: Kunming kind healthy mice, effluent south medical university animal center is raised and is provided, and body weight 20 ± 2g is female. and male half and half.
3, test method
Animal is divided into 9 groups at random, 30 every group, respectively with ig (per os filling stomach), two kinds of administrations of ip (lumbar injection).It is all identical with the antagonism test that each organizes dosage, method.Each test group is 30 minutes (desolventizing outside the matched group) ipCCL after medication in first day 4Once, continue medication to 15 day, 10 of each treated animals of taking care of oneself respectively at 36 hours, 7 days, 15 days simultaneously.Get blood and cut open and get hepatic tissue, carry out biochemistry and histopathologic examination.(every index of detection is identical with the antagonism test).
4, result of the test
(1) gives ipCCL of animal 4After, CCL 4The survival condition of group and each treatment group animal in 15 days sees Table 12.
(2) give ipCCL of animal 4With ipCCL 4Back reuse MPG treatment 15 days, each biochemical indicator sees table 13 and table 14 for details.
(3) singly use CCL 4Tangible focal inflammation appears in the treated animal hepatic tissue cell to be soaked into, and focal necrosis and lobules of liver central authorities are downright bad, and through with each the treated animal hepatocyte after the MPG treatment, damage in various degree obviously alleviates, and treats that the hepatic injury cell recovers normal substantially after 7-15 days.MPG compares its result with GSH treatment group and intends substantially mutually.See Table 15.
5, conclusion
(1) singly uses CCL 4Group (model group): animal mortality rate in 15 days is 23%, solvent control group ipCCL 4Once, be subjected to the heavy dose of group of reagent, (MPG, GSH) be none only death of animal in 15 days treatment, and the small dose group animal dead is respectively 7%, 3%.This result of the test shows that this product has reduction by CCL 4Due to the death that causes of acute liver damage.
(2) singly use CCL 4Group, liver function ALT, AST obviously increase, and T value descends, and A, C value are inverted.With MPG treatment 15 days, to handle each treated animal respectively at 36 hours, 7 days, 15 days and record ALT, AST and all have in various degree and reduce, T value progressively raises.A, G-value ratio recover normal gradually.With singly use CCL 4Group is compared, and both have notable difference; The therapeutical effect of GSH is compared with MPG, and both intend substantially mutually.The result shows that MPG has the effect of quickening the hepatic injury functional rehabilitation.
(3) singly use CCL 4Group and ipCCL 4After, to treat the group enlightening with MPG and compare, the hepatic injury area obviously dwindles, and has significant difference.The therapeutical effect no significant difference of GSH and MPG.The result shows that MPG has obvious acceleration by CCL 4Due to the restitution of hepatic injury cell function.
(2). the pharmacokinetic characteristics and the comparison of freeze dried tiopronin powder for injection and tiopronin aqueous injection and tiopronin tablet
Give the oral tiopronin tablet of rat, excretion lower (0.015%) in urinating certainly, excretion then obviously increases (22.35%) in urinating behind the intravenous injection tiopronin freeze-dried powder injection, can reach maximum plasma concentration in 30 minutes after the intravenous injection; Reached maximum plasma concentration, and also can detect in oral back 60 minutes until 120 minutes.Illustrate that the injection freeze dried tiopronin powder for injection is more rapid-action than tiopronin tablet, bioavailability height, good effect.
After, the intramuscular injection oral at human body, excretion close (intramuscular injection 10-12%, 15.47%) in the urine but drain time lengthening after the intramuscular injection needs 8-24 hour, the more oral height of blood plasma level but low than intravenous injection illustrates that quiet notes tiopronin freeze-dried powder injection is than intramuscular injection tiopronin liquid drugs injection good effect.
Therefore, change route of administration, the tiopronin freeze-dried powder injection that is prepared into quiet notes has rapid-action, advantages such as bioavailability is high, good effect than intramuscular injection tiopronin aqueous injection, oral tiopronin tablet.
Table 12:MPG is to CCL 4Due to the influence of animal dead
Group dosage and usage number of animals death toll mortality rate (mg/kg/d) (only) (only) are (%)
Solvent control group 20ml * 15 ig, 30 00 CCL 4(0.25％)??10ml×15?ip?????30????????7?????????23 ?CCL 4+GSH??????250×15?ig??????30????????0?????????0 ?CCL 4+MPG??????125×15?ig??????30????????2?????????7 ?CCL 4+MPG??????250×15?ig??????30????????0?????????0
Solvent control group 10ml * 15 ip, 30 00 CCL 4+GSH??????150×15?ip??????30????????0?????????0 ?CCL 4+MPG??????75×15??ip??????30????????1?????????3 ?CCL 4+MPG??????150×15?ip??????30????????0?????????0
Annotate: each test group+CCL 4Amount be 0.25% concentration 10ml/kg, ip
Table 13:MPG treatment CCL 4The influence that induced mice liver ALT, AST change
Group Dosage and usage animal ALT (AST of u.X ± SD) (u.X ± SD)
(mg/kg/d) (only) 36h 7d 15d 36h 7d 15d
Solvent control 20ml * 15ig 30 41.5 ± 4.1 45.5 ± 8.2 49.3 ± 8.2 60.3 ± 8.8 65.3 ± 12.3 59.5 ± 8.2 CCL 4(0.25％)??????10ml×1?ip????23????185.5±13.1 ΔΔ???125±13.9 ΔΔ????50±12.3????21.5±12.3 ΔΔ???155±8.2 ΔΔ???50±8.2 CCL 4+GSH??????????250×15?ig????30????150±12.3***?????50±12.2***????45±12.3????135±12.3***????75±4.1***????63±6.3 CCL 4+MPG??????????125×15?ig????28????161±17.2***?????88±8.2***?????56.5±6.3???110±12.3***????70±8.9***????60±6.9 CCL 4+MPG??????????250×15?ig????30????120±12.3***?????49±13.7***????45±4.1?????101±8.2***?????75±4.1***????69±9.0
Solvent control 10ml * 15 ip 30 45.7 ± 6.0 45.9 ± 6.0 46.2 ± 5.3 59.6 ± 4.4 61 ± 4.0 63.6 ± 4.5 CCL 4+GSH??????????150×15?ip????30????100±8.2***??????75±8.7***?????50.6±8.4???90±12.3***?????75±8.2***????60±9.8 CCL 4+MPG??????????75×15??ip????29????105±8.2***??????83±9.8***?????65±8.2?????110±1938**?????89±12.2***???75±9.0 CCL 4+MPG??????????150×15?ip????30????90±12.3***??????78.8±9.0***???5.8±8.2????101±8.2***?????80±4.1***????62±10.6
* P＜0:05*** P＜0.01 and CCL 4Group is compared;
△ Δ P＜0.01 is compared with the solvent control group.
Annotate: each test group+CCL 4Amount be 10ml/kg (0.25%), ip is once.
Table 14:MPG treatment is by CCL 4The influence that induced mice liver T, A, G change
Group Dosage and usage animal T (A of g/dl.X ± SD) (G of g/dl.X ± SD) (g/dl.X ± SD)
(mg/kg/d) (only) 36h 7d 15d 36h 7d 15d
Solvent control 20ml * 15 ig 30 7.0 ± 1.2 7.1 ± 0.7 6.9 ± 1.1 4.4 ± 0.3 4.5 ± 0.2 4.0 ± 0.3 2.6 ± 1.1 2.6 ± 0.7 2.9 ± 1.0 CCL 4(0.25％?10ml×1?ip????23????5.9±0.3 Δ??????55±0.4 Δ??????6.1±0.7?????2.2±0.2 Δ????????2.2±0.4 Δ???????3.1±0.5??????3.7±0.3 Δ??????????33±0.1 Δ??????????3.0±0.2 CCL 4+GSH????250×15?ig????30????6.3±0.2??????74±0.2??????7.5±0.5?????3.3±0.2**?????4.1±0.4**?????4.7±0.2??????3.0±0.3**??????3.0±0.5???????2.8±0.4 CCL 4+MPG????125×15?ig????28????7.3±0.3??????6.8±0.4?????7..2±0.7????4.5±0.2**?????4.0±0.2**?????4.5±0.2??????2.8±0.4**??????2.8±0.4**?????2.7±0.8 CCL 4+MPG????250×15?ig????30????7.1±0.6??????6.9±0.6?????7.1±0.4?????3.9±0..5**????3.8±0..3**????3.9±0.2??????3.2±0..8**?????3.1±0..5**????3.2±0.5
Solvent control 10ml * 15 ip 30 7.0 ± 0.1 7.0 ± 0.1 7.0 ± 0.2 4.1 ± 0.2 4.1 ± 0.2 4.2 ± 0.3 2.9 ± 0.2 2.9 ± 0.1 2.8 ± 0.1 CCL 4+GSH????150×15?ip????30????6.9±0.8??????7.1±0.7?????7.6±0.4?????3.9±0.4**?????3.5±0.4**?????4.3±0.2**????3.0±0.5**??????3.6±0.4???????3.3±0.4 CCL 4+MPG????75×15??ip????29????7.3±0.3??????7.5±03??????7.1±0.5?????3.7±0.2**?????43.5±0.1**????4.1±0.3**????3.8±0.2????????3.8±0.2???????3.0±0.4 CCL 4+MPG????150×15?ip????30????7.2±0.8??????7.2±0.8?????7.0±0.3?????3.6±0..3**????3.3±0..4**????4.3±0.2**????3.5±0..6???????3.6±0..4??????2.7±0.2
Δ P＜0.05 is compared with the solvent control group, and * * P＜0.05 is with CCL 4Group is compared.
Annotate: each test group+CCL 4Amount be 10ml/kg (0.25%), ip is once.
The influence (7D) of table 15:MPG treatment CCL4 induced mice hepatic injury
Group dosage and usage number of animals hepatic injury area Δ (mg/kg/d) (only) (only)
Solvent control group 20ml * 15 ig, 30 0 CCL 4(0.25％)??10ml×15?ip??????23???????341±53.4 CCL 4+GSH??????250×15?ig???????30???????150±24.5*** CCL 4+MPG??????125×15?ig???????28???????149.5±39.4*** CCL 4+MPG??????250×15?ig???????30???????108.5±30.6***
Solvent control group 10ml * 15 ip, 30 0 CCL 4+GSH??????150×15?ip???????30???????97.5±21.9*** CCL 4+MPG??????75×15??ip???????29???????124±35.0*** CCL 4+MPG??????150×15?ip???????30???????99±25.6***
* * P＜0.01, equal and CCL 4Group is compared.Annotate: each test group+CCL 4Amount be 10ml/kg.ip.
Δ 1, under light microscopic, amplify and take pictures with 10/20.2, with the overlay of 10 * 8cm, being divided into 900 lattices is unit, the focus in the above-mentioned photo is measured, relatively the focus size of each group.
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.Except as otherwise noted, the percent among the present invention is percetage by weight.
Embodiment 1: the preparation Thiopronine freeze dried powder injection agent
Tiopronin 100g
Dextran 40 50g
Water for injection 1000ml
Make 1000 of dried frozen aquatic productses altogether
Preparation technology:
Preparating liquid:
Take by weighing the injection raw material (tiopronin content must not be less than 98.5%, contains heavy metal and must not cross 15/1000000ths) of recipe quantity, add aseptic apyrogeneity distilled water, make dissolving, concentration is 0.2g/ml.The 20% Dextran 40 solution mixing of handling through the degerming depyrogenation in advance that adds recipe quantity then.Add water to 1000ml again, making tiopronin content is 0.1g/ml, and Dextran 40 content is 0.05/ml;
Depyrogenation:
Add injection in the above-mentioned medicinal liquid with active carbon (activated carbon dosage is the 0.3-0.5% of tiopronin raw material weight),, filter, collect filtrate 60-80 ℃ of heating 30 minutes.
Sterilization:
Above-mentioned medicinal liquid is carried out the malleation degerming by aseptic manipulation to be filtered.Pressure with 0.22 μ microporous filter membrane, should carry out the bubbling point test earlier before filtering below 0.1Mpa, the filtrate sample presentation carries out pyrogen test and semi-finished product content is checked packing then;
Fill:
The processing of control cillin bottle: control cillin bottle, specification are 5ml.With 0.5-1.0HCl liquid the control cillin bottle is filled during pretreatment, heat-treated in following 30 minutes for 100 ℃, industrial water is washed control cillin bottle (slightly washing), and----pure water is washed control cillin bottle (fine purifiation), and--the control cillin bottle that----injection washing control cillin bottle (washing eventually) is cleaned is through 220 ℃ of bakings in following 2 hours, thoroughly remove pyrogen, it is standby to move sterilizing room after reducing to 60 ℃;
Fill: carry out fill, the false add plug 100 grades of cleanliness factor ultra-clean workplaces.
Lyophilizing:
At pre-freeze 1.5-2 below-40 ℃ hour, under-25 ℃, 1.33Pa (0.01 holder) vacuum, distil then, remove after 90% at free moisture, heat drying (maximum temperature must not above 35 ℃) treats that temperature curve overlaps respectively with vacuum curve, promptly can be considered lyophilizing and finish, jump a queue entirely automatically in the freeze drying box;
Seal: the control cillin bottle takes out from freeze drying box in batches, adds aluminium lid.
Embodiment 2: the preparation Thiopronine freeze dried powder injection agent
Tiopronin 100g
Lactose 50g
Mannitol 50g
Water for injection 1000ml
Make 1000 of dried frozen aquatic productses altogether
Preparation method is except that the adjuvant difference that adds, and other are with embodiment 1
Embodiment 3: the preparation Thiopronine freeze dried powder injection agent
Tiopronin 100g
Lactose 50g
Water for injection 1000ml
Make 1000 of dried frozen aquatic productses altogether
Preparation method is except that the adjuvant difference that adds, and other are with embodiment 1
Embodiment 4: the preparation Thiopronine freeze dried powder injection agent
Tiopronin 100g
Cyclodextrin 50g
Water for injection 1000ml
Make 1000 of dried frozen aquatic productses altogether
Preparation method is except that the adjuvant difference that adds, and other are with embodiment 1
Embodiment 5: the preparation Thiopronine freeze dried powder injection agent
Tiopronin 100g
HPMC 50g
Water for injection 1000ml
Make 1000 of dried frozen aquatic productses altogether
Preparation method is except that the adjuvant difference that adds, and other are with embodiment 1.

Claims (15)

1. tiopronin chemical compound that is used to prepare the freezing-dried powder injection of treatment chronic hepatopathy medicine, it has following structural formula:
Figure A0215941300021
2. Thiopronine freeze dried powder injection agent for the treatment of chronic hepatopathy, it contains as the tiopronin chemical compound of active component and medicine acceptable carrier.
3. according to the injection of claim 2, its Chinese medicine acceptable carrier is selected from one or more in low molecular dextran, mannitol, cyclodextrin, soluble starch, glucide, sodium chloride, benzoic acid or the cellulose substances.
4. according to the injection of claim 3, wherein the weight ratio between tiopronin chemical compound and the medicine acceptable carrier can be 1-10: 1.
5. according to the injection of claim 4, wherein the weight ratio between tiopronin chemical compound and the medicine acceptable carrier can be 1-2: 1.
6. according to the injection of claim 3, its Chinese medicine acceptable carrier is a low molecular dextran.
7. according to the injection of claim 6, wherein low molecular dextran is a Dextran 40.
8. according to the injection of claim 7, wherein the weight ratio of tiopronin chemical compound and Dextran 40 can be 1-3: 1.
9. injection according to Claim 8, wherein the weight ratio of tiopronin chemical compound and Dextran 40 can be 2: 1.
10. according to the injection of claim 9, wherein the content specification of tiopronin chemical compound is 1-1000mg.
11. according to the injection of claim 10, wherein the content specification of tiopronin chemical compound is 50mg, 100mg or 200mg.
12. according to the injection of claim 11, wherein every injection contains the 100mg tiopronin, the 50mg Dextran 40.
13. the preparation method according to the injection of one of claim 2-12 is characterized in that comprising the following steps:
A. preparating liquid: be about to the active component tiopronin and add the dissolving of injection water, add medicine acceptable carrier mixing, add the injection water to ormal weight;
B. depyrogenation: in the medicinal liquid of step a, add injection and filtered in 30 minutes in 60-80 ℃ of heating with active carbon;
C. degerming: the filtrate of step b is carried out the malleation degerming with germ tight filter filter;
D. canned: as to carry out sterile filling with the control cillin bottle;
E. lyophilizing: under cryogenic vacuum, carry out lyophilization.
14. according to the preparation method of claim 13, its Chinese medicine acceptable carrier is a Dextran 40, degerming adopts the germ tight filter malleation to filter method, and pressure is below 0.1Mpa.
15. the Thiopronine freeze dried powder injection agent of one of claim 2-12 is used to prepare the purposes of the medicine for the treatment of chronic hepatopathy.
CN 02159413 2002-10-08 2002-12-31 Tiopronin freeze-dried powder injection Expired - Lifetime CN1194678C (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1305845C (en) * 2005-05-16 2007-03-21 河南省新谊药业股份有限公司 Anhydrous tiopronin natrium for curing acute or chronic liver disease and preparation method
CN100356912C (en) * 2005-07-08 2007-12-26 王建标 Tiopronin freeze-dried prepn. and its preparing method
CN100383521C (en) * 2005-09-23 2008-04-23 复旦大学 Method for determining concentration of tiopronin
WO2014101743A1 (en) * 2012-12-26 2014-07-03 Li Hewei Freeze-dried excipient and preparation method thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1305845C (en) * 2005-05-16 2007-03-21 河南省新谊药业股份有限公司 Anhydrous tiopronin natrium for curing acute or chronic liver disease and preparation method
CN100356912C (en) * 2005-07-08 2007-12-26 王建标 Tiopronin freeze-dried prepn. and its preparing method
CN100383521C (en) * 2005-09-23 2008-04-23 复旦大学 Method for determining concentration of tiopronin
WO2014101743A1 (en) * 2012-12-26 2014-07-03 Li Hewei Freeze-dried excipient and preparation method thereof

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