CN100342909C - Thymosin alpha-1 aqua prepn and its prepn process and application - Google Patents
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Abstract
The present invention relates to a water solution preparation of thymosin alpha 1, a preparation process and the application of preparing medicine for treating chronic viral hepatitis and immune damage diseases. The preparation is composed of thymosin alpha 1, medicinal auxiliary materials and water, wherein the specification of the thymosin alpha 1 can be from 0.1 to 1000 mg/pipe; the volume can be from 0.1 to 500 ml; the auxiliary materials are selected from and are not limited by carbohydrates, such as mannitol, or polyethylene glycol, etc., twenty kinds of human amino acid, such as all kinds of cyclodextrin, glycine, etc., low molecular dextran, poloxamer, buffering salts, such as phosphate, or acetate, etc. The preparation process of the preparation comprises the steps of solution compounding, disinfection, separated packing, tamponage, packing, etc. The water solution preparation has the characteristics of good stability and convenient preparation, and better keeps the structure and the activity of the thymosin alpha 1; the water solution preparation also has the characteristic of wide application prospect in the preparation of medicine for treating chronic viral hepatitis and immune damage diseases.
Description
Technical field
The present invention relates to medicine and formulation art thereof.The core of invention has been to provide a kind of novel formulation, its preparation method of thymosin and has been used for the treatment of application in the medicine of chronic viral hepatitis and immunity infringement disease in preparation.
Background technology
Thymosin (Thymosin-α 1, T α 1) is the secreted extremely strong polypeptide hormone of a kind of immunocompetence of human body central immune organ thymus, is found in 1966 the earliest, is successfully separated in 1975 to obtain monomer and to have determined aminoacid sequence and nucleotide sequence.The T α 1 of external chemical synthesis process production at the beginning of the nineties enters the clinical trial of III phase human, goes on the market in the U.S. in 1998.
T α 1 molecule contains 28 aminoacid, extensively is present in thymic epithelial cell, peripheral blood, brain, hypophysis, seminal fluid, folliculi liquor and the amniotic fluid of body.T α 1 can promote to be subjected to the T lymphocytic emiocytosis immune cell factor (interferon, interleukin etc.) after various antigens or the former activation of mitogenesis, improves its expression of receptor, and promotes gathering of NK precursor and strengthen its cytotoxicity.T α 1 plays the part of crucial role in the immune response process.
Mutchniek at first was used for the treatment of thymosin the minority hepatitis B in 1991, had obtained challenging result.13 unit consolidations carry out the clinical research of thymosin (T α 1) treatment hepatitis B, adopt 1 group of 96 routine HBV DNA of T α and the HBeAg person of turning out cloudy 45 examples (46.9%); Adopt T α 1 to add interferon group 54 examples, two person's of turning out cloudy 33 examples (61.1%); Adopting two rates of rotation of interferon group is 39%.The mechanism of action aspect of T α 1 anti-HBV, think at present may with strengthen T cell and NK cell response function and strengthen IL-2 and IFN produces relevantly, can not get rid of directly effect hepatocyte of T α 1, excite the ability of the anti-HBV of hepatocyte.In addition, Thymosin alpha 1 can increase the expression of histocompatibility complex's 1 class antigen at lymph and non-lymphoid lineage cell.
Patients with Viral Hepatitis is after the Thymosin alpha 1 treatment, produce the Th1 type CD4+T cytosis of IFN γ, NK T cytosis in the liver, the CD4+/CD8+T cell proportion lowers, thereby think that Thymosin alpha 1 can strengthen NK T cell and CD8+T cytotoxic cell function, thereby remove hepatitis virus.The thymosin curative effect is basic similar to interferon, and its advantage is without any side effects.
In recent years, there are many reports to adopt Thymosin alpha 1 and IFN α or lamivudine therapeutic alliance chronic viral hepatitis B, obtained effect preferably.Saurc etc. merge IFN α or lamivudine therapy HBeAg feminine gender but the male chronic hepatitis of HBV DNA with Thymosin alpha 1, and the 1st group is 27 examples, use Thymosin alpha 1 1.6mg, and 2 times weekly, 26 add IFN α 10MU when all, 3 times weekly, treat for 52 weeks altogether; The 2nd group of 10 examples, list treated for 52 weeks with IFN α; The 3rd group of 15 examples, IFN α adds lamivudine 100mg/d and treated for 52 weeks, continues to use lamivudine therapy again.During to 78 all drug withdrawals, 3 groups of HBV DNA turn out cloudy and the normal person of liver function recovery is respectively 74%, 40% and 53%; Be respectively 70%, 20% and 27% behind the December; Be 70%, 10% and 20% respectively after 18 months, show and adopt Thymosin alpha 1 and IFN α therapeutic alliance to have remarkable result that single is excellent with IFN or IFN associating lamivudine therapy.
In sum, thymosin demonstrates good immune dual regulation clinically, is mainly used in the disease of viral hepatitis and other immunologic function degression, is a kind of successful immunomodulator.
Be limited to the restriction of indexs such as stability, the lyophilized injectable powder of thymosin is only arranged in the market, this dosage form needs to dissolve in use, has also increased the chance of medicine pollution when having increased operating procedure.The present invention has formulated the aqueous solution preparation of thymosin just at the single situation of present thymosin dosage form, has solved the stability problem of thymosin in aqueous solution, and this is a main purpose of the present invention.
Summary of the invention
Mentality of designing of the present invention, research contents and technical scheme:
Main contents of the present invention comprise development, study on the stability and three parts of pharmaceutical research of preparation process.Wherein, the stability of thymosin in aqueous solution preparation is the problem that needs emphasis to solve.
According to the requirement of human aqueous solution preparation research, this solution type preparation should be a solution clear and bright, safe, harmless, good stability.Solvent can be that aqueous also can be non-aqueous, and what aqueous solvent was the most frequently used is water for injection.According to the characteristics of active medicine, can select various pharmaceutic adjuvants, as osmotic pressure regulator, solubilizing agent, antioxidant, cosolvent, pH value regulator or the like.In conjunction with the characteristics of thymosin, we mainly consider to have used following adjuvant: osmotic pressure regulator, pH value regulator, solubilizing agent, antioxidant and antiseptic.
Optionally osmotic pressure regulator can be but be not limited only to inorganic salts chemical compound such as sodium chloride; Optionally the pH value regulator can be but be not limited only to phosphate buffer, acetate buffer solution, citrate buffer solution etc.; Optionally solubilizing agent or cosolvent can be but be not limited only to 20 kinds of human amino acids such as glycine and salt (as cysteine, leucine, methionine etc.) thereof, various cyclodextrin, glycerol carbohydrate, various cyclodextrin, low molecular dextran, poloxamers or the like such as (perhaps sorbitol, Polyethylene Glycol, propylene glycol); Optionally antioxidant can be but be not limited only to ethylenediaminetetraacetic acid and salt thereof, ascorbic acid, citric acid, cysteine, glutathion, methionine or the like; Available antiseptic can be but be not limited only to cinnamyl alcohol, formic acid or the like.
Show that through a large amount of orthogonal tests above-mentioned adjuvant has good stablizing effect to thymosin.Wherein, preferred pH value regulator is that phosphate buffer, preferred solubilizing agent are cyclodextrin compounds, and preferred osmotic pressure regulator is a sodium chloride, and preferred anti-oxidants is the EDTA disodium.
Aspect thymosin and the supplementary product consumption composition, thymosin can be that 0.1-1000mg/ props up in prescription, for example 0.5,1,2,5,10,20,50,100,250,500mg/ props up.The volume of unit formulation can be 0.1-500ml.
A preferred prescribed regimen is: the disodiumedetate (EDTA) of 0.5-250mg thymosin, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the sodium chloride of 0.5-5%.Preferred on this basis scheme is: the disodiumedetate (EDTA) of 0.5-10mg thymosin, 10-30mmol/L phosphate buffer, 0.5-5mmol/L, the sodium chloride of 0.5-2%.Most preferred scheme is: the disodiumedetate (EDTA) of 1.6mg thymosin, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, the preparation specification is that 1.6mg:1ml/ props up.
Another preferred prescribed regimen is: the disodiumedetate (EDTA) of 0.5-250mg thymosin, 5-50mmol/L phosphate buffer, 0.5-10mmol/L, the sodium chloride of 0.5-5%, 0.1-10% hydroxypropyl beta cyclodextrin.On this basis, preferred component solutions is: the disodiumedetate (EDTA) of 0.5-10mg thymosin, 10-30mmol/L phosphate buffer, 0.5-5mmol/L, the sodium chloride of 0.5-2%, 0.5-5% hydroxypropyl beta cyclodextrin.Most preferred component solutions is: the disodiumedetate (EDTA) of 1.6mg thymosin, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, 2% hydroxypropyl beta cyclodextrin, the preparation specification is that 1.6mg:1ml/ props up.
Above-mentioned preparation prescription can be prepared by following technology:
(1) under 100 grades of laminar flows, takes by weighing required sodium chloride, 12 water sodium hydrogen phosphates, 2 water sodium dihydrogen phosphate disodiumedetates, in the suitable container of packing into, add the amount of calculation sterilized water for injection dissolving is used immediately by inventory.
(2) the recipe quantity thymosin is added buffer, shake up after the dissolving, ultrafiltration post ultrafiltration depyrogenation, the filter that the reuse high pressure steam sterilization is crossed (the double-deck filter membrane of 0.22 μ m, 0.45 μ m) filtration sterilization is sealed, and prepares packing.
(3) adjust dosage with sterilized water for injection by every 1ml earlier before the packing, after dose titration is qualified, the liquid packing of changing dressings.After jumping a queue entirely, medicine bottle is sent into the bottle track, carry out gland.
(4) start Cover-rolling machine, medicine bottle is with the rotating disk injection, and aluminium lid adds on the medicine bottle through track, and is locked by head.Rolling lid back aluminium lid should be tightly, neat in edge.
So far, the design and the research of preparation process thereof has been finished in our invention, begins to investigate stability of formulation.Experiment with sample from the prepared product of embodiment 1.
According to corresponding research requirement, we have mainly investigated the clarity of appearance character, pH value, solution and color, related substance, content, clarity test, bacterial endotoxin and aseptic stability study.Influence factor's test, accelerated test and long term test have mainly been carried out.
It is high temperature and strong illumination that the influence factor tests main investigation factor.
Strong illumination experiment: test sample is placed in the clarity detector, is to place 10 days under the condition of 4000lx ± 500lx in intensity of illumination, in sampling in the 5th and the 10th day, detects by stable high spot reviews project, and compares with 0 day.Result such as table 1.The result shows that this product pH value after illumination obviously descends, and related substance increases, and content obviously descends, and all other indexs do not have significant change, so this product answers shading to preserve.
Table 1 exposure experiments to light study on the stability result
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | PH value | Clarity | Clarity and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.81 | Up to specification | Clarify colourless | 0.18 | 99.01 |
| 5 | Achromatism and clarity | 5.42 | Up to specification | Clarify colourless | 0.78 | 83.49 | |
| 10 | Achromatism and clarity | 5.10 | Up to specification | Clarify colourless | 1.44 | 79.23 | |
High temperature experiment: test sample is placed glass dish, placed 10 days down at 60 ℃ respectively, during this period,, detect by stable high spot reviews project respectively at sampling in the 5th and the 10th day, and with 0 day relatively.Testing result sees Table 2.
Table 2 hot test study on the stability result (60 ℃)
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | The pH value | Clarity | The clarity of solution and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.84 | Up to specification | Clarify colourless | 0.20 | 99.14 |
| 5 | Achromatism and clarity | 6.32 | Up to specification | Clarify colourless | 3.85 | 80.56 | |
| 10 | Achromatism and clarity | 6.11 | Up to specification | Clarify colourless | 5.02 | 77.29 | |
60 ℃ of experimental results of high temperature show: this product is behind 60 ℃ of high temperature 10 days, and pH value obviously descends, and related substance obviously increases, and content obviously descends, and all other indexs do not have significant change.Carry out 40 ℃ of tests of high temperature according to above some variation event.See Table 3.
Table 3 hot test study on the stability result (40 ℃)
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | The pH value | Clarity | The clarity of solution and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.83 | Up to specification | Clarify colourless | 0.19 | 99.27 |
| 5 | Achromatism and clarity | 6.37 | Up to specification | Clarify colourless | 0.64 | 93.10 | |
| 10 | Achromatism and clarity | 6.25 | Up to specification | Clarify colourless | 1.39 | 92.44 | |
40 ℃ of experimental results of high temperature show: this product is behind 40 ℃ of high temperature 10 days, and pH value descends, and related substance increases, and content descends, according to above some change so carry out 25 ℃ of tests.Met and saw Table 4.
Table 425 ℃ test study on the stability result
| Lot number | Time (my god) | The investigation project | |||||
| Appearance character | The pH value | Clarity | The clarity of solution and color | Related substance (%) | Content (%) | ||
| 01 | 0 | Achromatism and clarity | 6.82 | Up to specification | Clarify colourless | 0.23 | 99.58 |
| 5 | Achromatism and clarity | 6.79 | Up to specification | Clarify colourless | 0.45 | 99.17 | |
| 10 | Achromatism and clarity | 6.77 | Up to specification | Clarify colourless | 1.01 | 98.63 | |
Show in result under 25 ℃ of experiment conditions: this product is after 25 ℃ of conditions are placed 10 days, and pH value descends, and related substance slightly increases, and content has decline slightly; Belong to the preparation responsive especially to temperature so can determine this product, accelerated tests can be carried out under the condition of RH 60 ± 10% 25 ℃ ± 2 ℃ of temperature; Long-term experiment can carry out under 2 ℃ of-10 ℃ of conditions of temperature.
Accelerated test: this product packing is placed 25 ℃ ± 2 ℃ of temperature, in the environment of RH 60 ± 10%, placed 6 months, respectively at 1st month, 2 months, 3 months, 6 samplings at the end of month detected by stable high spot reviews project.Result of the test sees Table 5.
Table 5 accelerated test is investigated result's (25 ℃ ± 2 ℃, RH60 ± 10%)
| Lot number | Month | The investigation project | ||||||
| Appearance character | pH | Clarity | Related substance (%) | Endotoxin | Aseptic | Content (%) | ||
| 02 | 0 | Achromatism and clarity | 6.80 | Up to specification | 0.22 | Up to specification | Up to specification | 100.00 |
| 1 | Achromatism and clarity | 6.04 | Up to specification | 5.86 | - | - | 94.92 | |
| 2 | The solution muddiness | 5.86 | The solution muddiness | 9.20 | - | - | 87.41 | |
| 3 | The solution muddiness | 5.59 | The solution muddiness | 14.55 | - | - | 81.52 | |
| 6 | The solution muddiness | 4.97 | The solution muddiness | 20.64 | - | - | 72.48 | |
Accelerated test result shows that the thymosin aqueous solution was placed 6 months with this understanding, and pH value descends, and related substance increases, and content descends and illustrates that this product belongs to the preparation responsive especially to temperature, need put cold place and preserve.
Long term test: this product packing is placed under 2 ℃ of-10 ℃ of conditions of temperature, placed 6 months, sampling in per 3 months once detected by stable high spot reviews project respectively at 0 month, 3 months, 6 months.After 9 months, continued to investigate respectively at 12 months, 18 months, 24 months, 36 months.Result of the test sees Table 6.
Table 6 long term test is investigated result's (2 ℃-10 ℃)
| Lot number | Month | The investigation project | |||||||
| Appearance character | Clarity and color | PH value | Clarity | Related substance (%) | Endotoxin | Aseptic | Content (%) | ||
| 02 | 0 | Achromatism and clarity | Clarify colourless | 6.78 | Up to specification | 0.21 | Up to specification | Up to specification | 99.85 |
| 3 | Achromatism and clarity | Clarify colourless | 6.76 | Up to specification | 0.28 | Up to specification | Up to specification | 99.74 | |
| 6 | Achromatism and clarity | Clarify colourless | 6.74 | Up to specification | 0.30 | Up to specification | Up to specification | 99 70 | |
| 03 | 0 | Achromatism and clarity | Clarify colourless | 6.82 | Up to specification | 0.23 | Up to specification | Up to specification | 99.57 |
| 3 | Achromatism and clarity | Clarify colourless | 6.77 | Up to specification | 0.31 | Up to specification | Up to specification | 99.46 | |
| 6 | Achromatism and clarity | Clarify colourless | 6.75 | Up to specification | 0.35 | Up to specification | Up to specification | 99.21 | |
The result shows that the thymosin aqueous solution was placed 6 months under the long term test condition, every index does not all have obvious change, illustrates that this product has good stability.
The stability test conclusion: show by influence factor's result of the test, the thymosin aqueous solution in illumination, transfer postpone in 40 ℃, 25 ℃ conditions of high temperature (60 ℃) and find that pH value descends, content descends, related substance increases; Placed 6 months in accelerated test condition (25 ℃ ± 2 ℃, RH 60 ± 10%), pH value descends, and content descends, and related substance increases, and places 6 months in long term test condition (2 ℃-10 ℃), and every index does not all have obvious change.Determine that this product should be in shading, Leng Chu (2-10 ℃) preservation.
Another part content of the present invention is to investigate the pharmacology of described aqueous solution ejection preparation.The main purpose of pharmaceutical research is the biological activity of more this dosage form and existing thymosin freeze-dried powder dosage form.Thymosin has immunoloregulation function widely, and this is not the problem that the present invention will illustrate.What we need solve only is the activity whether novel formulation provided by the invention has thymosin, infers said preparation when the indication of treatment thymosin and the equivalence of existing preparation with this, and determines the said preparation practicality with this.We have adopted the E rosette test for this reason.
Thymosin is tested the influence of E rosette formation rate:
Material and reagent:
Porcine thymus, sheep anti blood coagulation, culture medium etc.
Medicine and numbering:
No. 01 sample, the thymosin lyophilized powder (Zadaxin) of embodiment of the invention preparation.
Experimental procedure:
Fresh pig thymus cleans and makes the lymphocyte suspension through grinding, and being diluted to concentration after the cleaning is 3 * 10
6-5 * 10
6Individual cell (work)/milliliter.Get the sheep anti blood coagulation, washing, centrifugal back dilution counting make it final concentration and are to take off 50 times of E receptor T lymphocyte concentration.Thymosin aqueous solution and lyophilized powder are diluted to the solution of 40ug/ml with the Hanks washing liquid.
Get 6 test tubes, 2 add Hank ' s washing liquid and without the T lymphocyte that takes off the E receptor, and 2 add Hank ' s washing liquid and take off E receptor T lymphocyte suspension, 2 add sample and take off E receptor T lymphocyte suspension, and 37 ℃ of insulations are after 60 minutes, and every pipe adds sheep erythrocyte suspension, shake up, centrifugal, spend the night.Get supernatant, fixing, dyeing, the cell number (in conjunction with the lymphocyte of 3 above sheep red blood cells) that microscopically statistics E rosette forms, result such as following table 7.
Table 7. thymosin to the influence of E rosette formation rate (mean ± standard deviation, n=6)
| Become footing/100 lymphocytes | Average one-tenth knot rate (%) | |
| Negative control | 38.2±4.7 | 38.2 |
| No. 01 sample | 54.6±3.6* | 54.6 |
| Freeze-dried powder contrast (Zadaxin) | 55.1±3.1* | 55.1 |
Annotate: * represent with negative control than p＜0.01.
The result shows, thymosin aqueous solution provided by the invention and traditional lyophilized injectable powder have same immunoloregulation function.
In sum, the invention provides the novel form of a thymosin, this dosage form manufacturing technique is simpler than existing freeze-dried powder agent producing process, is easy to amplify on producing, and is with the obvious advantage, is convenient to the realization of industrialization; Simultaneously, good as claim and the described dosage form stability of description aspect biological activity and preparation stability, can long term storage, it is active identical with existing lyophilized injectable powder.Therefore the present invention has embodied the patent key element of novelty, creativeness and practicality well.
The specific embodiment
For the implementation process of this patent is described better, we are listed below embodiment.Need to prove that cited embodiment is one of imbody of thinking of the present invention and spirit, is not the scope restriction to the patent of invention description, more is not the refinement to claim.Under thinking of the present invention, the aqueous products (injection, spray, drop etc.) of the thymosin that any this patent is described all should be included in the scope of this patent.
The preparation of embodiment 1, the described pharmaceutical preparation of claim 7
Sodium chloride 7.0g, sodium hydrogen phosphate (containing 12 water of crystallization) 4.37g, sodium dihydrogen phosphate (containing 2 water of crystallization) 1.22g, disodiumedetate 0.64g, thymosin 1.6g decided in accurate title, be dissolved in water for injection, fixed molten at last to 1000ml, be distributed into 1000 with the 2ml cillin bottle.Final specification is that 1.6mg/ props up.According to this 3 batches of production sample of writing out a prescription altogether, numbering is respectively 01,02,03.Operation sequence is described execution to specifications.
The preparation of embodiment 2, the described pharmaceutical preparation of claim 10
Sodium chloride 7.0g, sodium hydrogen phosphate (containing 12 water of crystallization) 4.37g, sodium dihydrogen phosphate (containing 2 water of crystallization) 1.22g, disodiumedetate 0.64g, thymosin 1.6g, hydroxypropyl beta cyclodextrin 20g decided in accurate title, be dissolved in water for injection, fixed molten at last to 1000ml, be distributed into 1000 with the 2ml cillin bottle.Final specification is that 1.6mg/ props up.According to this 1 batch of production sample of writing out a prescription altogether, numbering 04.Operation sequence is described execution to specifications.
Claims (5)
1, a kind of aqueous solution preparation of thymosin, it is mainly formed: the disodiumedetate of 0.5-10mg thymosin, 10-30mmol/L phosphate buffer, 0.5-5mmol/L, the sodium chloride of 0.5-2% are prepared into the preparation that unit volume is 0.1-500ml.
2, preparation as claimed in claim 1, it is mainly formed and is: the disodiumedetate of 1.6mg thymosin, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, being prepared into specification is the preparation that 1.6mg: 1ml/ props up.
3, preparation as claimed in claim 1, it is mainly formed: the disodiumedetate of 0.5-10mg thymosin, 10-30mmol/L phosphate buffer, 0.5-5mmol/L, the sodium chloride of 0.5-2%, 0.5-5% hydroxypropyl beta cyclodextrin are prepared into the preparation that unit volume is 0.1-500ml.
4, preparation as claimed in claim 3, it is mainly formed: the disodiumedetate of 1.6mg thymosin, 20mmol/L phosphate buffer, 1mmol/L, 0.7% sodium chloride, 2% hydroxypropyl beta cyclodextrin, being prepared into specification is the preparation that 1.6mg: 1ml/ props up.
5, any described preparation of claim 1-4 is used for the treatment of application in the medicine of viral hepatitis, tumor and other immune disease in preparation.
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| CN101361962B (en) * | 2008-10-07 | 2012-05-23 | 厦门大学 | New use of thymosin alpha1 |
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| CN102233130B (en) * | 2010-04-28 | 2013-05-01 | 江苏豪森药业股份有限公司 | Stable pharmaceutical preparation containing thymosin 1 derivatives |
| CN104511013A (en) * | 2013-09-26 | 2015-04-15 | 长春海悦药业有限公司 | Pharmaceutical composition containing thymulin and preparation thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0331934A1 (en) * | 1988-03-11 | 1989-09-13 | SCLAVO S.p.A. | New pharmaceutical compositions containing thymosin alpha 1 |
| CN1118143A (en) * | 1993-02-23 | 1996-03-06 | 基因技术股份有限公司 | Excipient stabilization of polypeptides treated with organic solvents |
| CN1402640A (en) * | 1999-10-04 | 2003-03-12 | 希龙公司 | Stabilized liquid polypeptide-confg. pharmaceutical compositions |
| CN1409758A (en) * | 1999-12-14 | 2003-04-09 | 热生物之星公司 | Stabilizing diluent for polypeptides and antigens |
| WO2004006958A1 (en) * | 2002-07-17 | 2004-01-22 | Lek Pharamaceuticals D.D. | Stable pharmaceutical composition comprising erythropoietin |
-
2005
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0331934A1 (en) * | 1988-03-11 | 1989-09-13 | SCLAVO S.p.A. | New pharmaceutical compositions containing thymosin alpha 1 |
| CN1118143A (en) * | 1993-02-23 | 1996-03-06 | 基因技术股份有限公司 | Excipient stabilization of polypeptides treated with organic solvents |
| CN1402640A (en) * | 1999-10-04 | 2003-03-12 | 希龙公司 | Stabilized liquid polypeptide-confg. pharmaceutical compositions |
| CN1409758A (en) * | 1999-12-14 | 2003-04-09 | 热生物之星公司 | Stabilizing diluent for polypeptides and antigens |
| WO2004006958A1 (en) * | 2002-07-17 | 2004-01-22 | Lek Pharamaceuticals D.D. | Stable pharmaceutical composition comprising erythropoietin |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101361962B (en) * | 2008-10-07 | 2012-05-23 | 厦门大学 | New use of thymosin alpha1 |
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