CN103536898A - Thymopentin (TP-5) drug composition - Google Patents
Thymopentin (TP-5) drug composition Download PDFInfo
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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 technical field, relate to a kind of pharmaceutical preparation, the pharmaceutical composition that particularly relates to a kind of Thymopentin is injection or lyophilization injectable powder for example.Thymopentin pharmaceutical composition of the present invention can be used for treating chronic viral hepatitis for example chronic hepatitis B, be used for the treatment of various constitutionales or Secondary cases T cell defect case as children with congenital immunodeficiency, be used for the treatment of some autoimmune disease for example rheumatoid arthritis, systemic lupus erythematosus (sle), be used for the treatment of the disease that various cellular immune functions are low, also can be used for treating tumor especially for the auxiliary treatment of tumor.
Background technology
Thymus is one-level lympho-epithelial tissue, is body central immune organ, is the cytocerastic center of T-organ, except providing the required microenvironment of T-cell development, also can produce multiple Thymic hormone.Thymosin can be induced differentiation and the maturation of each T-cell subsets, also can strengthen the reactivity worth of all kinds of T-cells, and then regulates whole immune function.Animal thymus (comprising the mankind) is flaccidity contracting degeneration gradually with advancing age after growing up, the secretory volume of thymosin also reduces gradually, obvious atrophy during to old age, only deposit a small amount of cortex and medullary substance, therefore there is people to think that old infectious disease, tumor, autoimmune disease sickness rate are high relevant with atrophy of thymus gland, thymosin activity decreased.There is obvious constitutional or secondary deficit in the insufficiency of function of thymus own or the immune system that relies on thymus, and the adjusting of self is while being not enough to repair, and 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, conventionally be abbreviated as TP-5) be a kind ofly by 5 amino acid residues, to form small peptide (Arg-Lys-Asp-Val-Tyr), this structure and thymopoietin (Tpymopoietin, TP) the 32-36 position order in 49 aminoacid is identical, and existing data proof TP-5 is the functional activity fragment of TP, TP-5 has the similar physiologically active of TP.Thymopentin CAS registration number: 69558-55-0, English chemical name: N-(N-(N-(N2-L-Arginyl-L-lysyl)-L-α-aspartyl)-L-valyl)-L-tyrosine, English 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 effect is raise and is mediated by cAMP level in born of the same parents.Another basic role of Thymopentin is the special receptors bind to ripe periphery blood T cell, makes cAMP level in born of the same parents increase, thereby brings out a series of intramicellar reactions, and this is also the basis of its immunoloregulation function.Under normal body state, Thymopentin manifests immunostimulation; can significantly increase E rosette formation rate and the conversion ratio of splenocyte; for the first time or the again different phase of secondary response to immunne response has potentiation, can increase the antibody forming cell of IgM type and IgG or IgA type.Thymopentin also can strengthen the phagocytic function of macrophage, increases enzyme and the phagocytic function of polymorph neutrophile leucocytes, and rising circulating antibody content strengthens 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, and the function of induction Ts cell.The resistance infection of Thymopentin is relevant with its enhancement TC cytoactive with therapeutical effect.In anti-infectious immunity, appropriate Thymopentin can obviously increase the generation of interferon, and induction and promotion T cell differentiation are ripe; Regulate t lymphocyte subset group ratio 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 expression of receptor level of interleukin-22; Strengthen the generation of peripheral blood lymphocytes IFN-γ; Strengthen SOD activity in serum.
Thymopentin is mainly used in treating tumor, immunologic hypofunction and autoimmune disease at present, and can regulate the thymus function going down, and makes the unbalance immunologic function normalization of body, promotes growth and the differentiation of thymocyte cell.The atrophy of thymus gland and the hypofunction that because of age and other factors, cause are had to important regulating action.Thymopentin is a kind of very safe drugs, no matter subcutaneous injection or intravenously administrable, toxic and side effects rarely all, some side effect that accidentally produce are also very slight, as injection site pruritus and erythema, conventionally without special handling just can disappear voluntarily (Sundal E, et al.Arzneimittelforschung, 1994:44 (10): 1145-1149).Therefore Thymopentin is a kind of immunomodulator of new type of safe, and its immune system class drug use person that is developed as has increased a kind of selection safely and effectively.
Thymopentin has dosage selectivity to the adjusting of immunologic function.When domestic and foreign literature report, animal experiment and human clinical verify performance, each 1mg dosage, the most obvious to the activation of the phagocytic function of macrophage in human body, erythrocytic immunologic function and human peripheral blood T cell; Surmount specific dosage range and do not show better curative effect.26 routine volunteers accept 1mg dosage injection at every turn, and the active 2-3 that can improve superoxide dismutase after 10 times doubly, have obvious scavenging action to superoxide anion free radical; The effective percentage that hematid immunity function is improved is 66.7%, and erythrocytic immunologic function, playing an important role aspect elimination immune complex and pathogen, also has activation to leukocytic immunologic function.And can promote Bcell growth factor and immunoglobulin to increase.Thymopentin energy promoting erythrocyte C3b receptor and erythrocyte immune complex, in higher level, illustrate that erythrocyte immune system is activated.
Thymopentin is degraded by the aminopeptidase in blood plasma rapidly after entering in body, t
1/2approximately 30 seconds, the tetrapeptide that catabolite is non-activity (Lys-Asp-Val-Tyl) and tripeptides (Lys-Asp-Val).But after single injection Thymopentin, very fastoperation, in target cell, causes a series of cascade reactions by second message,second messenger in born of the same parents (CAMP), makes vivo effect can be maintained until several weeks, therefore can guarantee its maintaining of drug effect in treatment.
Thymopentin (TP-5), as a kind of immunomodulator, was used in Italy's listing in 1985.But its existing inherent stability problem and the pharmacy research industry that perplexing.
Chinese Patent Application No. 200510102991.5 (two aigret) discloses a kind of aqueous solution preparation, its preparation method and application in the medicine for the preparation for the treatment of chronic viral hepatitis, tumor and other immune disease thereof of Thymopentin.Said preparation is comprised 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 carbohydrates such as mannitol or Polyethylene Glycol, various cyclodextrin, glycine etc.And specifically disclose pH value 7.05, by the sodium ethylene diamine tetracetate (EDTA) of 0.5-250mg Thymopentin, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the aqueous solution preparation that the sodium chloride of 0.5-5% forms.Stability test (comprising influence factor's test, accelerated test and long term test) shows: this aqueous solution preparation is all responsive especially to light and temperature, needs shading, and preserves at Leng Chu (2-10 ℃).
It is active component by Thymopentin that Chinese Patent Application No. 200810008117.9 (buchu) discloses a kind of; the injection that adds injection supplementary material, sterilized water for injection to be 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, can realize superior stablizing effect.Stability test shows: this injection can keep stable for 24 months in the low temperature environment of 2～10 ℃, can within 12 months, keep stable under the room temperature of 25 ± 2 ℃.
Chinese Patent Application No. 201310168339.8 (Li Site) discloses a kind of aqueous solution preparation of Thymopentin, it is to take Thymopentin as active raw materials, add pharmaceutic adjuvant, water is made after mixing, wherein adjuvant comprises the acetic acid-sodium-acetate buffer as pH value regulator, as protectant calcio-disodium edetate, sodium chloride as 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 that contains Thymopentin compound, a kind of ejection preparation particularly, its prescription, application and preparation method thereof, every 1000 injections, are made by the component of following proportioning: Thymopentin 0.5-2g; Mannitol 50-200g; EDTA calcium 1-3g; Vitamin C 1-2g, the DisodiumHydrogen Citrate that mol ratio is 1:4 and trisodium citrate buffer 1000ml; With water for injection standardize solution, to 2000ml, then through lyophilization, be prepared into lyophilization injectable powder.
A kind of raising immunity of Chinese Patent Application No. 201210295672.0 (Ji is raw), the compositions of the Thymopentin medicine being formed by 5 seed amino acids of the diseases such as treatment hepatitis, T cell defect disease, autoimmune disease, the Thymopentin being formed by 5 seed amino acids that contains 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 degerming obtains filtrate; Filtrate packing 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, is degraded to corresponding dipeptides Val-Tyr and tripeptides Arg-Lys-Asp.Although prior art has inherent quality for example content and the related substance of investigating Thymopentin with HPLC method, and there are no the report that detects related impurities situation of change in formulation products.
Therefore, provide a kind of for example Thymopentin product of physical stability and chemical stability of good stability that has, 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 good stability Thymopentin product that for example the Thymopentin product, particularly a kind of injectable of physical stability and chemical stability are used that has.The inventor has been surprisingly found that, the Thymopentin pharmaceutical composition with feature of the present invention has good pharmaceutical property.The present invention is based on this discovery 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 portions,
Optional water for injection 0～2000 weight portion.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, 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 be usually used as the filler of pharmaceutical preparation, to obtain the pharmaceutical preparation with good form, typically maltose or its hydrate for improving the physical aspect of pharmaceutical preparation; Yet have been surprisingly found that in the present invention maltose or its hydrate can suppress the degraded of active medicine effectively, this effect of improving pharmaceutical chemistry stability is that those skilled in the art had not known and cannot expect completely.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, wherein, for the Thymopentin of every 1 weight portion, the amount of maltose or its hydrate is 10～100 weight portions.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, wherein, for the Thymopentin of every 1 weight portion, the amount of maltose or its hydrate is 10～50 weight portions.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, wherein said maltose hydrate is maltose monohydrate.
Pharmaceutical composition according to described in the arbitrary embodiment of first aspect present invention, wherein also comprises mannitol.
Pharmaceutical composition according to described in the arbitrary embodiment of first aspect present invention, wherein also comprises mannitol, and the weight ratio of described mannitol and maltose or its hydrate is 1:5～12.
Pharmaceutical composition according to described in the arbitrary embodiment of first aspect present invention, wherein also comprises mannitol, and the weight ratio of described mannitol and maltose or its hydrate is 1:5～10.
Pharmaceutical composition according to described in the arbitrary embodiment of first aspect present invention, wherein also comprises mannitol, and the weight ratio of described mannitol and maltose or its hydrate is 1:5～8.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, wherein also comprise acid-base modifier (also conventionally can be described as pH adjusting agent).
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, wherein also comprise acid-base modifier, the amount of this acid-base modifier is when this pharmaceutical composition being dissolved with water for injection and/or being diluted to Thymopentin concentration and being 0.2mg/mL, and the pH value of solution is in 6.5～7.5 scopes.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, 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, for example 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.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, 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 water for injection of special interpolation.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, wherein, for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0～1200 weight portion; For example, the amount of optional water for injection is 500～1200 weight portions.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, wherein, for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0～1200 weight portion; For example, the amount of optional water for injection is 800～1200 weight portions.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, its injection that is solution-type, wherein comprises water for injection 500～1500 weight portions.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, its injection that is solution-type, wherein comprises water for injection 500～1200 weight portions.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, its injection that is solution-type, wherein comprises water for injection 800～1200 weight portions.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, its lyophilized injectable powder that is 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 (conventionally referred to as lyophilized injectable powder or freeze-dried powder) obtaining through freezing-vacuum drying, it is first by each dissolution with solvents for material (being typically with water dissolution), be mixed with a solution, then make this solution carry out freezing, carry out again evacuation, distillation, dry and obtain a kind of substantially anhydrous (typically water content is lower than 8%, 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 is controlled by the pH value of process for preparation regulator solution conventionally; Or can adjust so that the solid lyophilized products obtaining is controlled the pH value of this dissolve/dilute liquid under the dissolve/dilute degree of regulation and control (this is called the acid-base value of controlling solid lyophilized products) by prescription; A rear mode is more generally used conventionally, for example in pharmacopeia, contained many lyophilized injectable powders are all controlled the acid-base value of goods in this way, and the acid-base value that this mode the is controlled product recipe quantity of concrete regulation acid-base modifier not conventionally, and only stipulate the acid-base value of finished product.Be equally applicable to be of the present inventionly, according to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, the amount of wherein said optional acid-base modifier is, the amount of the pH value of this solution in 6.5～7.5 scopes while making obtained freeze-drying injectable powder be dissolved into the solution containing active component 0.2mg/ml concentration with water for injection.
According to the pharmaceutical composition described in the arbitrary embodiment of first aspect present invention, it is by comprising prepared by following step substantially:
(a) take Thymopentin and maltose or its hydrate of recipe quantity, and optional mannitol and other optional pharmaceutic adjuvant, add appropriate water for injection to make to dissolve, then add active carbon, stir filtering decarbonization;
(b) add water for injection, the weight ratio that makes Thymopentin and water for injection is (1:500～1200 for example, 1:500～1500,1:800～1200 for example), stir, measure pH and optional mensuration active component content, with acid-base modifier, regulate the pH value of this solution to scope up to specification if desired;
(c) by medicinal liquid aseptic filtration, fill is in vial;
(d) the medicinal liquid sealing of step (c) is obtained to the compositions as injection of solution-type; Or the medicinal liquid lyophilization of step (c) is removed to moisture, and tamponade sealing obtains the compositions as injectable powder of solid type.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein the described pH of step (b) scope up to specification refers to: when this solution is diluted to Thymopentin concentration and is 0.2mg/mL with water for injection, the pH value of solution is (particularly pH value is in 6.8～7.2 scopes, and particularly pH value is 7.0) in 6.5～7.5 scopes.Although the activity component concentration (about 1mg/ml) of step (b) gained solution is measured the normal concentration (being approximately 5 times) of pH value higher than finished product, but those skilled in the art can be easily by 5 times of step (b) solution dilutions and measure the pH value of gained diluent, according to this pH value determining step (b) gained solution, need to regulate the amplitude of Acidity of Aikalinity.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, the filtered filtrate of step (c) gained wherein, wherein solid content is 1～20% (w/v), preferred 1～15% (w/v), for example 1～12%.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein also optionally comprise 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.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in two of Pharmacopoeia of People's Republic of China versions in 2010 (in the present invention can referred to as " 2010 editions two of Chinese Pharmacopoeias " or similar address) appendix IX C particulate matter inspection technique, particle number containing >=10 μ m in each test sample container is less than 6000, for example be less than 3000, for example be less than 1500, for example be less than 1000, for example be less than 500, for example be less than 250, for example be less than 200, for example be less than 150, for example be less than 100, for example be less than 50, for example be less than 25.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in two of Pharmacopoeia of People's Republic of China versions in 2010 (in the present invention can referred to as " 2010 editions two of Chinese Pharmacopoeias " or similar address) appendix IX C particulate matter inspection technique, particle number containing >=25 μ m in each test sample container is less than 600, for example be less than 300, for example be less than 150, for example be less than 100, for example be less than 50, for example, be less than 25.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is injection or is lyophilization injectable powder, it checks according to " first method (light blockage method) " in two of Pharmacopoeia of People's Republic of China versions in 2010 (in the present invention can referred to as " 2010 editions two of Chinese Pharmacopoeias " or similar address) appendix IX C particulate matter inspection technique, the particle number that contains >=10 μ m in each test sample container is less than 6000 and (is for example less than 3000, for example be less than 1500, for example be less than 1000, for example be less than 500, for example be less than 250, for example be less than 200, for example be less than 150, for example be less than 100, for example be less than 50, for example be less than 25), and the particle number of >=25 μ m is less than 600 and (is for example less than 300, for example be less than 150, for example be less than 100, for example be less than 50, for example be less than 25).
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, after 35 ℃ of processing in 4 months of its experience, compare with 10 ℃ of processing in 4 months, microgranule percent change (%) is less than 200%, for example, in 50%～200% scope, for example, in 75%～200% scope, for example, in 90%～170% scope.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, after 35 ℃ of processing in 4 months of its experience, compare with 10 ℃ of processing in 4 months, dipeptides increment (%) is less than 50%, for example be less than 40%, for example, be less than 30%, for example, be less than 20%, for example dipeptides increment (%) is 0～50%, being for example 1～40%, for example, is 1～30%, for example, be 1～20%.
Above-mentioned microgranule percent change (%) is to measure according to following methods: pharmaceutical composition of the present invention is placed 4 months (being called high-temperature treatment) at 35 ℃, made abreast said composition lay down location 4 months (being called low temperature disposes) at 10 ℃ of same batch; Check the particulate matter (carrying out with " first method (light blockage method) ") of each sample, add up each sample >=10 μ m particle numbers, for the sample of same batch, be calculated as follows microgranule percent change:
Above-mentioned dipeptides increment (%) is to measure according to following methods: pharmaceutical composition of the present invention is placed 4 months (being called high-temperature treatment) at 35 ℃, made abreast said composition lay down location 4 months (being called low temperature disposes) at 10 ℃ of same batch; Dipeptides relative amount for Thymopentin while 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 below HPLC method of " mensuration of catabolite " part of the present invention, because having multiple and those skilled in the art, analytical method easily improves, and dipeptides relative amount in same sample can not change because of the change of analytical method, therefore when measuring dipeptides increment of the present invention (%), can not stipulate the analysis determining method that it is concrete.
The present invention has been surprisingly found that, in adding during appropriate mannitol, can give solubility property that lyophilization powder injection composition of the present invention is good and/or good particulate matter performance in the present composition.
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) take Thymopentin and maltose or its hydrate of recipe quantity, and optional mannitol and other optional pharmaceutic adjuvant, add appropriate water for injection to make to dissolve, then add active carbon, stir filtering decarbonization;
(b) add water for injection, the weight ratio that makes Thymopentin and water for injection is (1:500～1200 for example, 1:500～1500,1:800～1200 for example), stir, measure pH and optional mensuration active component content, with acid-base modifier, regulate the pH value of this solution to scope up to specification if desired;
(c) by medicinal liquid aseptic filtration, fill is in vial;
(d) the medicinal liquid sealing of step (c) is obtained to the compositions as injection of solution-type; Or the medicinal liquid lyophilization of step (c) is removed to moisture, and tamponade sealing obtains the compositions as injectable powder of solid type.
According to the method for the arbitrary embodiment of second aspect present invention, wherein the described pH of step (b) scope up to specification refers to: when this solution is diluted to Thymopentin concentration and is 0.2mg/mL with water for injection, the pH value of solution is (particularly pH value is in 6.8～7.2 scopes, and particularly pH value is 7.0) in 6.5～7.5 scopes.Although the activity component concentration (about 1mg/ml) of step (b) gained solution is measured the normal concentration (being approximately 5 times) of pH value higher than finished product, but those skilled in the art can be easily by 5 times of step (b) solution dilutions and measure the pH value of gained diluent, according to this pH value determining step (b) gained solution, need to regulate the amplitude of Acidity of Aikalinity.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein solid content is 1～20% (w/v), preferred 1～15% (w/v), for example 1～12%.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein the described activated carbon dosage of step (a) is 0.02%～0.5% (w/v) of solution weight, preferably 0.05%～0.2%.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein described in step (b), acid-base modifier is the aqueous solution that is 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 is well known to a person skilled in the art, for example 1～10%, for example 2%～5%.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for example 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.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein in step (d), remove after moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.
In the step of the above-mentioned preparation method of the present invention, although the step of the concrete steps of its description in some details or described in the preparation example of language description up and down literary composition specific embodiment part distinguished to some extent, yet the open in detail of those skilled in the art's full text according to the present invention can summarize the above method step completely.
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 characterictic goes for this technical characterictic in other embodiment, as long as they there will not be contradiction.Below the invention will be further described.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
According to pharmaceutical composition of the present invention, active component Thymopentin is wherein the pentapeptide fragmentation compound with following formula structure:
Arg-Lys-Asp-Val-Tyr
Thymopentin is the live part of a kind of thymopoietin II of thymus secretions.Thymopoietin II is the single polypeptide compound of separating from thymosin, by 49 aminoacid, formed, and the peptide chain fragment being wherein comprised of 5 aminoacid but has the whole physiological functions identical with thymopoietin II, so just this pentapeptide fragment is called to Thymopentin.
Thymopentin is comprised of arginine, lysine, aspartic acid, valine, tyrosine five seed amino acids.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 effect is raise and is mediated by cAMP level in born of the same parents.Another basic role of Thymopentin is the special receptors bind to ripe periphery blood T cell, makes cAMP level in born of the same parents increase, thereby brings out a series of intramicellar reactions, and this is also the basis of its immunoloregulation function.Under normal body state, Thymopentin manifests immunostimulation; can significantly increase E rosette formation rate and the conversion ratio of splenocyte; for the first time or the again different phase of secondary response to immunne response has potentiation, can increase the antibody forming cell of IgM type and IgG or IgA type.Thymopentin also can strengthen the phagocytic function of macrophage, increases enzyme and the phagocytic function of polymorph neutrophile leucocytes, and rising circulating antibody content strengthens 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, and the function of induction Ts cell.The resistance infection of Thymopentin is relevant with its enhancement TC cytoactive with therapeutical effect.In anti-infectious immunity, appropriate Thymopentin can obviously increase the generation of interferon.Induction and promotion T cell differentiation are ripe; Regulate t lymphocyte subset group ratio 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 expression of receptor level of interleukin-2; Strengthen the generation of peripheral blood lymphocytes IFN-γ; Strengthen SOD activity in serum.
Can be used for malignant tumor patient after chemicotherapy, damnification of immunity function person; The treatment of hepatitis B; Great surgical operation 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 using clinically at present comprises: (1) was for 18 years old above chronic hepatitis B patient.(2) various constitutionales or Secondary cases T cell defect sick (as children with congenital immunodeficiency).(3) some autoimmune disease (as rheumatoid arthritis, systemic lupus erythematosus (sle)).(4) the low disease of various cellular immune functions.(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 according to the state of an illness, determine the 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 is to well known to a person skilled in the art pharmaceutical technology, for example two kinds of schematic freeze-drying curves shown in following freeze-drying curve A and freeze-drying curve B:
In instantiation in below preparing lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.
Moisture in lyophilization injectable powder is generally below 8%, preferably lower than 5%, more preferably less than 3%.Moisture Control can be controlled by suitable adjustment lyophilization program.Moisture in this lyophilization injectable powder can be measured according to many known methods, for example dry weight-loss method.
In the present invention, in order to regulate where necessary the pH value of medicinal liquid, can in compositions, add suitable pH adjusting agent.Although the inventor is not only with having the strong acid of buffer capacity or a strong base solution, for example sodium hydrate aqueous solution and aqueous hydrochloric acid solution regulate, yet, those skilled in the art understand, if process the pH requirement that can meet system by this pH adjusting agent of not having buffer capacity, the pH adjusting agent with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can regulate pH value, and can stablize pH value.Therefore the listed arbitrary pH adjusting agent of the present invention or its combination include in spirit and scope of the invention.
When the injection of preparation solution-type of the present invention, the solid content in solution need not be done special restriction.In preparation, during lyophilized injectable powder of the present invention, in the medicinal liquid of preparing, solid content is to be 1～20% (w/v), preferred 1～15% (w/v), more more preferably 1～12%, be beneficial to obtain the lyophilized products with good form.Because normally carrying out lyophilization in tubulose cillin bottle, lyophilized injectable powder obtains, those skilled in the art understand this product and are obtaining finished product even before for doctor, conventionally all present a round pie, although lecture is than the volume of original aqueous solution few (slightly dwindling) in the volume theory of this cake, yet this dwindling can not narrow down to former aqueous solution volume 50% conventionally conventionally, conventionally can be between the 80-120% of former aqueous solution volume, be more typically between the 90-100% of former aqueous solution volume, and can be observed former aqueous solution liquid level vestige in finished product cillin bottle, (main body cake remains in the liquid level vestige on bottle wall dwindling because of lyophilizing, even if the dried frozen aquatic products in cillin bottle because of a variety of causes such as collision etc. former thereby be Powdered, conventionally still can retain original liquid level vestige), 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, yet still can roughly estimate it when preparing according to this injectable powder, the medicine liquid volume before lyophilization starts at least, the volume estimating according to this and the weight of the dry end-product in cillin bottle, also can calculate when preparation lyophilized injectable powder of the present invention the content of the solid content in the medicinal liquid of preparing.Therefore, according to the lyophilized injectable powder of first aspect present invention, its solid content at the medicinal liquid in when preparation is 1～20% (w/v), preferred 1～15% (w/v), more more preferably 1～12%.
Term " solid content " refers to solid matter (for example reactive compound of the present invention and whole excipient used, weight/gram) for example join, in solvent (water for injection), after dissolving, obtain a solution, the weight of described solid matter for example, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.For example in the present invention, with 1mg reactive compound and other solid content that amounts to about 100mg, add appropriate aqueous solution for injection, be mixed with the solution that final volume is 1ml, its solid content is about 10%.
In the present invention, symbol %, the linguistic context of using according to it, can have those skilled in the art and hold intelligible implication.For example, when mentioning solid content, this symbol represents the percent (w/v, for example g/100ml) of weight/volume; For example during " water content " in mentioning lyophilization injectable powder, for example water content is below 8% again, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, when solid is dispersed in liquid, % represents weight/volume percent; Solid be dispersed in solid or liquid dispersion in solid for example, when (water content of powder pin), % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.
When preparation medicinal liquid of the present invention, as well known to those skilled in the art, can example according to appointment the microporous filter membrane of 0.45um carry out coarse filtration filtration, by liquid medicine filling to before in cillin bottle, can example according to appointment the microporous filter membrane of 0.22um carry out fine straining filtration with degerming, can filter repeatedly if desired.
According to pharmaceutical composition of the present invention, its injection that is solution-type.In one embodiment, this injection is single-dose preparations (for example bottled aqueous injection of ampoule), and in per unit dosage, the amount of reactive compound can be 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 (for example bottled injectable powder in XiLin), and in per unit dosage, the amount of reactive compound can be 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 the time of typically redissolving 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 water is made and in every 1ml, is contained the solution of reactive compound 0.2mg and measure according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010, and 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 (lucifuge is also no more than 20 ℃) be preserved at least 24 months in cool dark place, can meet the Storage Requirement of general lyophilization injectable powder/aqueous injection.
The specific embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.Following examples further illustrate the present invention, rather than restriction the present invention.In example below, the pH adjusting agent of using (in the present invention that is acid-base modifier), unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is when the aqueous injection of preparation or injectable powder being dissolved with water for injection and/or being diluted to the solution containing active component 0.2mg/ml, reaches value or the scope of defined in following example.
The below object of preparation process in order to give an example, and the comparability based on respectively giving an example and making some specific description, those skilled in the art can therefrom summarize the method that the present invention prepares lyophilized injectable powder or aqueous injection that obtains completely according to existing knowledge.Dosing is prepared in various compositionss below, if not otherwise indicated, total dosing amount of every batch is 1000ml, still lists formula and preparation process constantly, all with every bottle of amount containing active component 1mg, illustrate, and divide and install to 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 2010 editions two appendix IX C particulate matter inspection techniques of Chinese Pharmacopoeia.
a, investigation method part
content assaying method:
According to two contained high effective liquid chromatography for measuring of appendix VD of Chinese Pharmacopoeia version in 2010;
Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica, be filler; 0.05mol/L phosphate buffer (pH7.0)-methanol (90:10) is mobile phase, and detection wavelength is 275nm; Number of theoretical plate calculates and should be not less than 1200 by Thymopentin peak;
Algoscopy: get 10 bottles of test samples (every bottle of labelled amount is the specification of 1mg), dissolve and/or dilute and make the solution that approximately contains Thymopentin 0.1mg in every 1ml respectively by mobile phase, precision measures 20 μ l, and injection liquid chromatography, records chromatogram; It is appropriate that the phosphorus pentoxide of separately learning from else's experience is dried to the Thymopentin reference substance of constant weight, is measured in the same method, and by external standard method, with calculated by peak area, calculates the average content of every bottle of test sample.
related substance inspection method:
According to the high performance liquid chromatography in above content assaying method, carry out; Injectable powder dissolves by mobile phase and is diluted to the solution containing active component 1mg/ml, as need testing solution; If injection concentration, higher than 1mg/ml, is dissolved and is diluted to the solution containing active component 1mg/ml by mobile phase, otherwise not diluting, as need testing solution; Precision measures need testing solution 2ml and puts in 100ml measuring bottle, by mobile phase, is diluted to scale, obtains the contrast solution that concentration is equivalent to need testing solution concentration 2%; Get contrast solution 20 μ l injection liquid chromatographies, regulate instrumental sensitivity, making main peak high is 10～20% of full scale; Get respectively each 20 μ l of need testing solution and contrast solution, injection liquid chromatography, is recorded to 3 times of main peak retention time again; Make in contrast solution chromatographic peak impurity peak area in main peak area and need testing solution chromatogram compare, calculate in test sample impurity phase for the content percent of main constituent.
the mensuration of catabolite:
With reference to synthetic Val-Tyr bis-fragments of peptides (it can be described as dipeptides, two fragments of peptides or Val-Tyr in the present invention) of the method for recording in CN1704430A embodiment;
Use HPLC method to measure the content of Val-Tyr bis-fragments of peptides 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 substance inspection method; The separation effectively of this gradient method, mensuration Thymopentin and above-mentioned two fragments of peptides, separating degree is greater than 3.0; (inventor is in complementary testing, have been found that and use CN1676162A (Chinese Patent Application No. 200410029852.X, middle section) the HPLC method that 2 page of 18 row of description starts to describe can not be separated Thymopentin and two fragments of peptides effectively, and the two separating degree is less than 0.9).
Use this chromatographic condition, with the dipeptides reference substance that synthesizes in contrast, two peptide contents that can measure in the various compositionss that the present invention makes with reference to the method for related substances and assay above (are absolute content, be the amount g/g of dipeptides in every 1 gram of material), by the content of the Thymopentin in the various compositionss that above the present invention of content assaying method mensuration makes, (be absolute content simultaneously, be the amount g/g of pentapeptide in every 1 gram of material), calculate thus survey dipeptides in material with respect to the relative amount of pentapeptide (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 can for example, for investigating the stability (physical stability and chemical stability) under the various product simulation Long-term Storage of the present invention condition.Concrete grammar is: the compositions making is placed 4 months at 35 ℃, measure [35 ℃-April of the content of Thymopentin in sample, can be described as high temperature average content, mg/ bottle, measures the meansigma methods of 10 bottles] while processing the corresponding time with respect to this sample at 10 ℃ the content of active component [10 ℃-April, can be described as low temperature average content, mg/ bottle, measure the meansigma methods of 10 bottles] percent, can be 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 approach 100% show more stable, unstable, more low more unstable lower than 100%.
In addition, check the particulate matter of each sample, add up each sample >=10 μ m particle numbers.For each sample, calculate the percent change of >=10 μ m particle numbers after above-mentioned high-temperature process, this parameter is called microgranule percent change, and calculating formula is as follows:
After wherein, after high-temperature treatment >=10 μ m particle numbers and low temperature are disposed >=10 μ m particle numbers are that sample obtains according to light blockage method assay method mentioned above.Above-mentioned microgranule percent change (%) more approaches 100% and shows more stablely, higher than 100% particulate matter, increases, 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
the compositions (injectable powder and aqueous injection) that preparation example 1, preparation comprise Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 30mg, |
| pH adjusting agent | appropriate if desired, be adjusted to pH7.0, |
| water for injection | in right amount, add to 1ml. |
Preparation method:
(1) take principal agent and the solid adjuvant material (except pH adjusting agent) of recipe quantity, be placed in stainless steel cask, the water for injection that adds recipe quantity approximately 80%, be stirred to dissolve, by liquor capacity, add again the active carbon of 0.1% (w/v), stir 30 minutes, filtering decarbonization, mends and injects water to approaching prescription full dose.
(2) filtrate sampling, measure pH value, by pH adjusting agent, be adjusted to setting (if desired, getting filtrate injects in right amount and is diluted with water to containing active component 0.2mg/ml, the pH value of measuring this diluent should reach 7.0, otherwise by pH adjusting agent, is that acid-base modifier suitably regulates again), then benefit injects water to prescription full dose, measure pH value, again by pH adjusting agent, be adjusted to as mentioned above if desired the pH7.0 of regulation; Measure the content of active component in medicinal liquid.
(3) medicinal liquid is first used 0.45um filtering with microporous membrane, 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, the aqueous injection of the present invention that obtains solution-type is injection.Separately get the filtrate of half amount, with every bottle of liquid drug 1ml fill, in 5ml cillin bottle, (in following example, while quoting this preparation example method, if not otherwise indicated, liquid drug amount is the medicine liquid volume that comprises 1mg reactive compound; If liquid drug volume obviously increases or obviously reduces in other example, can rule of thumb suitably adjust the volume of cillin bottle), false add plug is in order to carrying out lyophilization below.
(5) according to freeze-drying curve A described herein, carry out lyophilization, to moisture lower than 3%; After lyophilizing finishes, entirely jump a queue; Prick aluminium lid, obtain the injectable powder of this preparation example.The sample of preparation example 1 can be referred to as Ex1 in the present invention; The sample of other preparation example also can similarly represent.
Supplement preparation example 1:
Method with reference to above preparation example 1, different is that the amount of maltose monohydrate is wherein adjusted, be respectively 0mg, 2mg, 7mg, 10mg, 20mg, 40mg, 50mg, 65mg, 90mg, 150mg, the compositions obtaining (injectable powder and aqueous injection) numbering is respectively Ex101, Ex102, Ex103, Ex104, Ex105, Ex106, Ex107, Ex108, Ex109, Ex110;
Method with reference to above preparation example 1, different is replaces with maltose anhydride by maltose monohydrate wherein and amount is respectively 5mg, 15mg, 40mg, 70mg, 100mg, and the compositions obtaining (injectable powder and aqueous injection) numbering is respectively Ex111, Ex112, Ex113, Ex114, Ex115;
Method with reference to above preparation example 1, different is maltose monohydrate wherein to be replaced with respectively to mannitol, lactose, dextran, glycine, the sucrose of equivalent, and the compositions obtaining (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, different is that pH value is wherein adjusted to 6.5,6.8,7.2,7.5, and the compositions obtaining (injectable powder and aqueous injection) numbering is respectively Ex121, Ex122, Ex123, Ex124;
With reference to the method for above preparation example 1, different is that water for injection consumption is wherein adjusted to 0.5ml, 0.8ml, 1.2ml, 1.5ml, and the compositions obtaining (injectable powder and aqueous injection) numbering is respectively Ex125, Ex126, Ex127, Ex128.
Supplement preparation example 3:
Method with reference to above preparation example 1, different is to supplement wherein to add the mannitol of 1/20,1/15,1/12,1/10,1/8,1/7,1/6,1/5,1/4,1/2,1,5 times that is equivalent to maltose monohydrate consumption, and the compositions obtaining (injectable powder and aqueous injection) numbering is respectively Ex131, Ex132, Ex133, Ex134, Ex135, Ex136, Ex137, Ex138, Ex139, Ex140, Ex141, Ex142;
Method with reference to above preparation example 1, different is to supplement wherein to add the lactose of 1/10,1/7,1/3 times that is equivalent to maltose monohydrate consumption, 1/10, the dextran of 1/7,1/3 times, 1/10, the glycine of 1/7,1/3 times, the compositions obtaining (injectable powder and aqueous injection) numbering is respectively Ex143, Ex144, Ex145, Ex146, Ex147, Ex148, Ex149, Ex150, Ex151.
the compositions (injectable powder and aqueous injection) that preparation example 2, preparation comprise Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 10mg, |
| mannitol | 2mg, |
| pH adjusting agent | to pH7.0, |
| water for injection | in right amount, add to 1ml. |
Method for making: with reference to the method preparation of above preparation example 1, but carry out lyophilization according to freeze-drying curve B described herein, aqueous injection and the injectable powder of gained are designated as Ex2.
the compositions (injectable powder and aqueous injection) that preparation example 3, preparation comprise Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose (anhydride) | 50mg, |
| mannitol | 6.25mg, |
| lactose | 60mg, |
| pH adjusting agent | to pH6.5, |
| water for injection | in right amount, add to 1ml. |
Method for making: with reference to the method preparation of above preparation example 1, aqueous injection and the injectable powder of gained are designated as Ex3.
the compositions (injectable powder and aqueous injection) that preparation example 4, preparation comprise Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 40mg, |
| mannitol | 6.5mg, |
| glycine | 33mg, |
| pH adjusting agent | to pH7.5, |
| water for injection | in right amount, add to 1ml. |
Method for making: with reference to the method preparation of above preparation example 1, aqueous injection and the injectable powder of gained are designated as Ex4.
the compositions (injectable powder and aqueous injection) that preparation example 5, preparation comprise Thymopentin
Formula:
| thymopentin | 1mg, |
| maltose monohydrate | 30mg, |
| mannitol | 4.3mg, |
| dextran | 25mg, |
| pH adjusting agent | to pH7.0, |
| water for injection | in right amount, add to 1ml. |
Method for making: with reference to the method preparation of 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) capable recorded formula and the method for 2 pages of 9-17 of description, preparation is containing the sterile solution of glycine 50mg/ml, then according to the described method of the embodiment of the present invention 1 step (3) to (5), prepare aqueous injection and injectable powder, be designated as Co1.
Reference examples 2: according to CN1660407A (Chinese Patent Application No. 200510002507.1, dimension letter) 4 pages of embodiment 3 of description record formula and method, preparation is containing the sterile solution of sodium citrate and sodium chloride, then according to the described method of the embodiment of the present invention 1 step (3) to (5), prepare aqueous injection and injectable powder, be designated as Co2.
Reference examples 3: according to CN101024071A (Chinese Patent Application No. 200610008148.5, neutralization) 4 pages of embodiment 1 of description record formula and method, preparation is containing the sterile solution of sodium acetate, then according to the described method of the embodiment of the present invention 1 step (3) to (5), prepare aqueous injection and injectable powder, be designated as Co3.
Reference examples 4: according to CN101244255A (Chinese Patent Application No. 200810008117.9, buchu) 5 pages of embodiment 1 of description record formula and method, preparation is containing the sterile solution of mannitol, sodium pyrosulfite etc., then according to the described method of the embodiment of the present invention 1 step (3) to (5), prepare aqueous injection and injectable powder, be designated as Co4.
Reference examples 5: according to CN102764424A (Chinese Patent Application No. 201210295672.0, Ji life) 4 pages of embodiment 1 of description record formula and method, preparation is containing the sterile solution of citric acid, dipotassium hydrogen phosphate, sodium tartrate etc., then according to the described method of the embodiment of the present invention 1 step (3) to (5), prepare aqueous injection and injectable powder, be designated as Co5.
Reference examples 6: according to CN102988954A (Chinese Patent Application No. 201210302762.8, formula and method that Yao Yun) 4 pages of embodiment 1 of description record, preparation is containing the sterile solution of mannitol, EDTA calcium, sodium ascorbate etc., then according to the described method of the embodiment of the present invention 1 step (3) to (5), prepare aqueous injection and injectable powder, be designated as Co6.
test example part
study on the stability example 1:
According to study on the stability method above, in investigation above " B, compositions preparation example part ", the powder pin sample of each preparation example and reference examples gained is placed the physical stability chemical stability after 4 months at 35 ℃, 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, aspect dipeptides increment (%), demonstrates the difference that existing technology cannot be expected completely:
(a) for the sample that adds enough maltose or its hydrate, show that dipeptides increment is all lower than 13%, drug degradation is not obvious:
For Ex1, Ex2, Ex3, Ex4, the maltose of the specific consumption of these use the present invention of Ex5 or aqueous injection and the injectable powder of its hydrate, their dipeptides increment (%) is all in 3.6%～10.3% scope, and for example the dipeptides increment (%) of Ex1 liquid drugs injection is 5.2%, the dipeptides increment (%) of Ex2 powder pin is 4.7%;
For Ex104, Ex105, Ex106, Ex107, Ex108, Ex109, these use maltose of Ex110 or its hydrate consumption, 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 for example the dipeptides increment (%) of Ex105 liquid drugs injection is 8.6%, the dipeptides increment (%) of Ex109 powder pin is 4.3%;
For Ex112, Ex113, these use maltose anhydrides of Ex114, Ex115 and consumption, be 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 for example the dipeptides increment (%) of 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 aqueous injection and the injectable powder of 6.5～7.5 scopes, their dipeptides increment (%) is all in 2.3%～8.6% scope, and for example the dipeptides increment (%) of Ex121 liquid drugs injection is 6.1%, the dipeptides increment (%) of Ex123 powder pin is 2.3%;
Aqueous injection and the injectable powder of water yield when these use maltose hydrates but change dosing for Ex125, Ex126, Ex127, Ex128, their dipeptides increment (%) is all in 2.8%～9.7% scope, and for example the dipeptides increment (%) of 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, these aqueous injection and injectable powder that use maltose hydrate and increase appropriate mannitol of Ex141, Ex142, their dipeptides increment (%) is all in 2.2%～11.4% scope, and for example the dipeptides increment (%) of 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, these aqueous injection and injectable powder that use maltose hydrate and increase appropriate lactose, dextran or glycine of Ex151, their dipeptides increment (%) is all in 1.9%～10.7% scope, and for example the dipeptides increment (%) of Ex144 liquid drugs injection is 6.4%, the dipeptides increment (%) of Ex147 powder pin is 3.7%.
(b) still, for the sample that does not add maltose or its hydrate or addition deficiency, show that dipeptides increment increases greatly, all, more than 65%, drug degradation is obvious:
Aqueous injection and injectable powder for Ex101, Ex102, these maltose of Ex103 or its hydrate addition deficiency, their dipeptides increment (%) is all in 68.6%～133.8% scope, and for example the dipeptides increment (%) of Ex101 liquid drugs injection is 125.4%, the dipeptides increment (%) of Ex103 powder pin is 74.3%;
For Ex111, use anhydrous maltose instead but aqueous injection and the injectable powder of addition deficiency, 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 aqueous injection and the injectable powder of mannitol, lactose, dextran, glycine, sucrose instead, their dipeptides increment (%) is all in 91.2%～147.5% scope, and for example the dipeptides increment (%) of Ex116 liquid drugs injection is 133.7%, the dipeptides increment (%) of Ex118 powder pin is 102.8%;
Aqueous injection and the injectable powder for Co1, Co2, Co3, Co4, these prior art formula of not adding maltose or its hydrate of Co5, Co6, prepared, their dipeptides increment (%) is all in 88.6%～153.8% scope, and for example the dipeptides increment (%) of Co1 liquid drugs injection is 153.8%, the dipeptides increment (%) of Co4 powder pin is 97.5%.
Above result shows, to the stability of adding appropriate maltose or its hydrate in Thymopentin aqueous solution type or solid type preparation and contribute to improve Thymopentin, particularly reduce the wherein speed of active component degraded, therefore from this result of study, adding maltose or its hydrate more than amount with respect to 10 times of main constituents is favourable for the Thymopentin formulation products that obtains good chemical stability.
(2) dissolution time of injectable powder: various injectable powder prepared by above " B, compositions preparation example part ", measure as follows their dissolution time: open bottle cap plastic top, with syringe, from bottle stopper puncture, inject water for injection (consumption is about 3 times of liquor capacity respective sample lyophilization), with stopwatch, record the redissolution time, every batch sample test 5 times, averages.
Result:
For Ex108, Ex109, these maltose of Ex110 or its hydrate amount ratio active component, surpass the injectable powder of 50 times, their dissolution time is all more than 107 seconds, and show that maltose or the larger dissolution time of its hydrate consumption are longer, three samples are respectively 107 seconds, 131 seconds, 168 seconds; And Ex101, Ex102, Ex103, Ex104, Ex105, Ex106, these maltose of 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 for example the dissolution time of Ex101 and Ex104 is respectively 12 seconds and 9 seconds;
Formula and method with reference to preparation example 5, different is only to change maltose monohydrate into maltose anhydride, and its amount is respectively 0mg, 2mg, 7mg, 10mg, 20mg, 40mg, 50mg, 65mg, 90mg, 150mg, the injectable powder composition no obtaining 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 shows that Ex168, Ex169, Ex170 three are respectively 111 seconds, 128 seconds, 172 seconds; But the dissolution time of Ex161, Ex162, Ex163, Ex164, Ex165, Ex166, these powder pins of Ex167 is all in the scope of 7～21 seconds, and for example the dissolution time of Ex161 and Ex164 is respectively 11 seconds and 18 seconds;
With reference to formula and the method for preparation example 2,3,4,5, different is only to change maltose or its hydrate into 75mg respectively, and the injectable powder numbering obtaining is respectively Ex171, Ex172, Ex173, Ex174; With reference to formula and the method for preparation example 2,3,4,5, different is only to change maltose or its hydrate into 150mg respectively, and the injectable powder numbering obtaining is respectively Ex175, Ex176, Ex177, Ex178; Be measured in the same method the dissolution time of these injectable powder, result shows that 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 that these powder pin formula dissolution times that use relatively large maltose or its hydrate extend, the feature that need to avoid when this is clinical practice.
Except measuring above-mentioned powder pin, other injectable powder prepared by " B, compositions preparation example part ", they do not add maltose or its hydrate, or the maltose adding or the amount specific activity of its hydrate become component 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 for example the dissolution time of Ex1, Ex2, Ex3, Ex4, five kinds of powder pins of Ex5 is all in the scope of 8～15 seconds, and for example the dissolution time of Ex2 powder pin is 12 seconds;
---above result shows that maltose or its hydrate consumption excessive (particularly consumption is greater than 50 times of Thymopentin amount when above) can affect the dissolubility of injectable powder, affect product use clinically; Therefore,, from this angle, the consumption of maltose or its hydrate should not surpass 50 times of Thymopentin amount.
(3) various sample is after high-temperature process, and microgranule percent change (%) demonstrates different variation tendencies:
Whole injectable powder and aqueous injection that above prepared by " B, compositions preparation example part ", after preparation, with light blockage method, measure its particulate matter immediately, result show whole samples (be 1ml loading amount or before lyophilization liquor capacity be 1ml) containing the particle number of >=10 μ m all 13～31 scopes, show and there is 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, compare with the sample of K cryogenic treatment, show that microgranule percent change (%) is all in 113%～156% scope; But these do not add examination liquid drugs injection or the powder pin sample of mannitol Ex1, Ex101～Ex110, Ex111～Ex115, they are after high-temperature process, and microgranule percent change (%) all, in 306%～473% scope, shows that microgranule is significantly increased.
For Ex135, Ex136, Ex137, Ex138, Ex139, Ex140, Ex141, these are added with liquid drugs injection or the powder pin sample of the mannitol that is greater than 1/8 amount for maltose or its hydrate quantity Ex142, they are after high-temperature process, compare with the sample of K cryogenic treatment, show all (but Ex139 in 106%～161% scope of microgranule percent change (%), Ex140, Ex141, these mannitol relative quantities of Ex142 be greater than sample dissolution time of 1/5 all more than 68 seconds and the larger dissolution time of mannitol amount longer, but the dissolution time of tetra-kinds of powder pins of Ex135～Ex138 is all lower than 24 seconds), show to add appropriate mannitol and contribute to improve particulate matter feature, but mannitol addition affects the solubility property of injectable powder when excessive, for Ex131, Ex132, Ex133, Ex134, these are added with for maltose or its hydrate quantity lower than the liquid drugs injection or the powder pin sample that equal the mannitol of 1/10 amount, they are after high-temperature process, compare with the sample of K cryogenic treatment, demonstration microgranule percent change (%) all, in 282%～378% scope, shows that mannitol consumption can not effectively improve particulate matter feature when 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 that obtain and four injectable powder are after high-temperature process, and microgranule percent change (%) is in 113%～157% scope (and the dissolution time of four kinds of powder pins is all lower than 24 seconds) all; 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 that obtain and four injectable powder are after high-temperature process, and microgranule percent change (%) is in 94%～166% scope (but the dissolution time of four kinds of powder pins is all greater than 84 seconds) all; 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 that obtain and four injectable powder are after high-temperature process, and microgranule percent change (%) all (shows that mannitol consumption can not improve the microgranule percent change performance of product when very few) in 281%～434% scope;
For Ex143, Ex144, Ex145, Ex146, Ex147, Ex148, these supplement aqueous injection and the injectable powder sample that has added lactose, dextran, glycine (but not mannitol) Ex149, Ex150, Ex151, after high-temperature process, microgranule percent change (%) all, in 286%～452% scope, shows that these conventional pharmaceutical adjuncts 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 (%) all, in 254%～413% scope, shows that their microgranule performance is not enough.
Two regulations of version Chinese Pharmacopoeia in 2010, for indicating loading amount, be injection, used for intravenous injection sterilized powder, concentrated solution for injection and the injection sterile bulk drug for vein below 100ml, except separately there being regulation, the particle number containing >=10 μ m in each test sample container must not be crossed 6000.Even although above in each preparation example and reference examples gained liquid drugs injection and powder pin microgranule percent change (%) microgranule absolute number after high-temperature process up to 500% time after high-temperature process also can not surpass above-mentioned standards of pharmacopoeia value (approximately 160/bottle of peaks), but should see, this standard is the packing specification for " indicating loading amount is that 100ml is following ", and for the 1ml/ bottle powder pin or liquid drugs injection of packing of the present invention, this standard is obviously more loose, if correspondingly dwindle 100 times, the restriction of this standards of pharmacopoeia must not should be 60.And the sample that the relative consumption of the above-mentioned mannitol of the present invention is greater than 1/8, even if they also can not surpass the restriction of above-mentioned strict " must not cross 60 " after high-temperature process; But the sample that is less than 1/10 for other the relative consumption of mannitol, after high-temperature process by the restriction far beyond above-mentioned strict " must not cross 60 ".
In this sense, in Thymopentin pharmaceutical formulation, add maltose or its hydrate to improve on the basis of product chemical stability, adding relative quantity to be greater than 1/8 mannitol is useful for the further product physical property of improving, but the relative consumption of mannitol is greater than at 1/5 o'clock can cause the deliquescent deficiency of injectable powder, and the mannitol that comprises 1/8～1/5 amount is useful.
(4), after 4 months high-temperature treatments, the residual content (%) of Ex2, Ex3, Ex4, tetra-formula gained aqueous injection of Ex5 and injectable powder all, in 97.6～99.4% scopes, shows that they all have good chemical stability.
industrial applicability
The present composition can be clinically for 18 years old above chronic hepatitis B patient; For various constitutionales or Secondary cases T cell defect sick (as children with congenital immunodeficiency); For some autoimmune disease (as rheumatoid arthritis, systemic lupus erythematosus (sle)); For the low disease of various cellular immune functions; And for the auxiliary treatment of tumor.
Claims (10)
1. a pharmaceutical composition, wherein comprises: Thymopentin 1 weight portion, maltose or its hydrate 10～200 weight portions, optional water for injection 0～2000 weight portion.
2. according to the pharmaceutical composition of claim 1, wherein, for the Thymopentin of every 1 weight portion, the amount of maltose or its hydrate is 10～150 weight portions, 10～100 weight portions or 10～50 weight portions; Further, wherein said maltose hydrate is maltose monohydrate.
3. according to the pharmaceutical composition of claim 1, wherein also comprise mannitol; Further, the weight ratio of described mannitol and maltose or its hydrate is 1:5～12,1:5～10 or 1:5～8.
4. according to the pharmaceutical composition of claim 1-3 any one, wherein also comprise acid-base modifier; Further, the amount of this acid-base modifier is when this pharmaceutical composition being dissolved with water for injection and/or being diluted to Thymopentin concentration and being 0.2mg/mL, and the pH value of solution is in 6.5～7.5 scopes.
5. according to the pharmaceutical composition of claim 1-4 any one, wherein, for the Thymopentin of every 1 weight portion, the amount of optional water for injection is 0～1500 weight portion, 500～1500 weight portions, 0～1200 weight portion, 500～1200 weight portions, 0～1200 weight portion or 800～1200 weight portions.
6. according to the pharmaceutical composition of claim 1-5 any one, it is characterized in that:
It is the injection of solution-type, wherein comprises water for injection 500～1500 weight portions, 500～1200 weight portions or 800～1200 weight portions; Or
It is the lyophilized injectable powder of solid type; Further, the water content of this lyophilized injectable powder, lower than 8%, is particularly usually less than 5%, is particularly usually less than 3%.
7. according to the pharmaceutical composition of claim 1-6 any one, wherein also optionally comprise 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.
8. according to the pharmaceutical composition of claim 1-7 any one, it is injection or is lyophilization injectable powder, " first method (light blockage method) " inspection in two appendix IX C particulate matter inspection techniques of its photograph Pharmacopoeia of People's Republic of China version in 2010:
Particle number containing >=10 μ m in each test sample container is less than 6000, for example be less than 3000, for example be less than 1500, for example, be less than 1000, for example, be less than 500, for example be less than 250, for example be less than 200, for example, be less than 150, for example, be less than 100, for example be less than 50, for example, be less than 25; Or
Particle number containing >=25 μ m in each test sample container is less than 600, for example, be less than 300, for example, be less than 150, for example, be less than 100, for example, be less than 50, for example, be less than 25; Or
The particle number that contains >=10 μ m in each test sample container is less than 6000 and (is for example less than 3000, for example, is less than 1500, for example, be less than 1000, for example be less than 500, for example, be less than 250, for example, be less than 200, for example be less than 150, for example, be less than 100, for example, be less than 50, for example be less than 25), and the particle number of >=25 μ m is less than 600 and (is for example less than 300, for example, is less than 150, for example, be less than 100, for example be less than 50, for example, be less than 25).
9. according to the pharmaceutical composition of claim 1-8 any one, it is characterized in that:
After 35 ℃ of processing in 4 months of its experience, compare with 10 ℃ of processing in 4 months, microgranule percent change (%) is less than 200%, for example, in 50%～200% scope, for example, in 75%～200% scope, for example, in 90%～170% scope; Or
After 35 ℃ of processing in 4 months of its experience, compare with 10 ℃ of processing in 4 months, dipeptides increment (%) is less than 50%, for example, be less than 40%, for example be less than 30%, for example, be less than 20%, for example dipeptides increment (%) is 0～50%, being for example 1～40%, for example, is 1～30%, for example, be 1～20%.
10. the method for the pharmaceutical composition described in preparation claim 1-9 any one, it consists essentially of following steps:
(a) take Thymopentin and maltose or its hydrate of recipe quantity, and optional mannitol and other optional pharmaceutic adjuvant, add appropriate water for injection to make to dissolve, then add active carbon, stir filtering decarbonization;
(b) add water for injection, the weight ratio that makes Thymopentin and water for injection is (1:500～1200 for example, 1:500～1500,1:800～1200 for example), stir, measure pH and optional mensuration active component content, with acid-base modifier, regulate the pH value of this solution to scope up to specification if desired;
(c) by medicinal liquid aseptic filtration, fill is in vial;
(d) the medicinal liquid sealing of step (c) is obtained to the compositions as injection of solution-type; Or the medicinal liquid lyophilization of step (c) is removed to moisture, and tamponade sealing obtains the compositions as injectable powder of solid type;
Further,
Wherein the described pH of step (b) scope up to specification refers to: when this solution is diluted to Thymopentin concentration and is 0.2mg/mL with water for injection, the pH value of solution is (particularly pH value is in 6.8～7.2 scopes, and particularly pH value is 7.0) in 6.5～7.5 scopes;
Wherein in step (c) gained medicinal liquid, solid content is 1～20% (w/v), preferred 1～15% (w/v), for example 1～12%;
Wherein the described activated carbon dosage of step (a) is 0.02%～0.5% (w/v) of solution weight, preferably 0.05%～0.2%;
Wherein described in step (b), acid-base modifier is the aqueous solution that is 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; Or
Wherein in step (d), remove after moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.
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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. |