CN1840172A - Pidotimod solution capable of being administered from vein - Google Patents
Pidotimod solution capable of being administered from vein Download PDFInfo
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- CN1840172A CN1840172A CN 200610038082 CN200610038082A CN1840172A CN 1840172 A CN1840172 A CN 1840172A CN 200610038082 CN200610038082 CN 200610038082 CN 200610038082 A CN200610038082 A CN 200610038082A CN 1840172 A CN1840172 A CN 1840172A
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- pidotimod
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Abstract
The invention provides a Pidotimod solution for intravenous injection, which comprise reactive compound of ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid by a content of 0.4-200mg/ml, solvent for injection and solubilizing agent for injection, the solvent for injection comprises water, non-water solvent or their mixture.
Description
Technical field
The present invention relates to a kind of pidotimod solution capable of being administered from vein.
Background technology
Pidotimod (Pidotimod), i.e. (R)-3-[(S)-(5-oxygen-2-pyrrolidinyl) carbonyl]-Thiazolidine-4-carboxylic acid, be a kind of high-purity dipeptides of synthetic, be unique a kind of oral bioactive immunopotentiating agent that has.The later stage eighties 20th century is successfully synthesized by Italian poli chemical company, and gets permission listing in 1993 and be used for clinical.Itself does not have antibacterial activity this medicine, but combines with antibiotic therapy, can improve the sings and symptoms of infection effectively.
Pidotimod both can promote nonspecific immune reaction, can promote specific immune response again.The activate the phagocytic capacity that it can promote macrophage and neutrophilic granulocyte improves its chemotaxis, activates natural killer cell; The former lymphopoiesis that causes of mitosis promoting, the helper T lymphocyte when making immunologic hypofunction (CD4+) is normal with the ratio rising or the recovery of suppressor T lymphocyte (CD8+); By stimulating interleukin-2 and Y-interferon to promote cell immune response [1].As developing into acute lobe of the lung pneumonia behind the Wistar rat infection streptococcus pneumoniae very soon, mortality rate reaches 80%～90%.If take pidotimod in advance, then infected Rats survival rate significantly increases, and the energy rehabilitation; Then curative effect is little but treat with this medicine.Pidotimod and beta-lactam antibiotic share addition or collaborative anti-infectious function.For the mice of low dosage mengo virus, herpes simplex virus and influenza infection, give pidotimod in advance survival period is obviously prolonged, this antivirus action comes from its immune-stimulating effect.In addition, stimulate for surgery, pidotimod can partly slow down the variation of immunne response, and can suppress the YACl cancerous cell at external proliferation activity, causes the program death of cell.
Pidotimod is mainly used in respiratory tract infection (RRI), chronic bronchitis, the urinary tract infection of showing effect repeatedly and the adjuvant therapy of malignant tumor etc. that the control child shows effect repeatedly clinically.In the research of effectiveness for the treatment of repeated respiratory tract infections in children (RRI) and safety, the patient of 120 routine recurrent respiratory tract infection (2 years old-8 years old age) is divided into pidotimod group (n=60) and placebo group (n=60) at random, treats through pidotimod.(1) amynologic index: neutrophilic granulocyte chemotactic and activate the phagocytic capacity significantly strengthen (P＜0.05); (2) to the curative effect of actute infection: compare with placebo, the high pyretolysis of pidotimod group shifts to an earlier date 1.5d (4.4d vs 6.0d; P＜0.01), the recovery of main clinic symptoms such as cough, expectoration is also obviously accelerated; Compare with placebo, the hospital stays of pidotimod group obviously shortens (6.4d vs 8.5d; P＜0.01).(3) prevention of recurrence: total recurrent number of pidotimod group is 40 times, and total recurrent number of placebo is 149 times, and both have significant difference (P＜0.01); Because of the patient that recurrence is in hospital, the pidotimod group is 13%, and placebo group is 93% (P＜0.01); (4) safety: comprise that with more every laboratory parameters before the treatment erythrocyte (RBC), leukocyte (WDC), hemoglobin, blood urea nitrogen (BUN), creatinine, blood glucose, serum glutamic pyruvic transminase (ALT), serum glutamic oxalacetic transaminase (AST) etc. do not see change.In the research [5] of the curative effect of pidotimod treatment child urinary tract infection and safety, because of the acute attack 60 examples child patient of urinary tract infection repeatedly of being admitted to hospital, be divided into pidotimod group and placebo group at random, the result shows: compare with placebo group, (P＜0.01) is obviously accelerated in the recovery of pidotimod group acute urinary tract infection symptom; Compare percentage ratio decline 47% (P＜0.01) of pidotimod group recurrence urinary tract infection with placebo group; Compare with placebo group, pidotimod group neutrophil chemotaxis and engulfing property significantly strengthen (P＜0.01).
At present, the research of relevant pidotimod all concentrates on oral administration solution, solid preparation and freeze dried injection preparation.Under the state-of-the-art, the increase of pidotimod related substance in the preparation process directly influences the curative effect that it is used for the treatment of, and incidence rate of adverse reaction is increased.General Study shows the related substance of wanting in the strict control injection pidotimod preparation now, and the solution-type injection is difficult to reach owing to its preparation characteristic always.Studies show that the pidotimod aqueous solution is comparatively stable under the condition of sour partial neutral (especially pH5～7) down for room temperature (28 ℃); In different temperature ranges, along with the prolongation of time, pidotimod content is all on a declining curve, but temperature is high more, and pidotimod content descends fast more.
The now disclosed Chinese patent relevant with pidotimod has 7: the composite reagent thing (CN03159223.6) of interferon and its synergist; A kind of granule of pidotimod and preparation method thereof CN03106554.6); The application (CN200410000692.6) of pidotimod in preparation treatment hepatitis B medicine; A kind of levofloxacin and pidotimod compound preparation (CN20041006239.6); A kind of Wannailuowei hydrochloride and pidotimod compound preparation (CN200410006240.9); A kind of azithromycin and pidotimod compound preparation (CN200410006241.3); Be easy to water-soluble pidotimod double salt and preparation method thereof (CN200510009242.8).The present invention compares with prior art: preceding 6 contents of the patent and diversity of the present invention are bigger, and application number be CN200510009242.8 patent application protection be a kind of chemical compound of pidotimod double salt, do not study with regard to its stability.
Summary of the invention
The object of the present invention is to provide a kind of pidotimod solution capable of being administered from vein, external conditions such as temperature, light descend to the influence of this pidotimod solution, can guarantee the pidotimod long-term stability.
Technical scheme of the present invention is: a kind of pidotimod solution capable of being administered from vein, comprise the reactive compound pidotimod, solvent for injection, the injection solubilizing agent, described pidotimod is (R)-3-[(S)-(5-oxygen-2-pyrrolidinyl) carbonyl]-Thiazolidine-4-carboxylic acid, the content of pidotimod is 0.4～200 mg/ml in the described solution, the consumption of described injection solubilizing agent should be enough to make described pidotimod to dissolve in solvent for injection and keep stable, described solvent for injection comprises water, the non-water-soluble matchmaker of injection or be the mixed solvent that both mixture are formed at least, the amount of described solvent for injection should be enough to make described pidotimod dissolving and keep stable.
It also can comprise antioxidant, and the non-water-soluble matchmaker of described injection comprises one of ethanol, propylene glycol, glycerol, 1,3 butylene glycol, tertriary amylo alcohol, dimethyl sulfoxide, Polyethylene Glycol or wherein two or more mixtures.
Described antioxidant is the sulphite kind antioxidant, is one or more the mixture in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium formaldehyde sulphoxylate, the sodium dithionite.
Described antioxidant is thio-compounds, is one or more the mixture in thioglycerin, thiourea, 2 mercapto ethanol, dimercaptopropanol, BAL, the 1-sulfo-sorbitol.
Described antioxidant is polyatomic phenol, is one or more the mixture in hydroquinone, para-aminophenol, the oxine.
Described antioxidant is amino acids, is one or more the mixture in L-cysteine hydrochloride, L-methionine, L-lysine, L-propylhomoserin, L-arginine, L-leucine, L-isoleucine, L-tryptophan, the L-glutathion.
Described pidotimod solution has the mixed solvent solutions class of pidotimod aqueous solution class and pidotimod.
Described pidotimod aqueous solution class comprises that the aseptic aqueous solution of direct intravenous drip and dilution back supply the aseptic aqueous solution of intravenous drip.
Described injection solubilizing agent is the alkali compounds that can be used for injection.
The described alkali compounds that can be used for injection comprises organic base or inorganic base, and described organic base is one or more the mixture in ethanolamine, triethanolamine, the ethylenediamine; Described inorganic base is one or more the mixture in sodium hydroxide, sodium carbonate, sodium bicarbonate, liquor ammoniae fortis, Basionic, sodium acetate, tertiary sodium phosphate, sodium hydrogen phosphate, the sodium dihydrogen phosphate.
The scope of the pH value of described pidotimod aqueous solution class is 4.0～9.0.
The amount of employed injection usefulness solubilizing agent is relevant with the alkalescence of the amount of described reactive compound pidotimod and solubilizing agent itself, and with respect to 1 gram reactive compound, the injection of adding makes the pH value of solution reach 4.0～9.0 with solubilizing agent.
The weight ratio that the ratio of water accounts in the whole mixed solvent in the described mixed solvent is lower than 99%
At present, the preparation of relevant pidotimod is oral administration solution, solid preparation and freeze dried injection preparation.The listing of pidotimod solution type injection agent is not arranged as yet.Traditionally, do not make the increase of related substance in the solution process more than, directly influence the curative effect that it is used for the treatment of, incidence rate of adverse reaction is increased.The present invention has obtained guaranteeing that by a large amount of tests pidotimod makes the prescription of injection for intravenous with solution, has obtained better controlled with this its related substance of pidotimod solution that makes of writing out a prescription, and can reach the requirement of injection.
The pidotimod stability test:
According to the related content in two appendix of Chinese Pharmacopoeia version in 2000 " medicine stability experiment instruction principle ", the pidotimod injection of manufacturing experimently is carried out study on the stability.Do accelerated test and long term test.Totally 3 batches of pilot samples.
40 ℃ of accelerated tests of table 1 pidotimod injection are investigated the result
| Time | Lot number | The investigation project | ||||
| Character | pH | Clarity | Related substance (%) | Content (%) | ||
| 0 month (05.03.26) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.17 5.12 5.21 | Up to specification up to specification | 0.40 0.40 0.37 | 99.1 101.2 100.1 |
| 1 month (05.04.25) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.16 5.11 5.14 | Up to specification up to specification | 0.38 0.36 0.35 | 98.7 99.9 98.5 |
| 2 months (05.05.25) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.11 5.08 5.13 | Up to specification up to specification | 0.36 0.39 0.43 | 99.0 98.1 99.2 |
| 3 months (05.06.25) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.13 5.07 5.15 | Up to specification up to specification | 0.35 0.36 0.35 | 98.3 99.6 100.4 |
| 6 months (05.09.24) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.14 5.07 5.13 | Up to specification up to specification | 0.43 0.43 0.40 | 99.6 98.8 100.6 |
Table 2 pidotimod injection long term test is investigated the result
| Time | Lot number | Investigate | Project |
| Character | pH | Clarity | Related substance (%) | Content (%) | ||
| 0 month (05.03.26) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.17 5.12 5.21 | Up to specification up to specification | 0.41 0.40 0.37 | 99.1 101.2 100.1 |
| 3 months (05.06.25) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.15 5.11 5.10 | Up to specification up to specification | 0.37 0.42 0.37 | 99.8 99.0 99.6 |
| 6 months (05.09.24) | 050323 050324 050325 | Colourless clear liquid colourless clear liquid colourless clear liquid | 5.13 5.10 5.19 | Up to specification up to specification | 0.37 0.42 0.37 | 100.4 98.2 98.9 |
The specific embodiment
Below by embodiment technical scheme of the present invention is further described:
Pidotimod solution capable of being administered from vein, comprise reactive compound pidotimod ((R)-3-[(S)-(5-oxygen-2-pyrrolidinyl) carbonyl]-Thiazolidine-4-carboxylic acid), solvent for injection, injection solubilizing agent, antioxidant, the content of pidotimod is 0.4～200 mg/ml in the described solution; The consumption of described injection solubilizing agent should be enough to make described pidotimod to dissolve in solvent for injection and keep stable; Described solvent for injection comprises water, non-water-soluble matchmaker or its mixture; The amount of described solvent for injection should be enough to make described pidotimod dissolving and keep stable.
The non-water-soluble matchmaker of described injection comprises one of ethanol, propylene glycol, glycerol, 1,3 butylene glycol, tertriary amylo alcohol, dimethyl sulfoxide, Polyethylene Glycol or wherein several mixtures.Described antioxidant comprises sulfites antioxidant: sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium formaldehyde sulphoxylate, sodium dithionite; Thio-compounds: thioglycerin, thiourea, 2 mercapto ethanol, dimercaptopropanol, BAL, 1-sulfo-sorbitol; Polyatomic phenol: hydroquinone, para-aminophenol, oxine; And amino acids: L-cysteine hydrochloride, L-methionine, L-lysine, L-propylhomoserin, L-arginine, L-leucine, L-isoleucine, L-tryptophan, L-glutathion.Described pidotimod solution comprises the mixed solvent solutions of pidotimod aqueous solution and pidotimod.
The pidotimod aqueous solution of described injection for intravenous comprises that direct intravenous drip and dilution back supply the aseptic aqueous solution of intravenous drip, and the injection solubilizing agent that is used for the pidotimod aqueous solution comprises the alkali compounds that can be used for injection: organic base and inorganic base.Organic base is one or more the mixture in ethanolamine, triethanolamine, the ethylenediamine; Inorganic base is one or more the mixture in sodium hydroxide, sodium carbonate, sodium bicarbonate, liquor ammoniae fortis, Basionic, sodium acetate, tertiary sodium phosphate, sodium hydrogen phosphate, the sodium dihydrogen phosphate.The scope of pidotimod pH value of aqueous solution should be 4.0～9.0.The amount of employed injection usefulness solubilizing agent is relevant with the alkalescence of the amount of described reactive compound pidotimod and solubilizing agent itself, and with respect to 1 gram reactive compound, the injection of adding should be able to make the pH value of solution reach 4.0～9.0 with solubilizing agent.Preparation method is: the injection solubilizing agent is dissolved in the water, adds pidotimod, stir and make dissolving.The filled with solution that obtains and is fully filled nitrogen in injection container, promptly.
Described pidotimod mixes solvent solutions, and its mixed solvent comprises water, the non-water-soluble matchmaker of injection.The ratio of water is 0～99% in the mixed solvent, and the non-water-soluble matchmaker's of injection ratio is 1～100%.
Its preparation method is: in injection solubilizing agent dissolving solvent for injection, add pidotimod, stir and make dissolving.The filled with solution that obtains is in injection container, promptly.As the sterilize difference of visual specification of need, adopt different sterilizing methods.In case of necessity, can carry out nitrogen filled protection to injection.
Embodiment:
(1) pidotimod 4g
Sodium hydroxide 1g
Water for injection 100ml
(2) pidotimod 6g
Acetamide is an amount of
Water for injection 100ml
(3) pidotimod 5g
Ethylenediamine is an amount of
Ethanol 20ml
Water for injection 100ml
(4) pidotimod 12g
Diethanolamine is an amount of
Propylene glycol 35ml
Ethanol 100ml
(5) pidotimod 15g
Sodium bicarbonate is an amount of
Tertriary amylo alcohol 16ml
Water for injection 100ml
Pidotimod solution of the present invention all makes by following operation: the injection solubilizing agent that takes by weighing recipe quantity, the solvent that adds recipe quantity 80%, dissolving, the pidotimod that adds recipe quantity stirs and makes the dissolving adjust pH, and adds solvent to full dose, filter, embedding is in the container that liquid medicine injection allows to use, and sterility test is qualified, and packing promptly.
Correlation test shows: under normal storage requirement, pidotimod solution of the present invention can guarantee the pidotimod long-term stability.External condition such as temperature, light obviously descends to the influence of pidotimod.
Pidotimod solution of the present invention comprises the solution that is used for intravenous drip after the aqueous solution that can be directly used in intravenous drip and the dilution, the solution that is used for intravenous drip after the dilution can be diluted in multiple venous transfusions such as the clinical sodium chloride injection that generally uses, glucose injection, Dextrose and Sodium Chloride Inj., and methods such as employing intravenous drip are applied to the relevant treatment of human body or animal body.
The pidotimod solution of the injection for intravenous that the present invention relates to is used to prevent and treat respiratory tract infection (RRI), chronic bronchitis, the urinary tract infection of showing effect repeatedly and the adjuvant therapy of malignant tumor etc. that the child shows effect repeatedly.
Claims (13)
1. pidotimod solution capable of being administered from vein, comprise the reactive compound pidotimod, solvent for injection, the injection solubilizing agent, described pidotimod is (R)-3-[(S)-(5-oxygen-2-pyrrolidinyl) carbonyl]-Thiazolidine-4-carboxylic acid, it is characterized in that: the content of pidotimod is 0.4～200 mg/ml in the described solution, the consumption of described injection solubilizing agent should be enough to make described pidotimod to dissolve in solvent for injection and keep stable, described solvent for injection comprises water, the non-water-soluble matchmaker of injection or be the mixed solvent that both mixture are formed at least, the amount of described solvent for injection should be enough to make described pidotimod dissolving and keep stable.
2. pidotimod solution capable of being administered from vein according to claim 1, it is characterized in that: the non-water-soluble matchmaker of described injection comprises one of ethanol, propylene glycol, glycerol, 1,3 butylene glycol, tertriary amylo alcohol, dimethyl sulfoxide, Polyethylene Glycol or wherein two or more mixtures.
3. pidotimod solution capable of being administered from vein according to claim 1, it is characterized in that: it also comprises antioxidant, described antioxidant is the sulphite kind antioxidant, is one or more the mixture in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium formaldehyde sulphoxylate, the sodium dithionite.
4. pidotimod solution capable of being administered from vein according to claim 1, it is characterized in that: it also comprises antioxidant, described antioxidant is thio-compounds, is one or more the mixture in thioglycerin, thiourea, 2 mercapto ethanol, dimercaptopropanol, BAL, the 1-sulfo-sorbitol.
5. pidotimod solution capable of being administered from vein according to claim 1, it is characterized in that: it also comprises antioxidant, described antioxidant is polyatomic phenol, is one or more the mixture in hydroquinone, para-aminophenol, the oxine.
6. pidotimod solution capable of being administered from vein according to claim 1, it is characterized in that: it also comprises antioxidant, described antioxidant is amino acids, is one or more the mixture in L-cysteine hydrochloride, L-methionine, L-lysine, L-propylhomoserin, L-arginine, L-leucine, L-isoleucine, L-tryptophan, the L-glutathion.
7. pidotimod solution capable of being administered from vein according to claim 1 is characterized in that: described pidotimod solution has the mixed solvent solutions class of pidotimod aqueous solution class and pidotimod.
8. pidotimod solution capable of being administered from vein according to claim 7 is characterized in that: described pidotimod aqueous solution class comprises that the aseptic aqueous solution of direct intravenous drip and dilution back supply the aseptic aqueous solution of intravenous drip.
9. pidotimod solution capable of being administered from vein according to claim 1 is characterized in that: described injection solubilizing agent is the alkali compounds that can be used for injection.
10. pidotimod solution capable of being administered from vein according to claim 9, it is characterized in that: the described alkali compounds that can be used for injection comprises organic base or inorganic base, and described organic base is one or more the mixture in ethanolamine, triethanolamine, the ethylenediamine; Described inorganic base is one or more the mixture in sodium hydroxide, sodium carbonate, sodium bicarbonate, liquor ammoniae fortis, Basionic, sodium acetate, tertiary sodium phosphate, sodium hydrogen phosphate, the sodium dihydrogen phosphate.
11. pidotimod solution capable of being administered from vein according to claim 8 is characterized in that: the scope of the pH value of described pidotimod aqueous solution class is 4.0～9.0.
12. pidotimod solution capable of being administered from vein according to claim 8, it is characterized in that: the amount of employed injection usefulness solubilizing agent is relevant with the alkalescence of the amount of described reactive compound pidotimod and solubilizing agent itself, with respect to 1 gram reactive compound, the injection of adding makes the pH value of solution reach 4.0～9.0 with solubilizing agent.
13. pidotimod solution capable of being administered from vein according to claim 7 is characterized in that: the weight ratio that the ratio of water accounts in the whole mixed solvent in the described mixed solvent is lower than 99%.
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| CN 200610038082 CN1840172A (en) | 2006-01-25 | 2006-01-25 | Pidotimod solution capable of being administered from vein |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009004569A1 (en) | 2007-07-02 | 2009-01-08 | Ellenerre S.R.L. | Use of intranasally administered pidotimod to enhance antigen-specific humoral and cell-mediated immune response |
| CN101843580A (en) * | 2010-05-24 | 2010-09-29 | 南京威尔曼药物研究所 | Preparation method of pidotimod injection preparation |
| CN104274816A (en) * | 2013-07-02 | 2015-01-14 | 苏州麦克威尔生物医药科技有限公司 | Pidotimod injection and preparation method thereof |
| CN108261392A (en) * | 2018-02-09 | 2018-07-10 | 广东嘉博制药有限公司 | A kind of parenteral solution of muscle relaxants Mivacurium Chloride |
-
2006
- 2006-01-25 CN CN 200610038082 patent/CN1840172A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009004569A1 (en) | 2007-07-02 | 2009-01-08 | Ellenerre S.R.L. | Use of intranasally administered pidotimod to enhance antigen-specific humoral and cell-mediated immune response |
| EP2724726A1 (en) * | 2007-07-02 | 2014-04-30 | Polichem S.A. | Use of intranasally administered Pidotimod to enhance antigen-specific humoral and cell-mediated immune response |
| CN101843580A (en) * | 2010-05-24 | 2010-09-29 | 南京威尔曼药物研究所 | Preparation method of pidotimod injection preparation |
| CN104274816A (en) * | 2013-07-02 | 2015-01-14 | 苏州麦克威尔生物医药科技有限公司 | Pidotimod injection and preparation method thereof |
| CN108261392A (en) * | 2018-02-09 | 2018-07-10 | 广东嘉博制药有限公司 | A kind of parenteral solution of muscle relaxants Mivacurium Chloride |
| CN108261392B (en) * | 2018-02-09 | 2020-10-16 | 广东嘉博制药有限公司 | Injection of muscle-relaxing drug micaceium chloride |
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