CN103315949B - Thymopent aqueous solution preparation and use thereof - Google Patents
Thymopent aqueous solution preparation and use thereof Download PDFInfo
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- CN103315949B CN103315949B CN201310168339.8A CN201310168339A CN103315949B CN 103315949 B CN103315949 B CN 103315949B CN 201310168339 A CN201310168339 A CN 201310168339A CN 103315949 B CN103315949 B CN 103315949B
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Abstract
The present invention discloses a thymopent aqueous solution preparation, wherein thymopent is adopted as an active component raw material, a pharmaceutical adjuvant and water are added, and mixing is performed to prepare the thymopent aqueous solution preparation, wherein the adjuvant comprises an acetic acid-sodium acetate buffer solution adopted as a pH value adjustment agent, calcium sodium ethylene diaminetetracetate adopted as a protection agent, and sodium chloride adopted as an osmotic pressure adjustment agent, the thymopent amount is 0.1-100 mg/ml, the acetic acid-sodium acetate buffer solution amount is 1.5-1500 mg/ml, the calcium sodium ethylene diaminetetracetate amount is 0.1-40 mg/ml, and the sodium chloride amount is 0.3-300 mg/ml. The thymopent aqueous solution preparation has characteristics of stable low temperature long-time storage, stable room temperature storage, and stability under a strong illumination condition, and does not generate significant change after storing for 5 days at a high temperature of 60 DEG C so as to reduce transportation requirements, provide convenience for drug transportation, substantially reduce a drug cost, and timely provide drug requirements for patients.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, particularly a kind of aqueous solution preparation of Thymopentin and the application in the medicine of preparation treatment chronic viral hepatitis, tumor and other immune diseases thereof, belong to drug world.
Background technology
Thymopentin (thymopent, TP-5) be made up of (Arg-Lys-Asp-Val-Tyr) 5 amino acid residues, this structure and thymopoietin (Tpymopoietin, TP) the 32-36 position order in 49 aminoacid is identical, and existing data proves that TP-5 is the functional activity fragment of TP, the similar physiologic that TP-5 has TP is active.
The pharmacological action of Thymopentin: it is a kind of immunomodulator, one of its effect is inducing T cell differentiation.It optionally induces the prothymocyte of Thy-1-to be converted into the T cell of Thy-1+.Its T cell differentiation raises mediation by cAMP level in born of the same parents.Another basic role of Thymopentin combines the specific receptors of ripe periphery blood T cell, and make cAMP level in born of the same parents increase, thus bring out a series of intramicellar reaction, this is also the basis of its immunoloregulation function.Under normal body state, Thymopentin manifests immunostimulation; significantly can increase E red rose pigment rate and the conversion ratio of splenocyte; there is potentiation to the different phase of for the first time or again secondary response of immunne response, the antibody forming cell of IgM type and IgG or IgA type can be increased.Thymopentin also can strengthen the phagocytic function of macrophage, increases enzyme and the phagocytic function of polymorph neutrophile leucocytes, raises circulating antibody content, strengthen hematid immunity function.Thymopentin can activate CD
4and CD
8positive cell, makes single-minded Tc cell survival maintain the longer time, simultaneously also can activation Th cell, the function of induction Ts cell.It is relevant that TC cytoactive is promoted in resistance infection and therapeutical effect and it of Thymopentin.In anti-infectious immunity, appropriate Thymopentin obviously can increase the generation of interferon, induction and promotion T cell differentiation and maturation; T lymphocyte subset group ratio is regulated to make CD
4 +/ CD
8 +be tending towards normal; Strengthen macrophage phagocytic function; Strengthen hematid immunity function; Improve the vigor of natural killer cell; Improve generation level and the receptor expression level of interleukin-22; Strengthen the generation of peripheral blood lymphocytes IFN-γ; Strengthen SOD in serum active.
The pharmacology metabolism of Thymopentin: Thymopentin (Arg-Lys-Asp-Val-Tyr) is stable in the external preparation process of preparation, but it enters after in body and is degraded by the aminopeptidase in blood plasma rapidly, t
1/2about 30 seconds, catabolite was tetrapeptide (Lys-Asp-Val-Tyl) and the tripeptides (Lys-Asp-Val) of non-activity.But very fastoperation, in target cell, causes a series of cascade reaction by second message,second messenger in born of the same parents (CAMP) after single injection Thymopentin, makes vivo effect be maintained until several weeks, therefore the maintenance of its drug effect in the treatment can be ensured.
The toxicity of Thymopentin: Thymopentin is one very safe drugs, no matter be subcutaneous injection or intravenously administrable, all rarely toxic and side effects, some side effect accidentally produced are also very slight, as injection site pruritus and erythema, usually just can disappear voluntarily without the need to special handling.
Thymopentin (TP-5), as a kind of immunomodulator, used in 1985 in Italy's listing.But its aqueous solution preparation annoyings pharmacy research industry because of Thymopentin stability problem in aqueous.
At present about the patent application of Thymopentin aqueous solution preparation mainly contains:
1, application number 200510102991.5, denomination of invention " aqueous solution preparation of a kind of Thymopentin and uses thereof ", discloses a kind of aqueous solution preparation of Thymopentin, its preparation method and the application in the medicine for the preparation for the treatment of chronic viral hepatitis, tumor and other immune disease thereof.Said preparation is made up of Thymopentin, pharmaceutic adjuvant and water.Wherein the specification of Thymopentin can be that 0.1-1000mg/ props up, and volume can be 0.1-500ml.Adjuvant can be selected but be not limited only to buffering salts such as 20 kinds of human amino acids, low molecular dextran, poloxamer, phosphate or acetate such as the carbohydrate such as mannitol or Polyethylene Glycol, various cyclodextrin, glycine etc.And specifically disclose pH value 7.05, the aqueous solution preparation be made up of the sodium ethylene diamine tetracetate (EDTA) of 0.5-250mg Thymopentin, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the sodium chloride of 0.5-5%.Stability test (comprising influence factor's test, accelerated test and long term test) shows: this aqueous solution preparation, to light and temperature sensitivity all especially, needs shading, and preserves at Leng Chu (2-10 DEG C).
2, application number 200810008117.9; denomination of invention " a kind of thymus gland pentapeptide injection and uses thereof "; providing a kind of is active component by Thymopentin; add injection supplementary material, injection that sterilized water for injection is prepared from; wherein injection supplementary material comprises protective agent, antioxidant, pH adjusting agent, and its consumption is: Thymopentin 0.1 ~ 200mg/ml, protective agent 10 ~ 200mg/ml, antioxidant 0.1 ~ 10mg/ml, pH adjusting agent 0.5 ~ 20mg/ml.Described adjuvant also comprises isotonic, isotonic modifier, antiseptic, local pain palliative, and its consumption is: isotonic, isotonic modifier 0 ~ 10mg/ml, antiseptic 0 ~ 10mg/ml, local pain palliative 0 ~ 10mg/ml.And specifically disclose pH value 5 ~ 7, prescription is the thymus gland pentapeptide injection of Thymopentin 0.5 ~ 50mg/ml, mannitol 20 ~ 150mg/ml, sodium pyrosulfite 1 ~ 5mg/ml, Acetic acid-sodium acetate 2 ~ 15mg/ml, this is three kinds of optimum selection adjuvants, indispensable, superior stablizing effect can be realized.Stability test shows: this injection can keep stable for 24 months in the low temperature environment of 2 ~ 10 DEG C, within 12 months, can keep stable under the room temperature of 25 ± 2 DEG C.Difference compared with the application is to which are added unstable antioxidant sodium pyrosulfite,
From above-mentioned patent information: by adding the adjuvants such as protective agent, antioxidant, pH adjusting agent with Thymopentapeptide active components compatibility; Stabilization can be played to Thymopentin aqueous solution entirety; especially under the cryogenic conditions of 2 ~ 10 DEG C; all easily stablely to preserve, but along with the rising of temperature, as at room temperature; its stable time of preserving obviously shortens; and higher than room temperature, particularly higher than under the environment of 40 DEG C, the stability of solution substantially just can not be kept.
Medicine is in summer transportation; outdoor temperature often can more than 40 DEG C; adopting has the private carrier of cooling system not only to make cost increase; and also have significant limitation; likely occur that the rigors because of transport makes patient face the problem of scarce medicine; therefore, provide a kind of stability higher, under the higher temperature of 40 DEG C, the Thymopentin water soluble preparation of stability especially still can be kept very necessary.
Summary of the invention
The present invention is intended to solve Thymopentin stability problem in aqueous, provides the aqueous solution preparation of the Thymopentin that a kind of stability is higher.
For solving the problems of the technologies described above, the technical solution adopted in the present invention is as follows:
A kind of aqueous solution preparation of Thymopentin; it is characterized in that: it take Thymopentin as active raw materials; make after adding pharmaceutic adjuvant, water mixing; wherein adjuvant comprise as pH value regulator Acetic acid-sodium acetate buffer, as protectant calcio-disodium edetate, sodium chloride as osmotic pressure regulator, the consumption of supplementary material is: Thymopentin 0.1 ~ 100 mg/ml, Acetic acid-sodium acetate buffer 1.5 ~ 1500mg/ml, calcio-disodium edetate 0.1 ~ 40mg/ml, sodium chloride 0.3 ~ 300mg/ml.
The unit volume of described aqueous solution preparation is 0.1 ~ 500ml.
Described adjuvant adopts injection supplementary material, and obtains aqueous solution for injection with water for injection mixing Thymopentin and can be used as injection use.
The pH value of described aqueous solution for injection is 4.0 ~ 9.0; Preferred pH value is 6.0 ~ 7.0.
Optional pH value regulator can be but be not limited only to Acetic acid-sodium acetate buffer etc.; Optional protective agent can be but be not limited only to ethylenediaminetetraacetic acid and salt etc. thereof; Optional osmotic pressure regulator can be but be not limited only to sodium chloride etc.
Through a large number of experiments show that; above-mentioned adjuvant has good stabilizing effect to Thymopentin aqueous solution, and wherein preferred pH value regulator is Acetic acid-sodium acetate buffer, preferably osmotic pressure regulator is sodium chloride, preferred protective agent is calcio-disodium edetate.
What it was excellent select, and prescribed regimen is: Thymopentin 1mg/ml, Acetic acid-sodium acetate buffer 14.914mg/ml, calcio-disodium edetate 0.4mg/ml, sodium chloride 3mg/ml.
In described NaAc_HAc buffer solution, the weight proportion of acetic acid and sodium acetate is 1:50 ~ 1:200
The water soluble preparation of Thymopentin of the present invention can be prepared by following technique:
A, injection ampere bottle are stand-by after cleaning, sterilizing, drying;
B, supplementary material are pressed recipe quantity and are weighed, dissolve preparation, embedding after aseptic filtration.
Wherein,
The cleaning of ampoule bottle described in step A is carried out under C level background.
Carry out in the sterilization of ampoule bottle described in step A, dry local A level environment under C level background.
The weighing of supplementary material described in step B, dissolving preparation, aseptic filtration are carried out under C level background.
Be potted in described in step B in the local A level environment under B level background and carry out.
Present invention also offers the application of aqueous solution preparation in the medicine of preparation treatment chronic viral hepatitis, tumor and other immune diseases of described Thymopentin.
The technique effect that the present invention gives prominence to is:
1, the present invention is by pH value regulator, protective agent, the compatibility use simultaneously of osmotic pressure regulator three kinds of adjuvants; particularly the proportioning of supplementary material be Thymopentin 0.1 ~ 100 mg/ml, Acetic acid-sodium acetate buffer 1.5 ~ 1500mg/ml, calcio-disodium edetate 0.1 ~ 40mg/ml, sodium chloride 0.3 ~ 300mg/ml time carry out compatibility; reach fabulous stablizing effect; especially in high temperature 60 DEG C test, show the formula that stablizing effect is more better than in application number 200810008117.9, this effect is non-obvious for a person skilled in the art.
2, water soluble preparation of the present invention except have low temperature preserve for a long time stable, room temperature preserve stable, high light conditions under stable feature, the water soluble preparation of more outstanding is Thymopentin of the present invention can be preserved 5 days and without significant change at high temperature 60 DEG C, this not only reduces movement requirement, bring conveniently to the transport of medicine, also greatly reduce cost of drugs simultaneously, and can more timely for patient provides drug demand.
3, the present invention is using calcio-disodium edetate as protective agent; effectively can avoid the complexation of ethylenediaminetetraacetic acid or sodium ethylene diamine tetracetate and blood calcium; during especially quiet note, the rapid decline of the anti-hemostasis Free Calcium concentration of (especially when quiet note speed is fast) energy, stops the tic even generation of asystole phenomenon that severe patient may occur.
Obviously, according to foregoing of the present invention, according to ordinary skill and the customary means of this area, before not departing from the above-mentioned basic fundamental thinking of the present invention, the amendment of other various ways, replacement or change can also be made.
Detailed description of the invention is by the following examples described in further detail foregoing of the present invention, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, the aqueous products (injection, spray, drop) of all Thymopentin realized based on foregoing of the present invention all belongs to scope of the present invention.
Detailed description of the invention
Embodiment 1
Accurately weighed 0.1g Thymopentin, 0.015g sodium acetate, 1.485g glacial acetic acid, 0.5g calcio-disodium edetate, 0.3g sodium chloride, be dissolved in water for injection, be finally dissolved to 1000ml, is distributed into 1000 with 2ml glass ampere bottle.Final specification is that 1ml/ props up.
Embodiment 2
Accurately weighed 100g Thymopentin, 9.655g sodium acetate, 990.345g glacial acetic acid, 40g calcio-disodium edetate, 200g sodium chloride, be dissolved in water for injection, be finally dissolved to 1000ml, is distributed into 1000 with 2ml glass ampere bottle.Final specification is that 1ml/ props up.
Embodiment 3
Accurately weighed 10g Thymopentin, 0.966g sodium acetate, 99.034g glacial acetic acid, 10g calcio-disodium edetate, 20g sodium chloride, be dissolved in water for injection, be finally dissolved to 1000ml, is distributed into 1000 with 2ml glass ampere bottle.Final specification is that 1ml/ props up.
Embodiment 4
Accurately weighed 50g Thymopentin, 0.289g sodium acetate, 29.711g glacial acetic acid, 0.1g calcio-disodium edetate, 300g sodium chloride, be dissolved in water for injection, be finally dissolved to 1000ml, is distributed into 1000 with 2ml glass ampere bottle.Final specification is that 1ml/ props up.
Embodiment 5
Accurately weighed 5g Thymopentin, 0.772g sodium acetate, 79.228g glacial acetic acid, 30g calcio-disodium edetate, 10g sodium chloride, be dissolved in water for injection, be finally dissolved to 1000ml, is distributed into 1000 with 2ml glass ampere bottle.Final specification is that 1ml/ props up.
Embodiment 6
Accurately weighed 5g Thymopentin, 14.483g sodium acetate, 1485.517g glacial acetic acid, 25g calcio-disodium edetate, 50g sodium chloride, be dissolved in water for injection, be finally dissolved to 1000ml, is distributed into 1000 with 2ml glass ampere bottle.
Embodiment 7
Accurately weighed 2g Thymopentin, 29.54g sodium acetate, 0.288g glacial acetic acid, 0.8g calcio-disodium edetate, 6g sodium chloride, be dissolved in water for injection, be finally dissolved to 2000ml, is distributed into 2000 with 2ml glass ampere bottle.Final specification is that 1ml/ props up.
Embodiment 8
Accurately weighed 10g Thymopentin, 147.7g sodium acetate, 1.44g glacial acetic acid, 4g calcio-disodium edetate, 30g sodium chloride, be dissolved in water for injection, be finally dissolved to 10000ml, is distributed into 10000 with 2ml glass ampere bottle.Final specification is that 1ml/ props up.
The stability of preparation is investigated further below by following test.In stability study, the present invention is mainly with appearance character, pH value, related substance, content and aseptic for inspection target, using influence factor's test, accelerated test and long term test method as investigation method, proves Advantageous Effects of the present invention with this.
Experimental example 1 influence factor tests
One, 60 DEG C of influence factor's tests: the preparation of test sample prepared by embodiment 7, altogether produce 1 batch according to this prescription, are numbered Ad1.
Test specimen is positioned in the hot environment of 60 DEG C, respectively corresponding index was investigated in the 5th day, the 10th day after placement, the results are shown in Table 1.
Two, 40 DEG C of influence factor's tests: the preparation of test sample prepared by embodiment 8, altogether produce 3 batches according to this prescription, numbering is respectively 120201,120202,120203.
The test specimen being numbered 120201 is positioned in the hot environment of 40 DEG C, respectively corresponding index was investigated in the 5th day, the 10th day after placement, the results are shown in Table 2.
Three, illumination (4500LX) influence factor tests
The preparation of test sample prepared by embodiment 7, altogether produces 1 batch according to this prescription, is numbered Ad1.
Test specimen is positioned in illumination (4500LX) environment, respectively corresponding index was investigated in the 5th day, the 10th day after placement, the results are shown in Table 3.
The result of the test of table 1, table 2, table 3 shows, Thymopentin aqueous solution of the present invention illumination (4500LX) place 10 days, high temperature (60 DEG C, 40 DEG C) place 10 days indices without significant change.
Experimental example 2 accelerated test
The preparation of test sample prepared by embodiment 8, produces 3 batches altogether according to this prescription, and numbering is respectively 120201,120202,120203.
3 batches of test specimens are placed respectively under the condition of (25 ± 2 DEG C), respectively after placement the 1st, corresponding index was investigated in 2,3,4,5,6 months, the results are shown in Table 4-table 6.
The result of the test of table 4-table 6 shows, Thymopentin aqueous solution of the present invention is placed 6 months under (25 ± 2 DEG C) condition, and indices all meets the requirements, and content reduces on a small quantity, related substance increases on a small quantity, pH value increases on a small quantity.Result shows that said preparation is placed comparatively stable under (25 ± 2 DEG C) condition.
Test example 3 long term test
The preparation of test sample prepared by embodiment 8, produces 3 batches altogether according to this prescription, and numbering is respectively 120201,120202,120203.
By 3 batches of test specimens respectively at (6 ± 2 DEG C)) condition under place, respectively after placement the 1st, corresponding index was investigated in 2,3,4,5,6 months, the results are shown in Table 7-table 9.
The result of the test of table 7-table 9 shows, Thymopentin aqueous solution of the present invention is placed 6 months under (6 ± 2 DEG C) condition, and indices, without significant change, illustrates that this product has good stability.
For proving the Advantageous Effects that the present invention gives prominence to further, the present invention, equally using influence factor's test, accelerated test and long term test method as investigation method, has carried out following Comparative trail with related substance, content for inspection target.
Test sample be respectively in test example of the present invention be numbered Ad1,120201, the sample of 120202 or 120203, the sample of embodiment 1 in the sample of embodiment 1 and application number 200810008117.9 in application number 200510102991.5.
Wherein, being prepared as of embodiment 1 sample in application number 200510102991.5: accurately weighed sodium chloride 7.0g, sodium hydrogen phosphate (containing 12 water of crystallization) 4.37g, sodium dihydrogen phosphate (containing 2 water of crystallization) 1.22g, disodiumedetate 0.64g, Thymopentin 1.0g, be dissolved in water for injection, finally be dissolved to 1000ml, after filtration sterilization, be distributed into 1000 with 2ml cillin bottle.Final specification is that 1ml:1mg/ props up.Numbering S1.
Being prepared as of embodiment 1 sample in application number 200810008117.9: precision takes Thymopentin 1.0g, mannitol 40.0g, sodium pyrosulfite 2.0g, acetic acid and sodium acetate (3:4) 5.0g and is dissolved in water for injection, be dissolved to 1000ml after last, after filtration sterilization, be distributed into 1000 with 2ml cillin bottle.Final specification is that 1ml:1mg/ props up.Numbering S2.
Contrast test 1 influence factor tests
Test specimen is positioned over respectively in the environment of 60 DEG C and illumination (4500LX), respectively corresponding index was investigated in the 5th day, the 10th day after placement, the results are shown in Table 10.
Contrast test 2 accelerated test
Test specimen is placed respectively under the condition of (25 ± 2 DEG C), respectively after placement the 1st, corresponding index was investigated in 2,3,6 months, the results are shown in Table 11.
Contrast test 3 long term test
By test specimen respectively at (6 ± 2 DEG C)) condition under place, respectively after placement the 3rd, corresponding index was investigated in 6,9 months, the results are shown in Table 12.
Can find out from the result of the test of table 10-table 12: Thymopentin aqueous solution of the present invention except have low temperature preserve for a long time stable, room temperature preserve stable, high light conditions stable feature, it also shows the character being better than comparative sample in high temperature 60 DEG C test, goods of the present invention can be preserved 5 days and without significant change, thus especially bring conveniently to transport at high temperature 60 DEG C.
Claims (2)
1. the aqueous solution preparation of a Thymopentin, it is characterized in that: accurately weighed 2g Thymopentin, 29.54g sodium acetate, 0.288g glacial acetic acid, 0.8g calcio-disodium edetate, 6g sodium chloride, be dissolved in water for injection, finally be settled to 2000ml, be distributed into 2000 with 2ml glass ampere bottle.
2. the aqueous solution preparation of a Thymopentin, it is characterized in that: accurately weighed 10g Thymopentin, 147.7g sodium acetate, 1.44g glacial acetic acid, 4g calcio-disodium edetate, 30g sodium chloride, be dissolved in water for injection, finally be settled to 10000ml, be distributed into 10000 with 2ml glass ampere bottle.
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| CN1739786A (en) * | 2005-05-11 | 2006-03-01 | 北京双鹭药业股份有限公司 | Thymic pentapeptide aqua prepn and its prepn process and application |
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| CN1739786A (en) * | 2005-05-11 | 2006-03-01 | 北京双鹭药业股份有限公司 | Thymic pentapeptide aqua prepn and its prepn process and application |
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| Title |
|---|
| 人工合成胸腺五肽在水溶液中的稳定性-pH及缓冲溶液对降解的影响;洪丽娟等;《齐鲁药事》;20060831;第25卷(第8期);第473页摘要部分以及第474页左栏表1 * |
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