CN104013951A - Nitric oxide donor type glutathione compound injection and application thereof - Google Patents

Abstract

The invention discloses nitric oxide donor type glutathione compound injection, a preparation method and an application in preparing anticancer medicines. Safe and stable compound I injection is prepared, a method that a solvent is firstly prepared and then a compound I solution is prepared is adopted, the quality of the injection is ensured, and the safety tests show that the injection does not cause anaphylactic reaction or vascular stimulation reaction in intravenous drip, and agglutination or hemolysis is also not resulted, so that the injection is safe in clinical intravenous administration.

Description

Nitric oxide donator type glutathion compounds injection and application

Technical field

The present invention relates to nitric oxide donator type glutathion compounds injection, preparation method and the application in anticancer medicine thereof.

Background technology

Tumor is a kind of common major disease, the serious threat mankind's healthy and life security.Though there is clinically multiple antitumor drug, due to reasons such as complexity, the drug resistance of tumor and the toxic and side effects of antitumor drug of cancer pathology factor, existing medicine still can not meet clinical needs.Therefore, searching curative effect new type antineoplastic medicine outstanding, that targeting effect is strong and toxic and side effects is low is significant.Compound I can be optionally by the GST activation that P identifies of tumor cell surface overexpression, and discharges a large amount of NO and cytotoxicity fragment, reaches the object of targeting killing tumor cells, and does not affect normal cell.

Chinese patent CN102627685A discloses preparation method and the antitumor action of Compound I.

Compound I is dissolved in methanol, ethanol or chloroform, and almost insoluble in water, the dissolubility in water only has 0.006mg/ml, and in human body, effectively bioavailability is low.Adopt cosolvent and the direct dissolved compound I of solvent to be mixed with injection.Safety, stability are all inadequate.

Summary of the invention

Object: for solving the clinical and safety of going on the market in the future, stable, effectively administration, the invention provides Compound I injection of a kind of safe, stable nitric oxide donator type glutathion class and preparation method thereof.

Technical scheme: for solving the problems of the technologies described above, the technical solution used in the present invention is:

A kind of nitric oxide donator type glutathion compounds I injection, it is characterized in that, the proportioning raw materials of every 1000ml nitric oxide donator type glutathion compounds I injection is as follows: Compound I 0.6～3.0g, dehydrated alcohol 200～400ml, PEG400 are that 200～400ml, Tween 80 are 20～40g, needle-use activated carbon 0.2～0.5g, surplus is normal saline; Compound I molecular structural formula is as follows:

Described nitric oxide donator type glutathion compounds injection adopts bulk capacity injection dosage form.

Described bulk capacity injection dosage form refers to that every 50ml nitric oxide donator type glutathion compounds injection is containing Compound I 30mg or 100mg or 150mg.

The present invention also provides the preparation method of nitric oxide donator type glutathion compounds injection, it is characterized in that, comprises the following steps: according to formula proportion,

1) get after dehydrated alcohol 200～400ml, normal saline stirring, add PEG400 200～400ml, stir evenly to obtain mixed solvent 1;

2) in mixed solvent 1, add Tween 80 20～40g, mix thoroughly, add 0.2～0.5g needle-use activated carbon, heat 35～40 DEG C, coarse filtration, pH value 3～5, filters, embedding, at 100～125 DEG C, sterilizing 20～35min obtains mixed solvent 2;

3) after infusion bottle is cleaned, in 230～260 DEG C of dry 25～35min, butyl rubber plug sterilizing;

4) get Compound I 0.6～3.0g and add dissolving in mixed solvent 2, aseptic filtration, under aseptic condition, pours into infusion bottle, and sealing, to obtain final product.

The present invention also provides above-mentioned nitric oxide donator type glutathion compounds injection in the application of preparing in anticancer medicine, and wherein cancer is nonsmall-cell lung cancer, promyelocytic leukemia or breast carcinoma.

Beneficial effect: the present invention has the following advantages: the nitric oxide donator type glutathion compounds injection that (1) provides, comprises solvent and cosolvent; Solvent has ethanol, PEG400 and normal saline, and cosolvent has Tween 80.The each component of solvent system compatibility according to a certain percentage, synergism mutually, can ensure complete dissolved compound I, can ensure again, after the 5% glucose injection dilution alive of preparation Compound I injection normal saline out, to maintain clear and bright certain hour and unlikely precipitation compounds I crystallization; Safety experiment shows, this injection intravenous drip can not cause allergic reaction and vascular stimulation reaction, has no coagulation and haemolysis yet, shows this injection clinical vein administration safety.

Concrete effect of the present invention is by experimental results show that as follows:

The present invention carries out stability test, 25 DEG C ± 2 DEG C of test temperatures, and result shows: the present invention is through accelerated test, and quality is stable, in table 1, table 2.

Table 1: Compound I injection Accelerated stability test result

Table 2: Compound I injection stability long-term test results

(2) adopt and first join solvent, after join the method for Compound I solution, ensured the quality of injection.

Compound I is heat-sensitive materials, can be destroyed under hot conditions, as adopt conventional heating adsorption, and the method for high temperature sterilize, Compound I will be destroyed.The present invention is by solvent, cosolvent mixed dissolution, and sterilizing, is made into after solvent, then dissolved compound I, and degerming is filtered, and so neither affects the content of Compound I, does not increase again related substance, and aseptic, bacterial endotoxin passed examination can ensure the quality of injection.

(3) adopt bulk capacity injection dosage form.Compound I injection of the present invention is high-capacity injection, and the every 50ml of specification is containing Compound I 30mg, 100mg or 150mg Compound I injection, easy to use, reduces the chance of polluting.When use, by the present invention and normal saline or 5% glucose injection mixed diluting, diluent can keep the clear and bright of certain hour.When the present invention uses, control injection speed, can maintain the administration of 3～5h completely.

Detailed description of the invention

Below in conjunction with example, the present invention is illustrated:

Embodiment mono-

Get after dehydrated alcohol 400ml, normal saline 300ml stirring, add PEG400 300ml, stir evenly; Then add Tween 80 30g, mix thoroughly, add 0.3g needle-use activated carbon, heat 40 DEG C of absorption, coarse filtration de-carbon, pH value is 5, with 0.3 μ m filtering with microporous membrane, embedding, sterilizing 20mi at 125 DEG C, is solvent; After glass infusion bottle is cleaned with potassium dichromate sulfuric acid solution, in 230 DEG C of dry 35min, butyl rubber plug is done sterilizing; Get Compound I 2g and add in solvent and dissolve, aseptic filtration, under sterile purification condition, pours into glass infusion bottle sealing, and making specification is that 50ml contains Compound I 100mg Compound I injection.

Embodiment bis-

Get after dehydrated alcohol 400ml, normal saline 400ml stirring, add PEG400 300ml, stir evenly; Then add Tween 80 40g, mix thoroughly, add 0.25g needle-use activated carbon, heat 35 DEG C of absorption, coarse filtration de-carbon, pH value is 3, with 0.22 μ m filtering with microporous membrane, embedding, sterilizing 35mi at 115 DEG C, is solvent; After glass infusion bottle is cleaned with potassium dichromate sulfuric acid solution, in 260 DEG C of dry 25min, butyl rubber plug is done sterilizing; Get Compound I 3g and add in solvent and dissolve, aseptic filtration, under sterile purification condition, pours into glass infusion bottle sealing, and making specification is that 50ml contains Compound I 150mg Compound I injection.

Embodiment tri-

Get after dehydrated alcohol 300ml, normal saline 400ml stirring, add PEG400 300ml, stir evenly; Then add Tween 80 20g, mix thoroughly, add 0.5g needle-use activated carbon, heat 40 DEG C of absorption, coarse filtration de-carbon, pH value is 5, with 0.4 μ m filtering with microporous membrane, embedding, sterilizing 35mi at 100 DEG C; After glass infusion bottle is cleaned with potassium dichromate sulfuric acid solution, in 250 DEG C of dry 30min, butyl rubber plug is done sterilizing; Get Compound I 0.6g and add in solvent and dissolve, aseptic filtration, under sterile purification condition, pours into glass infusion bottle sealing, and making specification is that 50ml contains Compound I 30mg Compound I injection.

By the Compound I being diluted in 5% glucose intravenous fluid, in 30min with 100mg/m ²predose intravenously administrable to the patient who suffers from small cell lung cancer; And this dosage is increased to 250mg/m ², 500mg/m ², 750mg/m ²and 1000mg/m ².To give this compound the interval of one week.There are other patients of same cancer the interval of 2 weeks and 3 weeks identical dosage increase is administered to patient, there is good therapeutic effect.

Below disclose the present invention with preferred embodiment, so it is not intended to limiting the invention, and all employings are equal to replaces or the technical scheme that obtains of equivalent transformation mode, within all dropping on protection scope of the present invention.

Claims (5)

1. a nitric oxide donator type glutathion compounds injection, it is characterized in that, the proportioning raw materials of every 1000ml nitric oxide donator type glutathion compounds injection is as follows: Compound I 0.6～3.0g, dehydrated alcohol 200～400ml, PEG400 are that 200～400ml, Tween 80 are 20～40g, needle-use activated carbon 0.2～0.5g, surplus is normal saline; Compound I molecular structural formula is as follows:

2. nitric oxide donator type glutathion compounds injection according to claim 1, is characterized in that: described nitric oxide donator type glutathion compounds injection adopts bulk capacity injection dosage form.

3. nitric oxide donator type glutathion compounds injection according to claim 2, is characterized in that: described bulk capacity injection dosage form refers to that every 50ml nitric oxide donator type glutathion compounds injection is containing Compound I 30mg or 100mg or 150mg.

4. according to the preparation method of the nitric oxide donator type glutathion compounds injection described in claims 1 to 3 any one, it is characterized in that, comprise the following steps: according to formula proportion,

1) get after dehydrated alcohol 200～400ml, normal saline stirring, add PEG400 200～400ml, stir evenly to obtain mixed solvent 1;

2) in mixed solvent 1, add Tween 80 20～40g, mix thoroughly, add 0.2～0.5g needle-use activated carbon, heat 35～40 DEG C, coarse filtration, pH value 3～5, filters, embedding, at 100～125 DEG C, sterilizing 20～35min obtains mixed solvent 2;

3) after infusion bottle is cleaned, in 230～260 DEG C of dry 25～35min, butyl rubber plug sterilizing;

4) get Compound I 0.6～3.0g and add dissolving in mixed solvent 2, aseptic filtration, under aseptic condition, pours into infusion bottle, and sealing, to obtain final product.

5. in claims 1 to 3, described in any one, nitric oxide donator type glutathion compounds injection is in the application of preparing in anticancer medicine, and wherein cancer is nonsmall-cell lung cancer, promyelocytic leukemia or breast carcinoma.