CN101683319B - Tirapazamine parenteral hydrous preparation and preparation method thereof - Google Patents
Tirapazamine parenteral hydrous preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a Tirapazamine parenteral hydrous preparation and a preparation method thereof. The preparation comprises the following basic components: a citrate buffer solution and Tirapazamine or available salts thereof, wherein the concentration of the buffer solution is 0.02-0.99 mmol/l, and the buffer solution is acceptable in medical preparations; the concentration of the Tirapazamine or available salts thereof is 0.056-0.091 mmol/l; and the pH value of the preparation is 3.0-6.5. The preparation solves the problem of easy precipitation when the solution of Tirapazamine is put still in the prior art, enhances the stability and the safety of the preparation and meets the clinical and broad patients' requirements for the preparation.
Description
Technical field:
The invention belongs to technical field of medicine, be specifically related to a kind of tirapazamine parenterai administration aqueous compositions and preparation method thereof.
Background technology:
Tirapazamine, English name tirapazamine or TPZ, chemical name: 3-amino-1,2,4 phentriazines-1, the 4-dioxide (3-Amino-1,2,4-benzotuiazine-1 4-dioxide) has another name called Win59075 or SR4233, and its chemical structural formula is following:
(chemical structural formula of tirapazamine)
Molecular formula: C
7H
6N
4O
2
Molecular weight: 178
Tirapazamine is a kind of novel biological reducing active matter.It can be reduced in the tumor tissues anoxic cell and generate a kind of metabolite with cytotoxic effect.This metabolite significantly surpasses its parent compound to the lethal effect of anoxic cell; Make anoxic cell death in the tumor tissues; The antitumor action of tumour radiotherapy and a series of chemotherapeutic agents of tumor be can significantly increase simultaneously, thereby basis and clinical experiment are introduced into as a kind of anoxic cell sensitizer of novelty.
The mechanism of action of tirapazamine: tirapazamine has special cytotoxicity to anoxic cell.Under the situation that anoxic cell exists, tirapazamine produces free radical at endocellular metabolism, and free radical combines with the DNA macromole, causes DNA infringement and cell death.Katherineb etc. think that tirapazamine is that tirapazamine causes that DNA destroys and produce Cytotoxic main cause at the nucleus intracellular metabolite.They also confirm that through lot of test tirapazamine suppresses dna replication dna in anoxic cell effect is significantly higher than ionizing radiation.Simultaneously, delahoussayeym etc. carries out deep research to the metabolic mechanism of tirapazamine: but tirapazamine equal dna single chain interruption of the metabolite after some reductase effect in anoxic cell nuclear.And on the other hand the double-strand break of DNA be since tirapazamine by due to the chemical compound that a unknown active reductase reduction of dependence NADPH produces in the nucleus.
Tirapazamine is as radiotherapeutic sensitizer: confirm through long term studies with the mechanism of action of lonizing radiation therapeutic alliance malignant entity tumor; In nearly all human malignant's entity tumor no matter the size of tumor all have anoxic cell; Generally account for about 10%～20% of tumor cell; Also have up to 50% or few, also have some cells between anoxia state and aerobic state to 1%.Anoxic cell in the malignant entity tumor will produce when oxygen tension is lower than 0.5mmHg radiocurable repellence; Its OER (Oxygenationenhancementrate OER) is 25～30, promptly kills the anoxic cell required dosage and be three times that kill the aerobic cell required dosage.Under aerobic state, under the damaging fixed that should in irradiation, can obtain repairing, no longer produce and repair owing to the existence of molecular oxygen.Therefore, in the damage that the tumor hypoxia cell produces,, also just increased repellence after shining to lonizing radiation because weary oxygen can make them obtain repairing.Tirapazamine can optionally kill and wound anoxic cell, and low LET ray then mainly kills and wounds non-anoxic cell, and The combined is used, and radiocurable effect will be strengthened greatly.Brown etc. have reported the C to lotus SCCV I I, RIF, EMT6, KHT/R tumor
3H/Km mice and BALB/c mouse result of experiment: the tirapazamine that before fractionation of radiation, gives 008mmol/Kg; Adopt experiment in the body/survival analysis method that exsomatizes to estimate; The proof tirapazamine can significantly increase the caused death of neoplastic cells of radiation, and tirapazamine dose modification factor (DMF) value is significantly greater than traditional radiosensitizer SR2508
Tirapazamine is as the recent advances in research of molecular mechanism of chemotherapeutic sensitizer and cisplatin combined application of treatment malignant tumor.Former studies shows, tumor cell depends on the expression of two kinds of DNA crosslinked reparation albumen Ercc1 and XRA to the sensitivity of cisplatin, and cisplatin can raise the expression of ERCC1.Application tirapazamines such as Goldbergz and cisplatin are handled respectively two kinds of different cells strains; Two kinds of cell strains are a kind of extremely sensitive a kind of insensitive to cisplatin to cisplatin; Processing method is divided into while medication and two kinds of medications successively, and the result finds that two kinds of processing methods all change less than remarkable cisplatin responsive group ERCC1mRNA and protein expression, insensitive group of cisplatin; Tirapazamine can raise the expression of ERCC1, and cisplatin is to the not influence of expression of ERCC1.Each group that is expressed in of XRA is not all seen change.In view of the above, Goldbergz etc. think the synergism of tirapazamine and cisplatin, and tirapazamine suppresses due to the expression of ERCC1 and XRA no thanks to, and perhaps the anoxic cell toxicity of tirapazamine played even more important effect.
The external at present clinical trial to tirapazamine and radiotherapy and chemicals Combined application treatment malignant entity tumor launches on a large scale.Tirapazamine is as a kind of radiotherapy, chemotherapeutical hypersitization medicine; Has collaborative anti-tumor activity during with radiotherapy and chemotherapy Combined application; Increased radiotherapy, chemotherapy lethal effect to tumor; Toxicity can tolerate, and life-threatening or expendable toxic and side effects do not occur, for antineoplaston has been opened up new field.Therefore, in tumor treatment, expection has good application prospects.
The US5175827 of December in 1992 publication on the 29th discloses 1,2, and the 4-benzotriazine oxides combines to be used to treat the application of tumor with radiotherapy.1,2, the 4-benzotriazine oxides makes tumor cell responsive to radiotherapy, and makes the patient more comply with the modality of treatment.
It (is 3-amino-1 that Holden etc. (1992) (JNCI84:187-193) disclose SR-4233 " strengthening the activity of alkylating reagent in FSaIIC Mus fibrosarcoma with SR-4233 "; 2; 4-phentriazine-1; The 4-dioxide, this chemical compound is known, and also is known as tirapazamine hereinafter) and the bonded application of antitumor alkylating reagent.
International application PC/US1989/01037 discloses as 1,2 of radiosensitizer and selecting cell toxic agent, 4-benzotriazine oxides.Other relevant patents comprise: US3868372 and US4001410 wherein disclose 1,2, the derivant of 4-benzotriazine oxides.
International Application PCT/US1996/13550 discloses 1,2, the preparation of 4-benzotriazine oxides.It is a kind of aqueous compositions of parenterai administration, and its principal character is for containing citrate buffer, and the concentration that defines citrate is 0.001M-0.1M, and the citric acid that adds in the most preferred prescription is 0.9605 gram, and thin up is to 1000ml.The dosage range of pointing out the principal agent tirapazamine simultaneously is preferably 0.5-0.810 gram, adds tirapazamine 0.7 gram in the most preferred prescription, and thin up is to 1000ml.Through converting, the concentration range of the tirapazamine of mentioning in the patent is 0.0028M-0.0046M.
But the shortcoming of tirapazamine is that the dissolubility in the pharmaceutical carrier of parenterai administration is not enough, and unstable in these carriers.Even according to the preparation of the disclosed scheme of International Application PCT/US1996/13550 preparation in the low-temp storage process, still exist unstable, storage period is short, be prone to temperature influence and defective such as separate out.
In aqueous formulation research to tirapazamine; We find the non-constant of the dissolubility of tirapazamine in water; Injection instability very according to prior art (comprising the disclosed scheme of International Application PCT/US1996/13550) preparation; In room temperature (20 ℃) condition held a period of time, will separate out small amount of crystalline, back proof crystallization is a tirapazamine.And after low temperature (4 ℃) is placed 24 hours, also have the tirapazamine crystallization to separate out, because the tirapazamine aqueous formulation is to use as injection, separating out of principal agent tirapazamine can have a strong impact on safety and the effectiveness that the patient uses, and increases the risk of drug use.Therefore, develop a kind of safelyr, stable, effectively and meet the tirapazamine aqueous formulation that the human injection requires,, become pharmaceutical preparation research worker's the task of top priority to better meet the needs of extensive patients.
Summary of the invention
The purpose of this patent invention; Be to find a kind of more stable tirapazamine parenterai administration aqueous compositions to solve the problem that the tirapazamine placement is separated out easily in the prior art; Strengthen the stability and the safety of said preparation, satisfy clinical and the demand of extensive patients this medicine.
For improving the tirapazamine stability of formulation and prolonging storage period, we have carried out research all sidedly to the parenterai administration aqueous compositions of novel tirapazamine.
We find; If reduce the concentration of tirapazamine in aqueous solution; Directly be mixed with the large capacity transfusion of 1000ml, in put procedure, solution is highly stable; Problems such as crystallization can not occur separating out, and the test of the vein irritating of animal and muscle irritation shows that all this injection is as safe as a house.
The invention provides the parenterai administration aqueous compositions of a kind of tirapazamine or its officinal salt, it basic composition is, and acceptable citrate buffer and concentration are tirapazamine or its officinal salt of 0.056-0.091mmol/l in the pharmaceutical formulations that concentration is 0.02-0.99mmol/l; PH value is 3.0 ~ 6.5.
Further, the concentration of citrate buffer is 0.08-0.5mmol/l in the said preparation, and the concentration of tirapazamine or its officinal salt is 0.056-0.091mmol/l, and the 1000ml aqueous solution basic composition is:
0.01-0.16 gram tirapazamine or its officinal salt;
0.0168 gram-0.105 gram citric acid;
0.004-0.03 gram sodium hydroxide;
PH value is 3.2 ~ 5.3.
Further, said preparation 1000ml aqueous solution basic composition is:
0.014 gram tirapazamine or its acceptable salts;
0.0192 gram citric acid;
0.005 gram sodium hydroxide;
PH value is 5.0.
The present invention also provides a kind of method for preparing tirapazamine parenterai administration aqueous compositions, it is characterized in that: water is prepared described buffer, elevated temperature; And make the buffer temperature keep about 60 ℃, slowly add tirapazamine or its officinal salt and stir and to make dissolving fully, be cooled to room temperature after; Add the used additives of infusion preparation; Add suitable quantity of water to 1000 milliliter, transfer PH, promptly get.Wherein said additives can be infusion preparation isoosmotic adjusting agent (like sodium chloride, glucose etc.) commonly used, stabilizing agent and antioxidant etc.
The purposes of the parenterai administration aqueous compositions that the present invention also provides a kind of tirapazamine or its officinal salt in the medicine of preparation treatment carcinoma, wherein said preparation prescription comprises: concentration is that acceptable citrate buffer and concentration are tirapazamine or its pharmaceutically useful salt of 0.056-0.091mmol/l in the pharmaceutical formulations of 0.02-0.99mmol/l; PH value is 3.0 ~ 6.5.
The specific embodiment
Below in conjunction with following instance the present invention is done to further describe, but the present invention is not restricted to this:
Formulation preparation instance one:
A: tirapazamine 0.01 gram
B: citric acid 0.0042 gram
C: sodium hydroxide 0.001 gram
Get 300 ml waters dissolving b, c.Dissolving back is an amount of fully heats up, and makes solution temperature keep about 60 ℃, slowly adds a, stirs to make it to dissolve fully, be cooled to room temperature after, add sodium chloride isosmoticity regulator, add suitable quantity of water and be settled to 1000 milliliters, PH is about 6.5.
Preparation administering mode: intravenous drip.
Formulation preparation instance two:
A: tirapazamine 0.16 gram
B: citric acid 0.0208 gram
C: sodium hydroxide 0.00594 gram
Get 300 ml waters dissolving b, c.Dissolving back is an amount of fully heats up, and makes solution temperature keep about 50 ℃, slowly adds a, stirs to make it to dissolve fully, be cooled to room temperature after, add sodium chloride isosmoticity regulator, add suitable quantity of water and be settled to 1000 milliliters, PH is about 3.0.
Preparation administering mode: intravenous drip.
Formulation preparation instance three:
A: tirapazamine 0.01 gram
B: citric acid 0.0168 gram
C: sodium hydroxide 0.004 gram
Get 300 ml waters dissolving b, c.Dissolving back is an amount of fully heats up, and makes solution temperature keep about 55 ℃, slowly adds a, stirs to make it to dissolve fully, be cooled to room temperature after, add glucose isosmoticity regulator, add suitable quantity of water and be settled to 1000 milliliters, PH is about 5.3.
Preparation administering mode: intravenous drip.
Formulation preparation instance four:
A: tirapazamine 0.16 gram
B: citric acid 0.105 gram
C: sodium hydroxide 0.03 gram
Get 300 ml waters dissolving b, c.Dissolving back is an amount of fully heats up, and makes solution temperature keep about 60 ℃, slowly adds a, stirs to make it to dissolve fully, be cooled to room temperature after, add glucose isosmoticity regulator, add suitable quantity of water and be settled to 1000 milliliters, PH is about 3.2.。
Preparation administering mode: intravenous drip.
Formulation preparation instance five:
A: tirapazamine 0.014 gram
B: citric acid 0.0192 gram
C: sodium hydroxide 0.005 gram
Get 300 ml waters dissolving b, c.Dissolving back is an amount of fully heats up, and makes solution temperature keep about 60 ℃, slowly adds a, stirs to make it to dissolve fully, be cooled to room temperature after, add sodium chloride, glucose isosmoticity regulator, add suitable quantity of water and be settled to 1000 milliliters, regulate PH and be about 5.0.
Preparation administering mode: intravenous drip.
Stability comparative study
We have chosen the clear and bright tirapazamine infusion solutions (embodiment of the invention one to five) that the technical scheme according to above invention makes; Under 20 ℃ of constant temperatures and 4 ℃ of constant temperatures, store jointly with tirapazamine citrate injection of the prior art, observe its outward appearance and separate out situation.Specific as follows:
20 ℃ of constant temperatures, the stability of observing concrete prescription of tirapazamine infusion solutions of the present invention and tirapazamine citrate injection, the result sees table one:
The stability of the tirapazamine injection of table one, different formulations under 20 ℃ of constant temperatures
4 ℃ of constant temperatures, the stability of observing tirapazamine infusion solutions and tirapazamine citrate injection, the result sees table two:
The stability of the tirapazamine solution of table two, different formulations under 4 ℃ of constant temperatures
Animal pharmacological test comparative study:
In order to observe prescription in use reaction and the toleration of animal in the technical scheme of the present invention, test of rabbit vascular stimulation and muscular irritation that we adopt are tested.And compare research with citrate buffer solution of the prior art.
One, tirapazamine injection vascular stimulation test:
Test objective: observe the new tirapazamine infusion solutions (embodiment of the invention one, four, five) of filling a prescription of intravenous injection and compare with the vascular stimulation reaction of tirapazamine citrate injection (pressing the open scheme preparation of PCT/US1996/13550).
Test material:
1, receives the reagent thing: tirapazamine infusion solutions (embodiment of the invention one, four, five), tirapazamine sodium citrate injection (pressing the open scheme preparation of PCT/US1996/13550).
2,0.9% sodium chloride injection
3, animal: rabbit, regular grade, male and female half and half, body weight 1.8-2.4kg plant in New Zealand.
Test method:
5 of rabbit; Be fixed in the rabbit hutch; Slowly inject and inject 1 every day respectively at the edge vein sterile working of picking up the ears; Injectable drug is respectively tirapazamine infusion solutions (embodiment of the invention one, four, five), tirapazamine sodium citrate injection (pressing the open scheme preparation of PCT/US1996/13550), normal saline solution 1.0ml, at the normal saline of opposite side injection with volume.At same position continuous 3 times, injection site and the place ahead 3cm blood vessel and surrounding tissue are got in the reaction of about 24 h observation injection site blood vessels and surrounding tissue after last administration, and carotid artery sacrificed by exsanguination rabbit, make the routine pathology histological observation.
Result of the test:
The slow intravenous injection tirapazamine of rabbit sodium acetate injection is not seen abnormal phenomenas such as significantly red, swollen or necrosis at its place ahead vein and surrounding tissue naked eyes.Histological section inspection finds that compare with the intravenous injection normal saline, the rabbit auricular vein blood vessel structure of intravenous injection tirapazamine sodium acetate injection is normal, reactions such as no hemorrhage, inflammation, tissue degeneratiaon and necrosis.
Rabbit is slowly injected tirapazamine citrate injection, trickle macroscopic red, swollen phenomenon occurs at its place ahead vein and surrounding tissue.Histological section's inspection finds that compare with the intravenous injection normal saline, the rabbit auricular vein blood vessel of intravenous injection tirapazamine citrate injection has a spot of hemorrhage, inflammatory reaction.
Conclusion (of pressure testing):
The result shows that slowly the more existing tirapazamine citrate of intravenous injection tirapazamine injection (infusion solutions) injection vascular stimulation is little.
Two, tirapazamine glucose injection intramuscular injection irritant test:
Test objective: observe new tirapazamine infusion solutions (embodiment of the invention one, four, five) of filling a prescription of intramuscular injection and tirapazamine citrate injection (pressing the open scheme preparation of PCT/US1996/13550) IR to muscle.
Test material:
1, receives the reagent thing: tirapazamine infusion solutions (embodiment of the invention one, four, five), tirapazamine sodium citrate injection (pressing the open scheme preparation of PCT/US1996/13550).
2,0.9% sodium chloride injection
3, animal: rabbit, regular grade, male and female dual-purpose are planted by New Zealand.
Test method:
5 of rabbit; About it, intersect up and down in two quadriceps femoris respectively injection tirapazamine infusion solutions (embodiment of the invention one, four, five) 2.0ml/ only, tirapazamine sodium citrate injection (0.7mg/ml) 2.0ml/ only or normal saline 2.0ml/ only; Injecting tapped the head in back 48 hours causes dusk; Vertically cut quadriceps femoris, observe injection site form, color and luster etc., and be converted into level of reaction by table three.
Table three. IR progression
| Order of reaction | IR |
| 0 | No significant change |
| 1 | Mild hyperaemia, its scope is below 0.5 * 1.0 centimetre |
| 2 | Moderate is congested, and its scope is more than 0.5 * 1.0 centimetre |
| 3 | Severe is congested, with myodegeneration |
| 4 | Necrosis occurs, the brown degeneration is arranged |
| 5 | It is downright bad popularity to occur |
Result of the test:
The rabbit quadriceps femoris is injected tirapazamine infusion solutions and tirapazamine sodium citrate injection respectively, and the position reaction is all the same with normal saline, and the order of reaction is 0 grade, no obvious variation.
Conclusion (of pressure testing):
Tirapazamine infusion solutions of the present invention (embodiment of the invention one, four, five) and tirapazamine sodium citrate injection (by the open scheme preparation of PCT/US1996/13550) all do not have tangible IR.
Claims (4)
1. moisture great transfusion preparation of tirapazamine parenterai administration, it is characterized in that: the 1000ml aqueous solution basic composition is:
0.01-0.16 gram tirapazamine or its officinal salt;
0.0168 gram-0.105 gram citric acid;
0.004-0.03 gram sodium hydroxide;
PH value is 3.2 ~ 5.3.
2. the moisture great transfusion preparation of tirapazamine parenterai administration according to claim 1, it is characterized in that: the 1000ml aqueous solution basic composition is:
0.014 gram tirapazamine or its officinal salt;
0.0192 gram citric acid;
0.005 gram sodium hydroxide;
PH value is 5.0.
3. method for preparing the moisture great transfusion preparation of tirapazamine parenterai administration as claimed in claim 1, it is characterized in that: water is prepared described buffer, elevated temperature; And make the buffer temperature keep 50-60 ℃, slowly add tirapazamine or its officinal salt and stir and make dissolving fully, be cooled to room temperature after; Add the used additives of infusion preparation; Add suitable quantity of water to 1000 milliliter, transfer PH, promptly get.
4. the purposes of the moisture great transfusion preparation of tirapazamine parenterai administration as claimed in claim 1 in the medicine of preparation treatment carcinoma.
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| CN1207736A (en) * | 1995-12-04 | 1999-02-10 | 圣诺菲公司 | Process for preparing 3-amino-1,2,4-benzotriazine dioxide |
| US6153610A (en) * | 1995-09-25 | 2000-11-28 | Sanofi-Synthelabo Inc. | 1,2,4-benzotriazine oxides formulations |
| WO2007041546A2 (en) * | 2005-10-03 | 2007-04-12 | Genetix Pharmaceuticals, Inc. | Method for selectively depleting hypoxic cells |
| CN101054367A (en) * | 2006-04-13 | 2007-10-17 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 3-Amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate, its preparation method and application in tumour radiotherapy and chemotherapy |
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2008
- 2008-09-24 CN CN200810161582A patent/CN101683319B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6153610A (en) * | 1995-09-25 | 2000-11-28 | Sanofi-Synthelabo Inc. | 1,2,4-benzotriazine oxides formulations |
| CN1207736A (en) * | 1995-12-04 | 1999-02-10 | 圣诺菲公司 | Process for preparing 3-amino-1,2,4-benzotriazine dioxide |
| WO2007041546A2 (en) * | 2005-10-03 | 2007-04-12 | Genetix Pharmaceuticals, Inc. | Method for selectively depleting hypoxic cells |
| CN101054367A (en) * | 2006-04-13 | 2007-10-17 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 3-Amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate, its preparation method and application in tumour radiotherapy and chemotherapy |
Non-Patent Citations (2)
| Title |
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| Urban Emmenegger等.Low-Dose Metronomic Daily Cyclophosphamide and Weekly Tirapazamine: A Well-Tolerated Combination Regimen with Enhanced Efficacy That Exploits Tumor Hypoxia.《Cancer Research》.2006,第66卷(第3期),1664-1674. * |
| 张鹏 等.替拉扎明乏氧细胞增敏剂的基础及临床研究进展.《华西医学》.2003,第18卷(第1期),129-130. * |
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