CN103536898B - Thymopentin (TP-5) drug composition - Google Patents
Thymopentin (TP-5) drug composition Download PDFInfo
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- CN103536898B CN103536898B CN201310529316.5A CN201310529316A CN103536898B CN 103536898 B CN103536898 B CN 103536898B CN 201310529316 A CN201310529316 A CN 201310529316A CN 103536898 B CN103536898 B CN 103536898B
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Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a thymopentin (TP-5) drug composition and in particular relates to a drug composition. The drug composition comprises 1 part of TP-5, 10-200 parts of sugar and 0-2000 parts of optional water for injection by weight. The TP-5 drug composition can be used for treating chronic viral hepatitis such as chronic hepatitis B, various primary or secondary T cell deficiency diseases such as congenital immunodeficiency diseases in children, some autoimmune diseases such as rheumatoid arthritis and systematic lupus erythematosus, various diseases caused by cellular immune hypofunction and tumors, and can be especially used for adjuvant treatment of tumors.
Description
Technical field
The invention belongs to medical art, relate to a kind of pharmaceutical preparation, particularly relate to a kind of pharmaceutical composition such as injection or lyophilization injectable powder of Thymopentin.Thymopentin pharmaceutical composition of the present invention can be used for treatment chronic viral hepatitis such as chronic hepatitis B, be used for the treatment of various constitutional or Secondary cases T cell defect case as children with congenital immunodeficiency, be used for the treatment of some autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus (sle), be used for the treatment of the disease that various cellular immune function is low, also can be used for treating the auxiliary treatment of tumor especially for tumor.
Background technology
Thymus is one-level lympho-epithelial tissue, is body central immune organ, is T-cytocerastic center organ, except providing the microenvironment needed for a T-cell development, also can produce multiple Thymic hormone.Thymosin can induce differentiation and the maturation of each T-cell subsets, also can strengthen the reactivity worth of all kinds of T-cell, and then regulates whole immune function.Animal thymus (comprising the mankind) retreating of flaccidity gradually with advancing age after growing up, the secretory volume of thymosin also reduces gradually, to obvious atrophy time old, only deposit a small amount of cortex and medullary substance, therefore old infectious disease, tumor, autoimmune disease sickness rate height reduces with atrophy of thymus gland, thymosin activity to have people to think relevant.There is obvious constitutional or secondary deficit in the immune system of the insufficiency of function of thymus own or dependence thymus, and when the adjustment of self is not enough to repair, gives exogenous thymosin and can obtain obvious curative effect.If body immune system dysfunction, low or hyperfunction, additional thymosin can produce obvious dual regulation.
Thymopentin (Thymopentin, usually TP-5 is abbreviated as) be that one forms small peptide (Arg-Lys-Asp-Val-Tyr) by 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.Thymopentin CAS registration number: 69558-55-0, English language Chemical name: N-(N-(N-(N2-L-Arginyl-L-lysyl)-L-α-aspartyl)-L-valyl)-L-tyrosine, English language Chemical name: N-(N-(N-(N
α-L-arginyl-L-lysyl)-L-α-aspartoyl)-L-valyl)-TYR, molecular formula: C
30h
49n
9o
9, molecular weight 679.76, its chemical structural formula is as follows:
Thymopentin is a kind of immunomodulator, and 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.
Current Thymopentin is mainly used in treating tumor, immunologic hypofunction and autoimmune disease, and can regulate the thymus function gone down, the immunologic function normalization making body unbalance, promotes the growth and differ entiation of thymocyte cell.To the atrophy of thymus gland caused because of age and other factors and hypofunction, there is important regulating action.Thymopentin is one very safe drugs, no matter subcutaneous injection or intravenously administrable, all rarely toxic and side effects, some side effect of accidental generation are also very slight, as injection site pruritus and erythema, usually (Sundal E, et al.Arzneimittelforschung, 1994:44 (10): 1145-1149) can just be disappeared voluntarily without the need to special handling.Therefore Thymopentin is a kind of immunomodulator of new type of safe, and its immune system class drug use person that is developed as adds one and selects safely and effectively.
The adjustment of Thymopentin to immunologic function has dosage choice.Domestic and foreign literature report, animal experiment and human clinical verify performance, at every turn 1mg dosage time, the phagocytic function to macrophage in human body, erythrocytic immunologic function and human peripheral blood T cell activation the most obvious; Surmount specific dosage range and do not show better curative effect.26 routine volunteers accept the injection of 1mg dosage at every turn, can improve active 2-3 times of superoxide dismutase, have obvious scavenging action to Superoxide radical anion after 10 times; The effective percentage improved hematid immunity function is 66.7%, and erythrocytic immunologic function plays an important role in elimination immune complex and pathogen, also has activation to leukocytic immunologic function.And can promote that Bcell growth factor and immunoglobulin increase.Thymopentin energy promoting erythrocyte C3b receptor and erythrocyte immune complex are in higher level, illustrate that erythrocyte immune system is activated.
Thymopentin 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.
Thymopentin (TP-5), as a kind of immunomodulator, used in 1985 in Italy's listing.But the inherently stable sex chromosome mosaicism existing for it and annoying pharmacy research industry.
Chinese Patent Application No. 200510102991.5 (two aigret) 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).
It is active component by Thymopentin that Chinese Patent Application No. 200810008117.9 (buchu) discloses a kind of; 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.
Chinese Patent Application No. 201310168339.8 (Li Site) discloses a kind of aqueous solution preparation of Thymopentin, it take Thymopentin as active raw materials, add pharmaceutic adjuvant, make after water mixing, wherein adjuvant comprises the Acetic acid-sodium acetate buffer as pH value regulator, as protectant calcio-disodium edetate, as the sodium chloride of osmotic pressure regulator, the consumption of supplementary material is: Thymopentin 0.1 ~ 100mg/ml, Acetic acid-sodium acetate buffer 1.5 ~ 1500mg/ml, calcio-disodium edetate 0.1 ~ 40mg/ml, sodium chloride 0.3 ~ 300mg/ml.
Chinese Patent Application No. 201210302762.8 (Yao Yun) discloses a kind of pharmaceutical composition containing thymopentin compound, particularly a kind of ejection preparation, its prescription, application and preparation method thereof, every 1000 injections, are made up of the component of following proportioning: Thymopentin 0.5-2g; Mannitol 50-200g; EDTA calcium 1-3g; Vitamin C 1-2g, mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 1000ml of 1:4; With water for injection standardize solution to 2000ml, be then prepared into lyophilization injectable powder through lyophilization.
Chinese Patent Application No. 201210295672.0 (Ji is raw) is a kind of improves immunity, the compositions of the Thymopentin medicine be made up of 5 seed amino acids of the diseases such as treatment hepatitis, T cell defect disease, autoimmune disease, the Thymopentin be made up of 5 seed amino acids containing 1 ~ 10 weight portion, the citric acid of 0.4-0.6 weight portion, the dipotassium hydrogen phosphate of 1.4-1.6 weight portion and the glucose of 48-52 weight portion.Its method for making comprises: get citric acid, dipotassium hydrogen phosphate and glucose and add in water for injection and dissolve; Then add Thymopentin stirring and dissolving and stir, adding needle-use activated carbon and stir, filtering decarbonization, membrane filtration is degerming obtains filtrate; Namely filtrate subpackage or lyophilization obtain Thymopentin pharmaceutical composition.
It is believed that the peptide bond less stable of the Asp in Thymopentin strand, easy fracture in aqueous solution or acid solution, be degraded to corresponding dipeptides Val-Tyr and tripeptides Arg-Lys-Asp.Although prior art has the inherent quality such as content and related substance of investigating Thymopentin with HPLC method, and there are no detecting the report of related impurities situation of change in formulation products.
Therefore, provide a kind of Thymopentin product with good stability such as physical stability and chemical stability, remain that those skilled in the art extremely expect.
Summary of the invention
The object of the present invention is to provide a kind of Thymopentin product of the Thymopentin product with good stability such as physical stability and chemical stability, particularly a kind of injectable.The present inventor has been surprisingly found that, the Thymopentin pharmaceutical composition with feature of the present invention has excellent pharmaceutical property.The present invention is based on this find and be accomplished.
For this reason, first aspect present invention provides a kind of pharmaceutical composition, wherein comprises:
Thymopentin 1 weight portion,
Maltose or its hydrate 10 ~ 200 weight portion,
Optional water for injection 0 ~ 2000 weight portion.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein for the Thymopentin of every 1 weight portion, the amount of maltose or its hydrate is 10 ~ 150 weight portions.Although maltose as well known to those skilled in the art or its hydrate are usually used as the filler of pharmaceutical preparation, to obtain the pharmaceutical preparation with good form, namely typically maltose or its hydrate for improving the physical aspect of pharmaceutical preparation; But have been surprisingly found that maltose or its hydrate can the degradeds of inhibit activities medicine effectively in the present invention, this effect improving pharmaceutical chemistry stability is that those skilled in the art had not known and cannot expect completely yet.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein for the Thymopentin of every 1 weight portion, the amount of maltose or its hydrate is 10 ~ 100 weight portions.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein for the Thymopentin of every 1 weight portion, the amount of maltose or its hydrate is 10 ~ 50 weight portions.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein said maltose hydrate is maltose monohydrate.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein also comprises mannitol.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein also comprises mannitol, and the weight ratio of described mannitol and maltose or its hydrate is 1:5 ~ 12.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein also comprises mannitol, and the weight ratio of described mannitol and maltose or its hydrate is 1:5 ~ 10.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein also comprises mannitol, and the weight ratio of described mannitol and maltose or its hydrate is 1:5 ~ 8.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein also comprises acid-base modifier (also usually can be described as pH adjusting agent).
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein also comprise acid-base modifier, the amount of this acid-base modifier be this pharmaceutical composition water for injection is dissolved and/or to be diluted to Thymopentin concentration be 0.2mg/mL time, the pH value of solution is in 6.5 ~ 7.5 scopes.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, sodium citrate, acetic acid, sodium acetate or its combination.
In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
In one embodiment, described acid-base modifier is citric acid, sodium citrate, acetic acid, sodium acetate.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0 ~ 1500 weight portion.Pharmaceutical composition of the present invention can be prepared into the formulation example of aqueous solution as injection, can also be prepared into cryodesiccated injectable powder.For injection, wherein comprise the water for injection as solvent/carrier, for the Thymopentin of every 1 weight portion, the amount of water for injection is preferably 500 ~ 1500 weight portions; And for injectable powder, wherein except the moisture of residual volume, substantially do not comprise the special water for injection added.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0 ~ 1200 weight portion; Such as, the amount of optional water for injection is 500 ~ 1200 weight portions.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, wherein for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0 ~ 1200 weight portion; Such as, the amount of optional water for injection is 800 ~ 1200 weight portions.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, it is the injection of solution-type, wherein comprises water for injection 500 ~ 1500 weight portion.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, it is the injection of solution-type, wherein comprises water for injection 500 ~ 1200 weight portion.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, it is the injection of solution-type, wherein comprises water for injection 800 ~ 1200 weight portion.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, it is the lyophilized injectable powder of solid type.In one embodiment, the water content of this lyophilized injectable powder, lower than 8%, is particularly usually less than 5%, is particularly usually less than 3%.
As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 5%, be particularly usually less than 3%) Powdered thing or block.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, the amount of pH value in 6.5 ~ 7.5 scopes of this solution during the solution making obtained freeze-drying injectable powder water for injection be dissolved into containing active component 0.2mg/ml concentration.
Pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, it is prepare by comprising following step substantially:
A () takes the Thymopentin of recipe quantity and maltose or its hydrate, and optional mannitol and other optional pharmaceutic adjuvant, adds appropriate water for injection and makes dissolving, then add active carbon, stir, filtering decarbonization;
B () adds water for injection, the weight ratio of Thymopentin and water for injection is made to be (such as 1:500 ~ 1200,1:500 ~ 1500, such as 1:800 ~ 1200), stir, measure solution ph and optional mensuration active component content, regulate the pH value of this solution to the scope conformed with the regulations with acid-base modifier if desired;
C (), by medicinal liquid aseptic filtration, fill is in vial;
D the sealing of the medicinal liquid of step (c) is obtained the compositions as injection of solution-type by (); Or by the medicinal liquid lyophilization of step (c) removing moisture, tamponade sealing obtains the compositions as injectable powder of solid type.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to Thymopentin concentration is 0.2mg/mL, the pH value (particularly pH value is in 6.8 ~ 7.2 scopes, and particularly pH value is 7.0) in 6.5 ~ 7.5 scopes of solution.Although the activity component concentration (about 1mg/ml) of step (b) gained solution measures the normal concentration (being about 5 times) of pH value higher than finished product, but step (b) solution dilution 5 times easily can be measured the pH value of gained diluent by those skilled in the art, needs according to this pH value determining step (b) gained solution the amplitude regulating Acidity of Aikalinity.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), such as 1 ~ 12%.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein also optionally comprises the acceptable excipient of other pharmacy.Described excipient is such as but not limited to mannitol, lactose, sucrose, glucose, sorbitol, glycine, dextran, sodium chloride and combination thereof.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=10 μm in each test sample container is less than 6000, such as be less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as be less than 250, such as be less than 200, such as be less than 150, such as be less than 100, such as be less than 50, such as be less than 25.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=25 μm in each test sample container is less than 600, such as be less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as, be less than 25.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, be less than 6000 containing the particle number of >=10 μm in each test sample container and (be such as less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as be less than 250, such as be less than 200, such as be less than 150, such as be less than 100, such as be less than 50, such as be less than 25), and the particle number of >=25 μm is less than 600 and (is such as less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as be less than 25).
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, compared with within 4 months, processing with 10 DEG C after the 35 DEG C of process in 4 months of its experience, microgranule percent change (%) is less than 200%, such as in 50% ~ 200% scope, such as in 75% ~ 200% scope, such as, in 90% ~ 170% scope.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, compared with within 4 months, processing with 10 DEG C after the 35 DEG C of process in 4 months of its experience, dipeptides increment (%) is less than 50%, such as be less than 40%, such as, be less than 30%, such as, be less than 20%, such as dipeptides increment (%) is 0 ~ 50%, being such as 1 ~ 40%, such as, is 1 ~ 30%, such as, be 1 ~ 20%.
Above-mentioned microgranule percent change (%) measures according to following methods: pharmaceutical composition of the present invention is placed 4 months (being called high-temperature treatment) at 35 DEG C, makes said composition 4 months (being called that low temperature is disposed) of lay down location at 10 DEG C of same batch abreast; Check the particulate matter (carrying out with " first method (light blockage method) ") of each sample, add up each sample >=10 μm of particle numbers, for the sample of same batch, be calculated as follows microgranule percent change:
Above-mentioned dipeptides increment (%) measures according to following methods: pharmaceutical composition of the present invention is placed 4 months (being called high-temperature treatment) at 35 DEG C, makes said composition 4 months (being called that low temperature is disposed) of lay down location at 10 DEG C of same batch abreast; Dipeptides relative amount for Thymopentin when being determined at 4 months in each sample, for the sample of same batch, is calculated as follows its dipeptides increment (%) after high-temperature process:
More than measure dipeptides relative amount and can use the present invention's hereafter " mensuration of catabolite " HPLC method partly, because analytical method has multiple and those skilled in the art easily to improve, and the dipeptides relative amount in same sample can not change because of the change of analytical method, therefore its concrete analysis determining method can not be specified when measuring dipeptides increment (%) of the present invention.
The present invention has been surprisingly found that, in adding in the compositions of the present invention during appropriate mannitol, can give the good solubility property of lyophilization powder injection composition of the present invention and/or good particulate matter performance.
Further, second aspect present invention provides the method for the pharmaceutical composition described in the arbitrary embodiment of preparation first aspect present invention, and it consists essentially of following steps:
A () takes the Thymopentin of recipe quantity and maltose or its hydrate, and optional mannitol and other optional pharmaceutic adjuvant, adds appropriate water for injection and makes dissolving, then add active carbon, stir, filtering decarbonization;
B () adds water for injection, the weight ratio of Thymopentin and water for injection is made to be (such as 1:500 ~ 1200,1:500 ~ 1500, such as 1:800 ~ 1200), stir, measure solution ph and optional mensuration active component content, regulate the pH value of this solution to the scope conformed with the regulations with acid-base modifier if desired;
C (), by medicinal liquid aseptic filtration, fill is in vial;
D the sealing of the medicinal liquid of step (c) is obtained the compositions as injection of solution-type by (); Or by the medicinal liquid lyophilization of step (c) removing moisture, tamponade sealing obtains the compositions as injectable powder of solid type.
The method of arbitrary embodiment according to a second aspect of the present invention, the scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to Thymopentin concentration is 0.2mg/mL, the pH value (particularly pH value is in 6.8 ~ 7.2 scopes, and particularly pH value is 7.0) in 6.5 ~ 7.5 scopes of solution.Although the activity component concentration (about 1mg/ml) of step (b) gained solution measures the normal concentration (being about 5 times) of pH value higher than finished product, but step (b) solution dilution 5 times easily can be measured the pH value of gained diluent by those skilled in the art, needs according to this pH value determining step (b) gained solution the amplitude regulating Acidity of Aikalinity.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein solid content is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), such as 1 ~ 12%.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein the described activated carbon dosage of step (a) is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.05% ~ 0.2%.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, sodium citrate, acetic acid, sodium acetate or its combination.The concentration of these aqueous solutions well known to a person skilled in the art, such as 1 ~ 10%, such as 2% ~ 5%.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.In one embodiment, described acid-base modifier is citric acid, sodium citrate, acetic acid, sodium acetate.
Method according to a second aspect of the present invention described in arbitrary embodiment, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.
State on the invention in the step of preparation method, although its concrete steps described in some details or the language step described in preparation example that describes up and down literary composition detailed description of the invention part distinguish to some extent, but those skilled in the art can summarize the above method step completely according to the open in detail of the present invention's full text.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
According to pharmaceutical composition of the present invention, active component Thymopentin is wherein the pentapeptide fragment compound with following formula structure:
Arg-Lys-Asp-Val-Tyr
Thymopentin is the live part of a kind of thymic neuroendocrine carcinoma of thymus secretions.Thymic neuroendocrine carcinoma is the single polypeptide compound separated from thymosin, be made up of 49 aminoacid, and the peptide fragments be wherein made up of 5 aminoacid, but there are the whole physiological functions identical with thymopoietin II, so just this pentapeptide fragment is called Thymopentin.
Thymopentin is made up of arginine, lysine, aspartic acid, valine, tyrosine five seed amino acid.One of effect of Thymopentin 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 CD4 and CD8 positive 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 CD4/CD8 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-2; Strengthen the generation of peripheral blood lymphocytes IFN-γ; Strengthen SOD in serum active.
Can be used for malignant tumor patient after chemicotherapy, damnification of immunity function person; The treatment of hepatitis B; Major surgery and severe infections; Autoimmune disease, as rheumatoid arthritis, lupus erythematosus; Type Ⅱdiabetes mellitus, climacteric syndrome; Immunologic hypofunction person worn with age.
The indication of the Thymopentin used clinically at present comprises: (1) was for the chronic hepatitis B patient of more than 18 years old.(2) various constitutional or Secondary cases T cell defect disease (as children with congenital immunodeficiency).(3) some autoimmune disease (as rheumatoid arthritis, systemic lupus erythematosus (sle)).(4) disease that various cellular immune function is low.(5) auxiliary treatment of tumor.Its usage and dosage is: intramuscular injection or add glucose medium-sized vein drop, each 1mg, every day or the next day once, within general 15 days, be a course for the treatment of, or determine according to the state of an illness course for the treatment of.
According to the present invention, term " excipient " also can be described as adjuvant, filler etc." the acceptable excipient of pharmacy " used herein refers to the excipient/adjuvant that can be used for compounding pharmaceutical, it there is no harmful effect to organism, and normally organism can tolerate.
The preparation process of lyophilization injectable powder well known to a person skilled in the art pharmaceutical technology, such as following kind of the schematic freeze-drying curve of two shown in freeze-drying curve A and freeze-drying curve B:
Hereafter preparing in the instantiation in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.
Moisture in lyophilization injectable powder is general below 8%, preferably lower than 5%, more preferably less than 3%.Moisture Control is by suitably adjusting lyophilization program to control.Moisture in this lyophilization injectable powder can measure according to many known methods, such as dry weight-loss method.
In the present invention, in order to regulate the pH value of medicinal liquid where necessary, suitable pH adjusting agent can be added in compositions.Although the present inventor only regulates with not having the strong acid of buffer capacity or strong base solution such as a sodium hydrate aqueous solution and aqueous hydrochloric acid solution, but, those skilled in the art understand, if the pH requirement of system can be met with this pH adjusting agent process of not having buffer capacity, the pH adjusting agent then with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can adjust ph, and can stablize pH value.Therefore arbitrary pH adjusting agent listed by the present invention or its combination include in spirit and scope of the invention.
When preparing the injection of solution-type of the present invention, the solid content in solution need not do special restriction.When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 12%, be beneficial to obtain the lyophilized products with good form.Obtain because lyophilized injectable powder normally carries out lyophilization in tubulose cillin bottle, those skilled in the art understand this product at acquisition finished product even before for doctor, usually a round pie is all presented, although in the volume theory of this cake, lecture is fewer than the volume of original aqueous solution (slightly reducing), but this reducing can not narrow down to former aqueous solution volume 50% usually usually, usual meeting is between the 80-120% of former aqueous solution volume, between the 90-100% being more typically in former aqueous solution volume, and can be observed in finished product cillin bottle former aqueous solution liquid level vestige (main body cake because of lyophilizing reduce after remain in liquid level vestige bottle wall, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collide, usually original liquid level vestige can still be retained), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still roughly can estimate it when preparing according to this injectable powder, medicine liquid volume at least before lyophilization starts, the weight of the dry end-product in the volume estimated according to this and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared.Therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparing is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 12%.
Term " solid content " refers to solid matter (such as reactive compound of the present invention and whole excipient used, weight/gram) join in solvent (such as water for injection), a solution is obtained after dissolving, the weight of described solid matter such as, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.Such as in the present invention, add appropriate aqueous solution for injection with 1mg reactive compound and other solid content amounting to about 100mg, be mixed with the solution that final volume is 1ml, namely its solid content is about 10%.
In the present invention, symbol %, according to the linguistic context that it uses, can have the implication of those skilled in the art's easy understand.Such as when mentioning solid content, this symbol represents the percent (w/v, such as g/100ml) of weight/volume; Again such as when mentioning " water content " in lyophilization injectable powder, such as water content is below 8%, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, solid dispersal in a liquid time, % represents weight/volume percent; Solid dispersal in solids or liquid dispersion in solids (such as the water content of powder pin) time, % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.
When preparing medicinal liquid of the present invention, as well known to those skilled in the art, the microporous filter membrane of example 0.45um according to appointment can carry out coarse filtration filtration, by before in liquid medicine filling to cillin bottle, the microporous filter membrane of example 0.22um according to appointment can carry out fine straining and filter with degerming, can filter repeatedly if desired.
According to pharmaceutical composition of the present invention, it is the injection of solution-type.In one embodiment, this injection is single-dose preparations (aqueous injection that such as ampoule is bottled), and in per unit dosage, the amount of reactive compound can such as but not limited to about 1mg, about 2mg, about 5mg, about 10mg, about 25mg, about 50mg.
According to pharmaceutical composition of the present invention, it is lyophilization injectable powder.In one embodiment, this lyophilization injectable powder is single-dose preparations (injectable powder that such as XiLin is bottled), and in per unit dosage, the amount of reactive compound can such as but not limited to about 1mg, about 2mg, about 5mg, about 10mg, about 25mg, about 50mg.
According to the pharmaceutical composition as lyophilization injectable powder of the present invention, it redissolves with water for injection, and typically the redissolution time is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.
According to pharmaceutical composition of the present invention (comprising lyophilized injectable powder and injection), its with water make in every 1ml containing reactive compound 0.2mg solution and according under Chinese Pharmacopoeia version in 2010 two annex VI H items method measure, the pH value of this solution is 6.5 ~ 7.5.In one embodiment, pH value is 6.8 ~ 7.2.
Pharmaceutical composition provided by the invention (comprising lyophilized injectable powder and injection) can be preserved at least 24 months at cool dark place (lucifuge is no greater than 20 DEG C), can meet the Storage Requirement of general lyophilization injectable powder/aqueous injection.
Detailed description of the invention
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.In example below, the pH adjusting agent (in the present invention that is acid-base modifier) used, unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption, when making the aqueous injection of preparation or injectable powder water for injection dissolve and/or be diluted to the solution containing active component 0.2mg/ml, reaches value or the scope of defined in following example.
The hereafter object of preparation process in order to illustrate, and based on each citing comparability and make some specific description, those skilled in the art therefrom can summarize the method obtaining the present invention and prepare lyophilized injectable powder or aqueous injection completely according to existing knowledge.Dosing is prepared in various compositions below, if not otherwise indicated, the total dosing amount often criticized is 1000ml, but lists formula and preparation process constantly, the amount all containing active component 1mg with every bottle is illustrated, and is dispensed into sealing preservation in vial with every bottle of amount containing active component 1mg.
In addition, the method that the particulate matter of aqueous injection or injectable powder checks is carried out according to " first method (light blockage method) " in Chinese Pharmacopoeia 2010 editions two annex IX C particulate matter inspection techniques.
a, investigation method part
content assaying method:
According to Chinese Pharmacopoeia version in 2010 two contained high effective liquid chromatography for measuring of annex VD;
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; 0.05mol/L phosphate buffer (pH7.0)-methanol (90:10) is mobile phase, and determined wavelength is 275nm; Number of theoretical plate calculates should be not less than 1200 by Thymopentin peak;
Algoscopy: get test sample 10 bottles (every bottle of labelled amount is the specification of 1mg), dissolves with mobile phase respectively and/or the solution about containing Thymopentin 0.1mg in every 1ml is made in dilution, and precision measures 20 μ l, injection liquid chromatography, record chromatogram; The Thymopentin reference substance that phosphorus pentoxide of separately learning from else's experience is dried to constant weight is appropriate, is measured in the same method, by external standard method with calculated by peak area, calculates the average content of every bottle of test sample.
related substances separation method:
Carry out according to the high performance liquid chromatography in above content assaying method; Injectable powder mobile phase dissolves and is diluted to the solution containing active component 1mg/ml, as need testing solution; If injection concentration is higher than 1mg/ml, dissolves with mobile phase and be diluted to the solution containing active component 1mg/ml, otherwise not diluting, as need testing solution; Precision measures need testing solution 2ml and puts in 100ml measuring bottle, is diluted to scale with mobile phase, obtains the contrast solution that concentration is equivalent to need testing solution concentration 2%; Get contrast solution 20 μ l injection liquid chromatography, conditioning instrumentation sensitivity, make main peak height be 10 ~ 20% of full scale; Get need testing solution and each 20 μ l of contrast solution more respectively, injection liquid chromatography, is recorded to 3 times of main peak retention time; To make in contrast solution chromatographic peak impurity peak area in main peak area and need testing solution chromatogram compare, to calculate in test sample impurity phase for the content percent of main constituent.
the mensuration of catabolite:
With reference to method described in CN1704430A embodiment synthesis Val-Tyr dipeptide fragment (it can be described as dipeptides, dipeptide fragment or Val-Tyr in the present invention);
HPLC method is used to measure the content of Val-Tyr dipeptide fragment in the present composition, HPLC adopts gradient method to carry out eluting, mobile phase A is that 0.05mol/L phosphate buffer is (wherein containing 0.1% trifluoroacetic acid, pH7.0), Mobile phase B is acetonitrile (wherein containing 0.1% trifluoroacetic acid), and Gradient program is:
| Time (min) | A% | B% |
| 0 | 90 | 10 |
| 40 | 50 | 50 |
| 45 | 50 | 50 |
| 50 | 90 | 10 |
| 55 | 90 | 10 |
Chromatograph 45min writing time, all the other HPLC conditions are with content assaying method and the contained HPLC condition of Related substances separation method; This gradient method can be separated effectively, measure Thymopentin and above-mentioned dipeptide fragment, and separating degree is greater than 3.0; (the present inventor is in complementary testing, have been found that and use CN1676162A (Chinese Patent Application No. 200410029852.X, middle section) description 2 page of 18 row start describe HPLC method can not effectively separate Thymopentin and dipeptide fragment, the two separating degree is less than 0.9).
Use this chromatographic condition, with the dipeptides reference substance of synthesis in contrast, two peptide contents that can measure in the various compositionss that the present invention obtains with reference to the method for related substances and assay above (are absolute content, the i.e. amount g/g of dipeptides in every 1 gram of material), the content of the Thymopentin simultaneously measured in the various compositionss that the present invention obtains by content assaying method above (is absolute content, the i.e. amount g/g of pentapeptide in every 1 gram of material), calculate thus survey the relative amount relative to pentapeptide of dipeptides in material (in every batch materials, two peptide contents are multiplied by 100% income value divided by pentapeptide content), be dipeptides relative amount.
study on the stability method:
This method may be used for the stability (such as physical stability and chemical stability) under investigation the present invention various product simulation Long-term Storage condition.Concrete grammar is: obtained compositions placed 4 months at 35 DEG C, measure the content [35 DEG C-April of Thymopentin in sample, can be described as high temperature average content, mg/ bottle, measures the meansigma methods of 10 bottles] when processing the corresponding time relative to this sample at 10 DEG C the content of active component [10 DEG C-April, can be described as low temperature average content, mg/ bottle, measure the meansigma methods of 10 bottles] percent, can referred to as residual content (%), calculating formula is as follows:
Wherein, high temperature average content (mg/ bottle) and low temperature average content (mg/ bottle) are that sample obtains according to content assaying method mentioned above.Above-mentioned residual content (%) more shows more stable close to 100%, lower than 100% instability, more low more unstable.
In addition, check the particulate matter of each sample, add up each sample >=10 μm of particle numbers.For each sample, calculate the percent change of >=10 μm of particle numbers after above-mentioned high-temperature process, this parameter is called microgranule percent change, and calculating formula is as follows:
Wherein, after high-temperature treatment after >=10 μm of particle numbers and low temperature are disposed >=10 μm of particle numbers are that sample obtains according to light blockage method assay method mentioned above.Above-mentioned microgranule percent change (%) more shows more stable close to 100%, increase higher than 100% particulate matter, and product is unstable, is worth more high more unstable.
In addition, measure the dipeptides increment (%) of each sample after high-temperature process, calculating formula is as follows:
b, compositions preparation example part
preparation example 1, preparation comprise the compositions (injectable powder and aqueous injection) of Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 30mg, |
| pH adjusting agent | appropriate if desired, be adjusted to pH7.0, |
| water for injection | in right amount, 1ml is added to. |
Preparation method:
(1) principal agent and the solid adjuvant material (except pH adjusting agent) of recipe quantity is taken, be placed in stainless steel cask, add the water for injection of recipe quantity about 80%, be stirred to dissolve, the active carbon of 0.1% (w/v) is added again by liquor capacity, stir 30 minutes, filtering decarbonization, mend and inject water to close to prescription full dose.
(2) filtrate sampling, measure pH value, setting is adjusted to (namely if desired by pH adjusting agent, get filtrate to inject in right amount and be diluted with water to containing active component 0.2mg/ml, the pH value measuring this diluent should reach 7.0, otherwise suitably regulates with pH adjusting agent and acid-base modifier again), then benefit injects water to prescription full dose, measure pH value, pH adjusting agent described above is adjusted to the pH7.0 of regulation again if desired; Measure the content of active component in medicinal liquid.
(3) 0.45um filtering with microporous membrane first used by medicinal liquid, then uses 0.22um filtering with microporous membrane 2 times.
(4) get the filtrate of half amount, with every bottle of liquid drug 1ml fill in 1ml ampoule bottle, sealing by fusing, obtains aqueous injection of the present invention and the injection of solution-type.Separately get the filtrate of half amount, with every bottle of liquid drug 1ml fill, in 5ml cillin bottle, (in following example, when quoting this preparation example method, if not otherwise indicated, liquid drug amount is the medicine liquid volume comprising 1mg reactive compound; If liquid drug volume obviously increases or obviously reduces in other example, the volume of cillin bottle rule of thumb suitably can be adjusted), false add plug is in order to carrying out lyophilization below.
(5) lyophilization is carried out, to moisture lower than 3% according to freeze-drying curve A described herein; After lyophilizing terminates, entirely jump a queue; Prick aluminium lid, obtain the injectable powder of this preparation example.The sample of preparation example 1 can referred to as Ex1 in the present invention; The sample of other preparation example also can similarly represent.
Supplement preparation example 1:
With reference to the method for above preparation example 1, adjust unlike by the amount of maltose monohydrate wherein, be respectively 0mg, 2mg, 7mg, 10mg, 20mg, 40mg, 50mg, 65mg, 90mg, 150mg, compositions (injectable powder and the aqueous injection) numbering obtained is respectively Ex101, Ex102, Ex103, Ex104, Ex105, Ex106, Ex107, Ex108, Ex109, Ex110;
With reference to the method for above preparation example 1, be respectively 5mg, 15mg, 40mg, 70mg, 100mg unlike maltose monohydrate wherein being replaced with maltose anhydride and measuring, compositions (injectable powder and the aqueous injection) numbering obtained is respectively Ex111, Ex112, Ex113, Ex114, Ex115;
With reference to the method for above preparation example 1, unlike the mannitol, lactose, dextran, glycine, the sucrose that maltose monohydrate are wherein replaced with respectively equivalent, the compositions obtained (injectable powder and aqueous injection) numbering is respectively Ex116, Ex117, Ex118, Ex119, Ex120.
Supplement preparation example 2:
With reference to the method for above preparation example 1, be adjusted to 6.5,6.8,7.2,7.5 unlike by pH value wherein, compositions (injectable powder and the aqueous injection) numbering obtained is respectively Ex121, Ex122, Ex123, Ex124;
With reference to the method for above preparation example 1, be adjusted to 0.5ml, 0.8ml, 1.2ml, 1.5ml unlike by water for injection consumption wherein, compositions (injectable powder and the aqueous injection) numbering obtained is respectively Ex125, Ex126, Ex127, Ex128.
Supplement preparation example 3:
With reference to the method for above preparation example 1, unlike supplementing the mannitol adding and be equivalent to 1/20,1/15,1/12,1/10,1/8,1/7,1/6,1/5,1/4,1/2,1,5 times of maltose monohydrate consumption wherein, the compositions obtained (injectable powder and aqueous injection) numbering is respectively Ex131, Ex132, Ex133, Ex134, Ex135, Ex136, Ex137, Ex138, Ex139, Ex140, Ex141, Ex142;
With reference to the method for above preparation example 1, unlike supplementing the lactose adding and be equivalent to 1/10,1/7,1/3 times of maltose monohydrate consumption wherein, 1/10, the dextran of 1/7,1/3 times, 1/10, the glycine of 1/7,1/3 times, compositions (injectable powder and the aqueous injection) numbering obtained is respectively Ex143, Ex144, Ex145, Ex146, Ex147, Ex148, Ex149, Ex150, Ex151.
preparation example 2, preparation comprise the compositions (injectable powder and aqueous injection) of Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 10mg, |
| mannitol | 2mg, |
| pH adjusting agent | to pH7.0, |
| water for injection | in right amount, 1ml is added to. |
Method for making: prepared by the method with reference to above preparation example 1, but carry out lyophilization according to freeze-drying curve B described herein, and aqueous injection and the injectable powder of gained are designated as Ex2.
preparation example 3, preparation comprise the compositions (injectable powder and aqueous injection) of Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose (anhydride) | 50mg, |
| mannitol | 6.25mg, |
| lactose | 60mg, |
| pH adjusting agent | to pH6.5, |
| water for injection | in right amount, 1ml is added to. |
Method for making: prepared by the method with reference to above preparation example 1, aqueous injection and the injectable powder of gained are designated as Ex3.
preparation example 4, preparation comprise the compositions (injectable powder and aqueous injection) of Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 40mg, |
| mannitol | 6.5mg, |
| glycine | 33mg, |
| pH adjusting agent | to pH7.5, |
| water for injection | in right amount, 1ml is added to. |
Method for making: prepared by the method with reference to above preparation example 1, aqueous injection and the injectable powder of gained are designated as Ex4.
preparation example 5, preparation comprise the compositions (injectable powder and aqueous injection) of Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 30mg, |
| mannitol | 4.3mg, |
| dextran | 25mg, |
| pH adjusting agent | to pH7.0, |
| water for injection | in right amount, 1ml is added to. |
Method for making: prepared by the method with reference to above preparation example 1, aqueous injection and the injectable powder of gained are designated as Ex5.
Reference examples 1: according to CN1676162A (Chinese Patent Application No. 200410029852.X, middle section) formula described in description 2 pages of 9-17 are capable and method, preparation is containing the sterile solution of glycine 50mg/ml, then prepare aqueous injection and injectable powder according to the embodiment of the present invention 1 step (3) to (5) described method, be designated as Co1.
Reference examples 2: according to CN1660407A (Chinese Patent Application No. 200510002507.1, dimension letter) formula described in description 4 pages of embodiments 3 and method, preparation contains the sterile solution of sodium citrate and sodium chloride, then prepare aqueous injection and injectable powder according to the embodiment of the present invention 1 step (3) to (5) described method, be designated as Co2.
Reference examples 3: according to CN101024071A (Chinese Patent Application No. 200610008148.5, neutralization) formula described in description 4 pages of embodiments 1 and method, preparation is containing the sterile solution of sodium acetate, then prepare aqueous injection and injectable powder according to the embodiment of the present invention 1 step (3) to (5) described method, be designated as Co3.
Reference examples 4: according to CN101244255A (Chinese Patent Application No. 200810008117.9, buchu) formula described in description 5 pages of embodiments 1 and method, preparation is containing the sterile solution of mannitol, sodium pyrosulfite etc., then prepare aqueous injection and injectable powder according to the embodiment of the present invention 1 step (3) to (5) described method, be designated as Co4.
Reference examples 5: according to CN102764424A (Chinese Patent Application No. 201210295672.0, Ji is raw) formula described in description 4 pages of embodiments 1 and method, preparation is containing the sterile solution of citric acid, dipotassium hydrogen phosphate, sodium tartrate etc., then prepare aqueous injection and injectable powder according to the embodiment of the present invention 1 step (3) to (5) described method, be designated as Co5.
Reference examples 6: according to CN102988954A (Chinese Patent Application No. 201210302762.8, formula Yao Yun) described in description 4 pages of embodiments 1 and method, preparation is containing the sterile solution of mannitol, EDTA calcium, sodium ascorbate etc., then prepare aqueous injection and injectable powder according to the embodiment of the present invention 1 step (3) to (5) described method, be designated as Co6.
test example part
study on the stability example 1:
According to study on the stability method above, the powder pin sample investigating each preparation example and reference examples gained in above " B, compositions preparation example part " places the physical stability chemical stability after 4 months at 35 DEG C, particularly measures their dipeptides increment (%), powder pin dissolution time, microgranule percent change (%), residual content (%).
Result:
(1) various sample that above, " B, compositions preparation example part " obtains, in dipeptides increment (%), demonstrates the difference that prior art cannot be expected completely:
A (), for the sample adding enough maltose or its hydrate, display dipeptides increment is all lower than 13%, and drug degradation is not obvious:
For Ex1, Ex2, Ex3, Ex4, Ex5, these use the maltose of the present invention specific consumption or the aqueous injection of its hydrate and injectable powder, their dipeptides increment (%) is all in 3.6% ~ 10.3% scope, and the dipeptides increment (%) of such as Ex1 liquid drugs injection is 5.2%, the dipeptides increment of Ex2 powder pin (%) is 4.7%;
For Ex104, Ex105, Ex106, Ex107, Ex108, Ex109, Ex110, these use maltose or its hydrate consumption to be more than or equal to 10 times of aqueous injection to principal agent and injectable powder, their dipeptides increment (%) is all in 3.3% ~ 11.7% scope, and the dipeptides increment (%) of such as Ex105 liquid drugs injection is 8.6%, the dipeptides increment of Ex109 powder pin (%) is 4.3%;
For Ex112, Ex113, Ex114, Ex115, these use maltose anhydrides and consumption is greater than 10 times of aqueous injection to principal agent and injectable powder, their dipeptides increment (%) is all in 3.6% ~ 9.6% scope, and the dipeptides increment (%) of such as Ex112 liquid drugs injection is 5.3%, the dipeptides increment of Ex114 powder pin (%) is 7.1%;
For Ex121, Ex122, Ex123, Ex124, these use maltose hydrates but pH at the aqueous injection of 6.5 ~ 7.5 scopes and injectable powder, their dipeptides increment (%) is all in 2.3% ~ 8.6% scope, and the dipeptides increment (%) of such as Ex121 liquid drugs injection is 6.1%, the dipeptides increment of Ex123 powder pin (%) is 2.3%;
The aqueous injection of water yield when these use maltose hydrate but change dosing for Ex125, Ex126, Ex127, Ex128 and injectable powder, their dipeptides increment (%) is all in 2.8% ~ 9.7% scope, and the dipeptides increment (%) of such as Ex125 liquid drugs injection is 6.4%, the dipeptides increment of Ex125 powder pin (%) is 3.7%;
For Ex131, Ex132, Ex133, Ex134, Ex135, Ex136, Ex137, Ex138, Ex139, Ex140, Ex141, Ex142, these use maltose hydrate and increase aqueous injection and the injectable powder of appropriate mannitol, their dipeptides increment (%) is all in 2.2% ~ 11.4% scope, and the dipeptides increment (%) of such as Ex131 liquid drugs injection is 6.8%, the dipeptides increment of Ex135 powder pin (%) is 4.3%;
For Ex143, Ex144, Ex145, Ex146, Ex147, Ex148, Ex149, Ex150, Ex151 these use maltose hydrates and increase aqueous injection and the injectable powder of appropriate lactose, dextran or glycine, their dipeptides increment (%) is all in 1.9% ~ 10.7% scope, and the dipeptides increment (%) of such as Ex144 liquid drugs injection is 6.4%, the dipeptides increment of Ex147 powder pin (%) is 3.7%.
But (b), for the sample not adding maltose or its hydrate or addition deficiency, display dipeptides increment increases greatly, and all more than 65%, drug degradation is obvious:
For aqueous injection and the injectable powder of these maltose of Ex101, Ex102, Ex103 or its hydrate addition deficiency, their dipeptides increment (%) is all in 68.6% ~ 133.8% scope, and the dipeptides increment (%) of such as Ex101 liquid drugs injection is 125.4%, the dipeptides increment of Ex103 powder pin (%) is 74.3%;
Use anhydrous maltose instead for Ex111 but the aqueous injection of addition deficiency and injectable powder, their dipeptides increment (%) is respectively 88.3% and 81.3%;
For Ex116, Ex117, Ex118, Ex119, Ex120, these do not add maltose or its hydrate and use mannitol, lactose, dextran, glycine, the aqueous injection of sucrose and injectable powder instead, their dipeptides increment (%) is all in 91.2% ~ 147.5% scope, and the dipeptides increment (%) of such as Ex116 liquid drugs injection is 133.7%, the dipeptides increment of Ex118 powder pin (%) is 102.8%;
Aqueous injection prepared by the prior art formula that these do not add maltose or its hydrate for Co1, Co2, Co3, Co4, Co5, Co6 and injectable powder, their dipeptides increment (%) is all in 88.6% ~ 153.8% scope, and the dipeptides increment (%) of such as Co1 liquid drugs injection is 153.8%, the dipeptides increment of Co4 powder pin (%) is 97.5%.
Above result display, the stability that appropriate maltose or its hydrate contribute to improving Thymopentin is added in Thymopentin aqueous solution type or Solid form preparations, particularly reduce the speed of wherein active ingredient degradation, therefore from this result of study, it is favourable for adding maltose more than relative to main constituent 10 times amount or its hydrate for the Thymopentin formulation products obtaining good chemical stability.
(2) dissolution time of injectable powder: various injectable powder prepared by above " B, compositions preparation example part ", measure their dissolution time as follows: open bottle cap plastic top, water for injection (consumption is about 3 times of liquor capacity before respective sample lyophilization) is injected from bottle stopper puncture with syringe, redissolve the time with stopwatch record, every batch sample tests 5 times, averages.
Result:
The injectable powder more than 50 times for these maltose of Ex108, Ex109, Ex110 or its hydrate amount ratio active component, their dissolution time is all more than 107 seconds, and show maltose or the larger dissolution time of its hydrate consumption is longer, three samples are respectively 107 seconds, 131 seconds, 168 seconds; And these maltose of Ex101, Ex102, Ex103, Ex104, Ex105, Ex106, Ex107 or its hydrate amount ratio active component are less than or equal to the injectable powder of 50 times, dissolution time is all in the scope of 6 ~ 19 seconds, and the such as dissolution time of Ex101 and Ex104 is respectively 12 seconds and 9 seconds;
With reference to formula and the method for preparation example 5, different is only change maltose monohydrate into maltose anhydride, and its amount is respectively 0mg, 2mg, 7mg, 10mg, 20mg, 40mg, 50mg, 65mg, 90mg, 150mg, and the injectable powder composition no obtained is respectively Ex161, Ex162, Ex163, Ex164, Ex165, Ex166, Ex167, Ex168, Ex169, Ex170; Be measured in the same method the dissolution time of these injectable powder, result display Ex168, Ex169, Ex170 three is respectively 111 seconds, 128 seconds, 172 seconds; But the dissolution time of these powder pins of Ex161, Ex162, Ex163, Ex164, Ex165, Ex166, Ex167 is all in the scope of 7 ~ 21 seconds, the such as dissolution time of Ex161 and Ex164 is respectively 11 seconds and 18 seconds;
Respectively with reference to formula and the method for preparation example 2,3,4,5, different is only change maltose or its hydrate into 75mg, and the injectable powder numbering obtained is respectively Ex171, Ex172, Ex173, Ex174; Respectively with reference to formula and the method for preparation example 2,3,4,5, different is only change maltose or its hydrate into 150mg, and the injectable powder numbering obtained is respectively Ex175, Ex176, Ex177, Ex178; Be measured in the same method the dissolution time of these injectable powder, result display Ex171, Ex172, Ex173, Ex174 are respectively 116 seconds, 121 seconds, 112 seconds, 119 seconds, Ex175, Ex176, Ex177, Ex178 are all within the scope of 168 ~ 191 seconds, show these powder pin formula dissolution times using relatively large maltose or its hydrate to extend, when this is clinical practice, need the feature avoided.
Except the above-mentioned powder pin of mensuration, other injectable powder prepared by " B, compositions preparation example part ", they do not add maltose or its hydrate, or the maltose added or the amount specific activity component amount of its hydrate are less than or equal to 50 times, after measured, the dissolution time of these powder pins is all in the scope of 6 ~ 24 seconds, and such as the dissolution time of Ex1, Ex2, Ex3, Ex4, Ex5 five kinds of powder pins is all in the scope of 8 ~ 15 seconds, and such as the dissolution time of Ex2 powder pin is 12 seconds;
---above result display maltose or its hydrate consumption excessive (when particularly consumption is greater than more than 50 times of Thymopentin amount) can affect the dissolubility of injectable powder, affect product use clinically; Therefore, from this angle, the consumption of maltose or its hydrate should not exceed 50 times of Thymopentin amount.
(3) various sample is after high-temperature process, and microgranule percent change (%) demonstrates different variation tendencies:
" B, compositions preparation example part " whole injectable powder of preparing and aqueous injection above, its particulate matter is measured immediately after the production with light blockage method, result shows whole sample (be 1ml loading amount or liquor capacity is 1ml before lyophilization) containing the particle numbers of >=10 μm all 13 ~ 31 scopes, and display has good particulate matter performance;
For Ex2, Ex3, Ex4, Ex5, these are added with liquid drugs injection or the powder pin sample of the mannitol of 1/5 ~ 1/8 amount for maltose or its hydrate quantity, they are after high-temperature process, compared with the sample of K cryogenic treatment, display microgranule percent change (%) is all in 113% ~ 156% scope; But Ex1, Ex101 ~ Ex110, Ex111 ~ Ex115 these do not add examination liquid drugs injection or the powder pin sample of mannitol, they are after high-temperature process, and microgranule percent change (%) is all in 306% ~ 473% scope, and display microgranule is significantly increased.
For Ex135, Ex136, Ex137, Ex138, Ex139, Ex140, Ex141, Ex142 these be added with for maltose or its hydrate quantity, be greater than the mannitol of 1/8 amount liquid drugs injection or powder pin sample, they are after high-temperature process, compared with the sample of K cryogenic treatment, display microgranule percent change (%) is (but Ex139 in 106% ~ 161% scope all, Ex140, Ex141, the sample dissolution time that these mannitol relative quantities of Ex142 are greater than 1/5 is all more than 68 seconds and the larger dissolution time of mannitol amount is longer, but the dissolution time of Ex135 ~ Ex138 tetra-kinds of powder pins is all lower than 24 seconds), show that adding appropriate mannitol contributes to improving particulate matter feature, but mannitol addition affects the solubility property of injectable powder time excessive, for Ex131, Ex132, Ex133, Ex134, these are added with for maltose or its hydrate quantity lower than the liquid drugs injection of mannitol or the powder pin sample that equal 1/10 amount, they are after high-temperature process, compared with the sample of K cryogenic treatment, display microgranule percent change (%), all in 282% ~ 378% scope, can not effectively improve particulate matter feature when display mannitol consumption is too low,
Respectively with reference to formula and the method for Ex2, Ex3, Ex4, Ex5, but mannitol consumption is 1/6 of maltose or its hydrate quantity, four aqueous injection obtained and four injectable powder are after high-temperature process, and microgranule percent change (%) all in 113% ~ 157% scope (and the dissolution time of four kinds of powder pins is all lower than 24 seconds); Respectively with reference to formula and the method for Ex2, Ex3, Ex4, Ex5, but mannitol consumption is 1/2 of maltose or its hydrate quantity, four aqueous injection obtained and four injectable powder are after high-temperature process, and microgranule percent change (%) all in 94% ~ 166% scope (but the dissolution time of four kinds of powder pins is all greater than 84 seconds); Respectively with reference to formula and the method for Ex2, Ex3, Ex4, Ex5, but mannitol consumption is 1/12 of maltose or its hydrate quantity, four aqueous injection obtained and four injectable powder are after high-temperature process, and microgranule percent change (%) all (can not improve the microgranule percent change performance of product) in 281% ~ 434% scope when display mannitol consumption is very few;
For Ex143, Ex144, Ex145, Ex146, Ex147, Ex148, Ex149, Ex150, Ex151 these supplement and with the addition of lactose, dextran, the aqueous injection of glycine (but not mannitol) and injectable powder sample, after high-temperature process, microgranule percent change (%) is all in 286% ~ 452% scope, and the pharmaceutical adjunct showing these routines can not improve the microgranule performance of product as mannitol.
For Co1, Co2, Co3, Co4, Co5, Co6, these comprise or do not comprise mannitol but all do not add aqueous injection and the injectable powder sample of maltose, after high-temperature process, microgranule percent change (%) is all in 254% ~ 413% scope, and the microgranule performance showing them is not enough.
Version Chinese Pharmacopoeia in 2010 two regulations, for sign loading amount be the vein injection of below 100ml, sterilized powder used for intravenous injection, concentrated solution for injection and injection sterile bulk drug, unless otherwise specified individual, the particle number containing >=10 μm in each test sample container must not cross 6000.Even if although above in each preparation example and reference examples gained liquid drugs injection and powder pin after high-temperature process microgranule percent change (%) up to 500% time high-temperature process after microgranule absolute number also can not exceed above-mentioned standards of pharmacopoeia value (peak about 160/bottle), but should see, this standard is the packing specification for " sign loading amount is below 100ml ", and for the 1ml/ bottle powder pin of subpackage of the present invention or liquid drugs injection, this standard is obviously more loose, if correspondingly reduce 100 times, then the restriction of this standards of pharmacopoeia must not should be 60.And the sample that the above-mentioned mannitol relative usage of the present invention is greater than 1/8, even if they also can not exceed the restriction of above-mentioned " must not cross 60 " strictly after high-temperature process; But for the sample that other mannitol relative usage is less than 1/10, by the restriction far beyond above-mentioned " 60 must not be crossed " strictly after high-temperature process.
In this sense, maltose or its hydrate is added to improve on the basis of product chemical stability in Thymopentin pharmaceutical formulation, adding the mannitol that relative quantity is greater than 1/8 is useful for improving product physical property further, but mannitol relative usage can cause injectable powder deliquescent deficiency when being greater than 1/5, the mannitol namely comprising 1/8 ~ 1/5 amount is useful.
(4) after 4 months high-temperature treatments, the residual content (%) of Ex2, Ex3, Ex4, Ex5 tetra-formula gained aqueous injection and injectable powder, all in 97.6 ~ 99.4% scopes, shows them and all has good chemical stability.
industrial applicability
The present composition can clinically for the chronic hepatitis B patient of more than 18 years old; For various constitutional or Secondary cases T cell defect disease (as children with congenital immunodeficiency); For some autoimmune disease (as rheumatoid arthritis, systemic lupus erythematosus (sle)); For the disease that various cellular immune function is low; And for the auxiliary treatment of tumor.
Claims (62)
1. a pharmaceutical composition, wherein comprises: Thymopentin 1 weight portion, maltose or its hydrate 10 ~ 50 weight portion, optional water for injection 0 ~ 2000 weight portion.
2. pharmaceutical composition according to claim 1, wherein said maltose hydrate is maltose monohydrate.
3. pharmaceutical composition according to claim 1, wherein also comprises mannitol.
4. pharmaceutical composition according to claim 3, the weight ratio of described mannitol and maltose or its hydrate is 1:5 ~ 12.
5. pharmaceutical composition according to claim 3, the weight ratio of described mannitol and maltose or its hydrate is 1:5 ~ 10.
6. pharmaceutical composition according to claim 3, the weight ratio of described mannitol and maltose or its hydrate is 1:5 ~ 8.
7. pharmaceutical composition according to claim 1, wherein also comprises acid-base modifier.
8. pharmaceutical composition according to claim 7, the amount of this acid-base modifier be this pharmaceutical composition water for injection is dissolved and/or to be diluted to Thymopentin concentration be 0.2mg/mL time, the pH value of solution is in 6.5 ~ 7.5 scopes.
9. pharmaceutical composition according to claim 1, wherein for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0 ~ 1500 weight portion.
10. pharmaceutical composition according to claim 1, wherein for the Thymopentin of every 1 weight portion, the amount of water for injection is 500 ~ 1500 weight portions.
11. pharmaceutical compositions according to claim 1, wherein for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0 ~ 1200 weight portion.
12. pharmaceutical compositions according to claim 1, wherein for the Thymopentin of every 1 weight portion, the amount of water for injection is 500 ~ 1200 weight portions.
13. pharmaceutical compositions according to claim 1, wherein for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0 ~ 1200 weight portion.
14. pharmaceutical compositions according to claim 1, wherein for the Thymopentin of every 1 weight portion, the amount of water for injection is 800 ~ 1200 weight portions.
15. pharmaceutical compositions according to claim 1, it is the injection of solution-type, wherein comprises water for injection 500 ~ 1500 weight portion.
16. pharmaceutical compositions according to claim 1, it is the injection of solution-type, wherein comprises water for injection 500 ~ 1200 weight portion.
17. pharmaceutical compositions according to claim 1, it is the injection of solution-type, wherein comprises water for injection 800 ~ 1200 weight portion.
18. pharmaceutical compositions according to claim 1, it is the lyophilized injectable powder of solid type.
19. pharmaceutical compositions according to claim 18, the water content of this lyophilized injectable powder is lower than 8%.
20. pharmaceutical compositions according to claim 18, the water content of this lyophilized injectable powder is lower than 5%.
21. pharmaceutical compositions according to claim 18, the water content of this lyophilized injectable powder is lower than 3%.
22. pharmaceutical compositions according to claim 1, wherein also comprise the acceptable excipient of other pharmacy; Described excipient is selected from: lactose, sucrose, glucose, sorbitol, glycine, dextran, sodium chloride and combination thereof.
23. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=10 μm in each test sample container is less than 6000.
24. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=10 μm in each test sample container is less than 3000.
25. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=10 μm in each test sample container is less than 1500.
26. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=10 μm in each test sample container is less than 1000.
27. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=10 μm in each test sample container is less than 500
28. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=10 μm in each test sample container is less than 200.
29. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=10 μm in each test sample container is less than 100.
30. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=25 μm in each test sample container is less than 600.
31. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=25 μm in each test sample container is less than 300.
32. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=25 μm in each test sample container is less than 100.
33. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=25 μm in each test sample container is less than 50.
34. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, and the particle number containing >=25 μm in each test sample container is less than 25.
35. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, particle number containing >=10 μm in each test sample container is less than 6000, and the particle number of >=25 μm is less than 600.
36. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, particle number containing >=10 μm in each test sample container is less than 3000, and the particle number of >=25 μm is less than 300.
37. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, particle number containing >=10 μm in each test sample container is less than 1000, and the particle number of >=25 μm is less than 100.
38. according to the pharmaceutical composition of any one of claim 1-22, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two annex IX C particulate matter inspection techniques, particle number containing >=10 μm in each test sample container is less than 500, and the particle number of >=25 μm is less than 50.
39. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, microgranule percent change (%) is less than 200%.
40. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, microgranule percent change (%) is in 50% ~ 200% scope.
41. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, microgranule percent change (%) is in 75% ~ 200% scope.
42. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, microgranule percent change (%) is in 90% ~ 170% scope.
43. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is less than 50%.
44. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is less than 40%.
45. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is less than 30%.
46. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is less than 20%.
47. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is 0 ~ 50%.
48. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is 1 ~ 40%.
49. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is 1 ~ 30%.
50. according to the pharmaceutical composition of any one of claim 1-22, and compared with processing with 10 ° of C4 months after 35 ° of C4 month process of its experience, dipeptides increment (%) is 1 ~ 20%.
The method of the pharmaceutical composition described in 51. any one of preparation claim 1-50, it comprises the following steps:
A () takes the Thymopentin of recipe quantity and maltose or its hydrate, and optional mannitol and other optional pharmaceutic adjuvant, adds appropriate water for injection and makes dissolving, then add active carbon, stir, filtering decarbonization;
B () adds water for injection, the weight ratio of Thymopentin and water for injection is made to be 1:500 ~ 1500, stir, measure solution ph and measure active component content, regulate the pH value of this solution to the scope conformed with the regulations with acid-base modifier, the scope that this pH conforms with the regulations refers to: when this solution water for injection is diluted to Thymopentin concentration is 0.2mg/mL, the pH value of solution is in 6.5 ~ 7.5 scopes;
C (), by medicinal liquid aseptic filtration, fill is in vial;
D the sealing of the medicinal liquid of step (c) is obtained the compositions as injection of solution-type by (); Or by the medicinal liquid lyophilization of step (c) removing moisture, tamponade sealing obtains the compositions as injectable powder of solid type.
52. according to the method for claim 51, and the scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to Thymopentin concentration is 0.2mg/mL, the pH value of solution is in 6.8 ~ 7.2 scopes.
53. according to the method for claim 51, and wherein in step (c) gained medicinal liquid, solid content is 1 ~ 20%w/v.
54. according to the method for claim 51, and wherein in step (c) gained medicinal liquid, solid content is 1 ~ 15% w/v.
55. according to the method for claim 51, and wherein in step (c) gained medicinal liquid, solid content is 1 ~ 12%w/v.
56. according to the method for claim 51, and wherein the described activated carbon dosage of step (a) is 0.02% ~ 0.5%w/v of solution weight.
57. according to the method for claim 51, and wherein the described activated carbon dosage of step (a) is 0.05% ~ 0.2%w/v of solution weight.
58. according to the method for claim 51, and wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, sodium citrate, acetic acid, sodium acetate or its combination.
59. according to the method for claim 51, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 10%.
60. according to the method for claim 51, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 8%.
61. according to the method for claim 51, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 5%.
62. according to the method for claim 51, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 3%.
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| CN106729608A (en) * | 2016-12-09 | 2017-05-31 | 上海上药第生化药业有限公司 | A kind of preparation method of thymopeptide-5 composition and its freeze-dried powder |
| CN107028897B (en) * | 2017-06-14 | 2020-09-04 | 北京元延医药科技股份有限公司 | Immune regulator thymopentin powder injection medicine composition and quality control method |
| CN111494600A (en) * | 2019-06-24 | 2020-08-07 | 南京安吉生物科技有限公司 | Medicine composition and medicine for treating hypoimmunity diseases |
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Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee after: Chengdu Tiantaishan Pharmaceutical Co.,Ltd. Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee before: CHENGDU TIANTAISHAN PHARMACEUTICAL Co.,Ltd. |