CN101768156A - Pidotimod arginine salt and preparation thereof - Google Patents
Pidotimod arginine salt and preparation thereof Download PDFInfo
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- CN101768156A CN101768156A CN200810240885A CN200810240885A CN101768156A CN 101768156 A CN101768156 A CN 101768156A CN 200810240885 A CN200810240885 A CN 200810240885A CN 200810240885 A CN200810240885 A CN 200810240885A CN 101768156 A CN101768156 A CN 101768156A
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- pidotimod
- arginine salt
- arginine
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Abstract
The invention discloses a pidotimod arginine salt and a preparation thereof. The pidotimod arginine salt can be used to cure: 1. repeated outbreak upper and lower respiratory tract infections (pharyngitis, trachitis, bronchitis and tonsillitis); 2. repeated ear-nose-throat infections (nasitis, nasosinusitis and otitis); 3. urinary system infections; 4. gynecologic infections; 5. cellular immune hypofunction of clinical patients after chemotherapy; 6. specific and non-specific immunodeficiency diseases such as cancers, and the like. The pidotimod arginine salt can reduce the times of acute attacks, shorten the course of diseases and relieve the degree of attacks; and the pidotimod arginine salt can be used as an auxiliary antibiotic for curing acute infections. After pidotimod and arginine react with each other in water or ethanol (but not limited to the solvents), the obtained product is concentrated and dried, or is added with insoluble organic solvent for crystallization or is lyophilized to obtain the pidotimod arginine salt. When pharmaceutically acceptable auxiliary materials are added in the pidotimod arginine salt, pharmaceutically acceptable preparations, including but not limited to tablets, capsules, injections and the like can be prepared. The pidotimod arginine salt can be made into infusions for intravenous injection, and can be added into glucose with content of 5 percent or sodium chloride injection with content of 0.9 percent to prepare injections, solvent-crystallized packed powder injections and lyophilized powder injections. The solubility of the pidotimod arginine salt in water is high and the stability of the pidotimod is improved. The pH value of the injections made of the pidotimod arginine salt is more close to the pH value of the human body.
Description
Technical field
The invention belongs to the medicine new technical field, relate to pidotimod arginine salt and injection type thereof.1. said preparation is used for the treatment of the last lower respiratory infection (pharyngitis, trachitis, bronchitis, tonsillitis) of outbreak repeatedly; 2. Otorhinolaryngologic Department repeated infection (rhinitis, sinusitis paranasal sinusitis, otitis); 3. urinary system infection; 4. gynecological infection; 5. the low clinical patients of cellular immune function after the chemotherapy; 6. specificity and non-specific immunity defective disorders such as cancers etc.In order to reduce the number of times of acute attack, shorten the course of disease, alleviate the degree of outbreak; Antibiotic assisting therapy when also can be used as acute infection.
Background technology
The immunity system of human body is being defended the health of human body just as a well-trained crack troops.Immunity system is people's usually said " immunizing power ", " resistibility " to the defence capability of pathogenic agent.
People's defence capability comprises non-specific immunity and specific immunity.Non-specific immunity is to be born with the man day, so be called the inherency immunity again, comprise the skin, mucous membrane of body barrier effect to pathogenic agent, phagocytic cell in the blood, neutrophil leucocyte be to the phagolysis of pathogenic agent, and complement, lyase bacterium, properdin, Interferon, rabbit etc. are to the killing action of pathogenic agent.Specific immunity is meant human body to the resistibility targetedly that certain pathogenic agent had, and this immunizing power varies with each individual, and generally can obtain by preventive vaccination, ill or inapparent infection.Specific immunity mainly forms after the people is born, so be Acquired immunity again.
Sound immunizing power is to guarantee that body avoids the important factor of pathogenic agent invasion and attack, and in fact, for some reason or other, often causes people's hypoimmunity.
Pidotimod (pidotimod) is a kind of brand-new chemosynthesis immunopotentiating agent, and its similar is in dipeptides.The later stage eighties 20th century is successfully synthesized by Italian Poli industria chimica S.P.A chemical company, and gets permission listing in 1993 and be used for clinical.
Pharmacodynamic study shows that pidotimod is an immunopotentiating agent, can promote nonspecific immune reaction, can promote specific immune response again.Pidotimod can promote the activate the phagocytic capacity of scavenger cell and neutrophil leucocyte, improves its chemotaxis; Activate natural killer cell; The former lymphopoiesis that causes of promoting mitosis, the helper T cell (CD that reduces when making immunologic hypofunction
4 +) and suppressor T cell (CD
8 +) ratio raise to recover normal; By stimulating interleukin-2 and gamma-interferon to promote cell immune response.
Although all showing pidotimod, animal experiment and clinical trial do not have directly antibiotic and antiviral activity, by bringing into play the curative effect that significant treatment bacterium (pneumococcus, intestinal bacteria, Pseudomonas aeruginosa, Bacillus proteus etc.) and virus (influenza virus, hsv, murine encephalomyocarditis virus and Mengo virus etc.) infect to the promotion of the immunologic function of human body.
Pidotimod is by cellular immunization, humoral immunization approach performance antibacterium, antiviral, the antifungic action of enhancing body.Clinical application has all obtained good effect in repeatedly respiratory tract infection of control children, the elderly's chronic bronchitis, urinary system infection, malignant tumour and the chemotherapy of outbreak repeatedly, the assisting therapy after the radiotherapy.The multicenter open clinical trial shows that curative effect is reliable, and the human tolerance is good, and toxic side effect is little.
Pidotimod was taken in the 31st edition Martin's pharmacopeia in 1996.Tianjin Jinshi Pharmaceutical Co., Ltd. has successfully developed the granule formulation of pidotimod in 2000, and is four kind new medicines by state approval.Calendar year 2001, there has been pidotimod tablet (trade(brand)name " Wan Shining ") production in China's sun-stone (Tangshan) Pharma Inc., we can say that the imported product of pidotimod and production domesticization product have been on the same starting line.
The present invention is with equimolar pidotimod and the arginine generation pidotimod arginine salt that reacts under certain condition.Because pidotimod destroys under soda acid and hot conditions easily, and hydrolysis takes place especially easily.Pidotimod is prepared into pidotimod arginine salt, has so both increased its stability, improved also simultaneously that it is water-soluble.
Pidotimod arginine salt of the present invention adds pharmaceutically acceptable various auxiliary material, can be prepared into pharmaceutically acceptable various formulation, includes but not limited to tablet, capsule, injection etc.Be particularly suitable for being prepared into the injection of muscle or intravenously administrable.Security is good, good stability, and the pH value is more near pH value of human body.
Summary of the invention
The common method for making of pidotimod arginine salt of the present invention is pidotimod is dissolved in or is suspended in water or the ethanol, adds equimolar arginine then, at room temperature be stirred to dissolving fully after, by concentrating, freeze-drying and the method that adds organic solvent obtain.
The present invention also provides a kind of pidotimod arginine salt can be prepared into pharmaceutically acceptable various formulation, includes but not limited to tablet, capsule, injection etc.Be particularly suitable for being prepared into the injection type of muscle or intravenously administrable, it is characterized in that it is the infusion solution that is used for intravenously administrable that is made by the aqueous solution that pidotimod arginine salt and water form and can adds to 5% glucose or the injection liquid of 0.9% sodium chloride injection, solvent crystal packing powder pin and lyophilized powder pin.The above-mentioned aqueous solution can be that pidotimod and arginine react in water and the pidotimod arginine salt aqueous solution that directly forms, also can be it is the soluble in water and aqueous solution that forms after obtaining pidotimod arginine salt.In the aqueous solution that forms by pidotimod arginine salt of the present invention, store at normal temperatures and do not separate out solid, and composition is still stable.
Injection liquid pH value of the present invention is about 5, more near pH value of human body.
Advantage of the present invention is:
1, the solubleness of the pidotimod arginine salt of Xing Chenging in water is big and improved the stability of pidotimod.
2, the pidotimod arginine salt of Xing Chenging make injection the time, the pH value is more near human body pH.
3, tablet or the capsule made of the pidotimod arginine salt of Xing Chenging, mouthfeel is more acceptant when taking.Reduced the acerbity of original pidotimod.Accepted easilier by children.
Embodiment
Following examples are to be used for illustrating the present invention, but do not limit the present invention in any way.
Embodiment 1:
With the 0.01mol pidotimod, 0.01mol arginine and 20ml water add in the 100ml glass cylinder, at room temperature stir 10min, and raw material dissolves rapidly, and gained solution is water white transparency, and the pH value that records solution with pH meter is 6.0.Gained solution is under reduced pressure concentrated, move in the plate then and in moisture eliminator, place, become white solid after making it fling to moisture fully gradually.This product is pidotimod arginine salt of the present invention.Add 20ml water in this solid and stir with glass stick, solid is dissolving fully rapidly.
Embodiment 2:
With the 0.01mol pidotimod, 0.01mol arginine and 15ml ethanol add in the 100ml glass cylinder, at room temperature stir 10min, and raw material dissolves rapidly, and gained solution is water white transparency.Gained solution is under reduced pressure concentrated or volatilize ethanol, gradually become white solid.This product is pidotimod arginine salt of the present invention.Add 20ml water in this solid and stir with glass stick, solid is dissolving fully rapidly.
Embodiment 3: the pidotimod arginine sheet
Prescription: pidotimod arginine salt (in pidotimod) 400g
Microcrystalline Cellulose 100g
Starch 100g
Dextrin 50g
5% 30 POVIDONE K 30 BP/USP 30 (40% ethanol) solution is an amount of
Magnesium Stearate 3.5g
Make 1000
Method for making: pidotimod arginine, Microcrystalline Cellulose, starch, the dextrin of getting recipe quantity are crossed 80 mesh sieves and are mixed, and it is an amount of to add 5% 30 POVIDONE K 30 BP/USP 30 (40% ethanol) solution, stir the system softwood, crossing 20 mesh sieves granulates, drying is 1 hour in 60 ℃ of baking ovens, adds Magnesium Stearate, with the whole grain of 20 mesh sieves.Compressing tablet, packing, promptly.
Embodiment 4: the pidotimod arginine injection liquid
Prescription: pidotimod arginine salt (by pidotimod) 100g
Water for injection 2000ml
Make 1000
Method for making: get pidotimod arginine salt and add the dissolving of 80% water for injection, add the pin charcoal, 60 ℃ were stirred 10 minutes, filtered decarburization and were diluted to 2000ml with water for injection, cross 0.2 μ m filter membrane and filter, divide in the ampere of packing into sealing by fusing, 2ml/ props up, and in 115 ℃ of 30min that sterilize down, promptly gets aqueous injection.
Embodiment 5: the injection pidotimod arginine
Prescription: pidotimod arginine salt (in pidotimod) 200g
N.F,USP MANNITOL 300g
Water for injection adds to 4000ml
Make 1000 bottles
Method for making: pidotimod arginine salt, the N.F,USP MANNITOL of getting recipe quantity add the dissolving of injection water, add pin and stir 10min down in 60 ℃ with charcoal, filter carbon removal, be diluted to total amount 4000ml, filter with 0.2 μ m filter membrane degerming with water for injection, under aseptic condition, pack in the cillin bottle, every 4ml, half tamponade, pre-freeze is 3 hours under-40 ℃ of conditions, be warming up to 30 ℃ by 3～5 ℃/hour then, be incubated dehydration in 2 hours.The lock aluminium lid is taken out in tamponade.Promptly get powder needle injection of the present invention.Face with before joining in 5% glucose or the transfusion of 0.9% sodium-chlor and can use.
Embodiment 6: the injection pidotimod arginine
Prescription: pidotimod arginine salt (in pidotimod) 200g
Method for making: get pidotimod arginine salt under sterile state, be sub-packed in the cillin bottle, 0.2g/ props up, and aluminium lid is pricked in tamponade, promptly gets powder needle injection of the present invention.Face with before joining in 5% glucose or the transfusion of 0.9% sodium-chlor and can use.
Embodiment 7: the pidotimod arginine sodium chloride injection
Prescription: pidotimod arginine salt (in pidotimod) 200g
Sodium-chlor 900g
Water for injection 100000ml
Make 1000 bottles
Method for making: the sodium-chlor of getting recipe quantity adds 9g pin charcoal after adding the 60% water for injection dissolving of total amount, 80 ℃ of stirrings 30 minutes, filter decarburization, and filter adds the recipe quantity pidotimod arginine salt again to clarification repeatedly, stirring makes dissolving, adds pin charcoal 2g, and 60 ℃ were stirred 10 minutes, filter decarburization, add water to full dose, cross 0.45 μ m or 0.2 μ m filter membrane or filter core and filter, divide in the infusion bottle of packing into, the 100ml/ bottle was sterilized 30 minutes or 45 minutes, and was promptly got the intravenous drip infusion solution for 115 ℃.
Embodiment 8: the pidotimod arginine capsule
Prescription: pidotimod arginine salt (in pidotimod) 400g
Method for making: get the pidotimod arginine salt of recipe quantity, can is in hard capsule, and the 0.4g/ grain is packed, promptly.
Embodiment 9: the pidotimod arginine dispersible tablet
Prescription: pidotimod arginine salt (in pidotimod) 400g
Microcrystalline Cellulose 100g
Starch 50g
Polyvinylpolypyrrolidone 80g
N.F,USP MANNITOL 100g
Aspartame 5g
5% 30 POVIDONE K 30 BP/USP 30 (40% ethanol) solution is an amount of
Magnesium Stearate 4.5g
Make 1000
Method for making: pidotimod arginine salt, Microcrystalline Cellulose, starch, polyvinylpolypyrrolidone, the N.F,USP MANNITOL of getting recipe quantity are crossed 80 mesh sieves and are mixed, it is an amount of to add 5% 30 POVIDONE K 30 BP/USP 30 (40% ethanol) solution, stir the system softwood, crossing 20 mesh sieves granulates, drying is 1 hour in 60 ℃ of baking ovens, add Magnesium Stearate, with the whole grain of 20 mesh sieves.Compressing tablet, packing, promptly.
Claims (10)
1. pidotimod arginine salt is characterized in that: formed by pidotimod and arginine reaction with same mole.
2. pidotimod arginine salt according to claim 1, it is characterized in that pidotimod arginine salt is after being reacted in water or ethanol (but being not limited to these solvents) by pidotimod and arginine, to obtain through concentrate drying or after adding insoluble organic solvent crystallization or lyophilize.
3. pidotimod arginine salt according to claim 2 is characterized in that the pidotimod arginine salt good water solubility, good stability, and 10% pH value of aqueous solution is 4.5～6.5.
4. pidotimod arginine salt according to claim 1 is characterized in that this salt adds pharmaceutically acceptable various auxiliary material, can be prepared into pharmaceutically acceptable various formulation, includes but not limited to tablet, capsule, injection etc.
5. the injection type of pidotimod arginine salt according to claim 4 is characterized in that it is the infusion solution of being made by pidotimod arginine salt that is used for intravenously administrable and can adds to 5% glucose or the injection liquid of 0.9% chlorination R-Gene 10, solvent crystal packing powder pin and lyophilized powder pin.
6. the injection type of pidotimod arginine salt according to claim 5, the specification that it is characterized in that transfusion, injection liquid and the powder pin made is every or every bottle and contains the pidotimod arginine salt that is equivalent to pidotimod 50mg～500mg.
7. the injection type of pidotimod arginine salt according to claim 6 is characterized in that containing additive in the injectable sterile powder of described solution-type injection liquid or lyophilization preparation.
8. the injection type of pidotimod arginine salt according to claim 6,, the pH value that it is characterized in that the solution of this injection is 4.0～6.0.
9. the preparation of pidotimod arginine salt according to claim 2 is characterized in that the preparation of pidotimod arginine includes but not limited to following steps:
Pidotimod is dissolved in or is suspended in water or the ethanol, add equimolar arginine, stir 10min, gained solution is under reduced pressure concentrated or volatilize ethanol, move in the plate then and in moisture eliminator, place, gradually become white solid.
10. 1. the preparation of pidotimod arginine according to claim 1 and pharmaceutical usage thereof is characterized in that being used for the treatment of the last lower respiratory infection (pharyngitis, trachitis, bronchitis, tonsillitis) of outbreak repeatedly; 2. Otorhinolaryngologic Department repeated infection (rhinitis, sinusitis paranasal sinusitis, otitis); 3. urinary system infection; 4. gynecological infection; 5. the low clinical patients of cellular immune function after the chemotherapy; 6. specificity and non-specific immunity defective disorders such as cancers etc.In order to reduce the number of times of acute attack, shorten the course of disease, alleviate the degree of outbreak; Antibiotic assisting therapy when also can be used as acute infection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810240885A CN101768156A (en) | 2008-12-26 | 2008-12-26 | Pidotimod arginine salt and preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810240885A CN101768156A (en) | 2008-12-26 | 2008-12-26 | Pidotimod arginine salt and preparation thereof |
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| CN101768156A true CN101768156A (en) | 2010-07-07 |
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|---|---|---|---|
| CN200810240885A Pending CN101768156A (en) | 2008-12-26 | 2008-12-26 | Pidotimod arginine salt and preparation thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103182067A (en) * | 2011-12-30 | 2013-07-03 | 齐鲁动物保健品有限公司 | Application of pidotimod as immune enhancer on livestock and poultry |
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| CN113004265A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Pidotimod histidine salt crystal form and preparation method thereof |
-
2008
- 2008-12-26 CN CN200810240885A patent/CN101768156A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103182067A (en) * | 2011-12-30 | 2013-07-03 | 齐鲁动物保健品有限公司 | Application of pidotimod as immune enhancer on livestock and poultry |
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| CN113004265A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Pidotimod histidine salt crystal form and preparation method thereof |
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| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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Open date: 20100707 |