Name | thymopentin |
Synonyms | TP-5 Immunox Timunox Thyopentin THYMOPENTIN thymopentin Sintomodulina Thymopent njection thymopentin (TP-5) Thymopoietin 32-36 32-36-Thymopoietin Thymopoietin II-(32-36) ThyMopentin for Injection Thymopoietin pentapeptide L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-OH Thymopoietin pentapeptide-Fluorescin-isothiocyanate N~5~-(diaminomethylidene)ornithyllysyl-alpha-aspartylvalyltyrosine N~5~-(diaminomethylidene)-L-ornithyl-L-lysyl-L-alpha-aspartyl-L-valyl-L-tyrosine |
CAS | 69558-55-0 |
EINECS | 811-641-8 |
InChI | InChI=1/C30H49N9O9/c1-16(2)24(28(46)38-22(29(47)48)14-17-8-10-18(40)11-9-17)39-27(45)21(15-23(41)42)37-26(44)20(7-3-4-12-31)36-25(43)19(32)6-5-13-35-30(33)34/h8-11,16,19-22,24,40H,3-7,12-15,31-32H2,1-2H3,(H,36,43)(H,37,44)(H,38,46)(H,39,45)(H,41,42)(H,47,48)(H4,33,34,35)/t19-,20-,21-,22-,24-/m0/s1 |
Molecular Formula | C30H49N9O9 |
Molar Mass | 679.77 |
Density | 1.44±0.1 g/cm3(Predicted) |
Solubility | DMSO:100 mg/mL (147.1 mM); Water:100 mg/mL (147.1 mM); Insoluble in ethanol. |
Appearance | Powder |
Color | White |
pKa | 3.07±0.10(Predicted) |
Storage Condition | Keep in dark place,Inert atmosphere,Store in freezer, under -20°C |
Refractive Index | 1.635 |
MDL | MFCD00214200 |
Physical and Chemical Properties | TP is a polypeptide extracted from calf thymus and two similar types were found: thymopoietin-I (TP-I) and thymopoietin-II(TP-II). TP-II is 49 peptide, consisting of 13 amino acids. The structural difference between TP-I and TP-II was that TP-II of the peptide chains were changed from Silk 1 and Su 43 to TP-I gan 1 and Group 43. The pentapeptide of Jing 32-casein 36 showed TP-II T cell differentiation activity in vitro and in vivo. 49 amino acids in 5 have physiological activity, has been artificial synthesis of spermidine peptide 5, namely thymopentin (timopentin), and for clinical use. In addition, the splenin isolated from the bovine spleen is similar to TP-II, so it is called TP-III. TP-II of the synthetic 5 peptides are temporarily referred to as thymus (TPe), and TP-III of the synthetic 5 peptides are temporarily referred to as spleen (SPe). TP-II and TPe act on neuromuscular transmission, inducing the differentiation of T cell precursor cells in vitro, while inhibiting the differentiation of B cells. TP-III and SPe can induce the differentiation of T and B cell precursor cells. Ubiquitin is composed of 74 amino acid residues, which can induce the differentiation of T cells and B cells. It is widely found in animal tissues (including thymus) and plants and fungi cells, associated with immune function. |
Use | Non-inhibitory function enhancer for the treatment of primary or secondary immunodeficiency |
WGK Germany | 3 |
This product is a derivative of the synthesis of the Sural thymus polypeptide (thymopopoitin), which can cause selective T cell differentiation, so it is the reason for the cell binding immune response. Although it is only pentapeptide, it has the same properties for the immune system.
This line consists of five amino acids in a synthetic polypeptide, it is N-[N-[N-[N2-L-arginyl-L-lysyl] -L-a aspartyl] -L-ascoryl] -L-tyrosine. The thymopentin (C30H49N9O9) should be 97.0% ~ 103.0% as calculated by water-free, solvent-free and acetic acid-free materials.
take this product, precision weighing, add water to dissolve and quantitative dilution to make a solution containing 20mg per lml, according to the law (General 0621), with no water, calculated without solvent and without acetic acid, the specific rotation is from one 14.0 ° to one 22.0 °.
occasional skin itching, rash, periorbital edema and other skin allergic reactions and medication local pain, erythema damage, local bleeding, infiltration, etc. Serious adverse reactions for leukopenia, medication should be regular check if see neutropenia, medication should be stopped.
take an appropriate amount of this product, add hydrochloric acid solution (1-2 ) , and hydrolyze it at 110 ° C. For 24 hours, then determine it according to the appropriate amino acid analysis method. The relative ratio of each amino acid was calculated by dividing the sum of the moles of arginine, aspartic acid, lysine, tyrosine and valine by 5 as 1, valine should be 0.8 to 1.2.
take 5mg of this product, add water 5ml to dissolve, according to the law (General 0631),pH value should be 7.0~9.0.
take 5mg of this product, add 5ml of water to dissolve, check according to law (General rule 0901 and general rule 0902 first method), the solution should be clear and colorless.
take an appropriate amount of this product, weigh it accurately, add diluent [mobile phase A (General 0872)-methanol (95:5)] A solution containing 10 mg per 1 ml was prepared by dissolution and quantitative dilution as a test solution. The content of acetic acid should not exceed 0872 as determined by the acetic acid assay in synthetic polypeptides (General rule 0.5%).
take an appropriate amount of this product, add the mobile phase to dissolve and dilute to make a solution containing 5mg per lml, as a test solution; Take a sample solution of lml with precision, set in a 100ml measuring flask, dilute to the scale with the mobile phase, and shake to serve as a control solution. According to the chromatographic conditions under the content determination item, 20 u1 of the test solution and the control solution are respectively injected into the liquid chromatograph, and the chromatogram is recorded to 2. Times of the retention time of the main peak. If there are impurity peaks in the chromatogram of the test solution, the area of a single impurity peak shall not be greater than the area of the main peak of the control solution (1.0% ), and the sum of the areas of each impurity peak shall not be greater than 2 times the area of the main peak of the control solution (2.0%).
take about 0.lg of this product, precision weighing, put it in 20ml headspace bottle, Precision Add internal standard solution (take appropriate amount of N-propanol, precision weighing, water was added to dissolve and quantitatively diluted to prepare 0.lmg solution) lml to dissolve, seal, as a test solution; Respectively, precision weighing methanol, ethanol, ether, acetonitrile, dichloromethane, Tetrahydrofuran, pyridine, N, add an appropriate amount of N-dimethylformamide into a 100ml volumetric flask, Add 10ml of dimethyl sulfoxide to dissolve, dilute with water to the scale, shake well, and use it as a reference stock solution. Take 1ml in a precise volume and put it into a 10ml volumetric flask, dilute to the scale with internal standard solution and shake well (each lm l contains 300 of methanol, 500 of ethanol, 500 of ether, 41 tons of acetonitrile, 60 tons of dichloromethane, 72% of tetrahydrofuran, pyridine (20 μg), JV,iV-dimethylformamide (88ug), 1ml was accurately measured, placed in a 20ml headspace bottle, sealed, and used as a reference solution. According to the determination method of residual solvent (General Principle 0861 second method), the capillary column with 6% cyanopropyl phenyl-94% dimethyl polysiloxane (or similar polar) as the stationary liquid is the column, 0.32mm x 30m; the initial temperature is 40°C, maintained for 4 minutes, heated to 140°C at a rate of 10°C per minute, maintained for 1 minute, and then heated to 220°C at a rate of 20°C per minute for 3 minutes; the detector temperature was 250°C; The inlet temperature was 230°C; The headspace bottle equilibrium temperature was 90°C and the equilibrium time was 30 minutes. The reference solution was injected in Headspace, and the peaks were obtained in the order of methanol, ethanol, diethyl ether, acetonitrile, dichloromethane, Tetrahydrofuran, pyridine and N,N-dimethylformamide, the degree of separation between peaks shall meet the requirements. Respectively take the test solution and the reference solution into the headspace, record the chromatogram, according to the internal standard method to calculate the peak area, Methanol, ethanol, ether, acetonitrile, dichloromethane, Tetrahydrofuran, pyridine, N,N-dimethylformamide residues shall be in accordance with the provisions.
take this product, according to the determination of moisture (General 0832 first method), the water content shall not exceed 5.0%.
immunomodulatory drugs.
sealed, stored in the cool dark.
This product is thymopentin sterilized aqueous solution, containing thymopentin (C30H49N909) should be labeled amount of 90.0% ~ 110.0%.
This product is a clear colorless liquid.
Same as thymopentin.
specification
(l) lml:lmg (2 )lml:1Omg
sealed and stored at 2-8°C.
This product is thymopentin with the right amount of mannitol and other excipients by freezing, drying made of sterile lyophilized product. Thymopentin (C30H49N909) should be 90.0% to 110.0% of the labeled amount.
This product is a white freeze-dried loose mass or powder.
Same as thymopentin.
(l)lmg ( 2 ) 10mg
sealed and kept in a cool dark place.
Introduction | Thymopentin TP5, whose English name is Thymopentin, is a synthetic immunoregulatory pentapeptide, is a very important immune-promoting active peptide drugs, can significantly improve human immunity, help humans effectively resist a variety of diseases, at the same time for a variety of diseases have significant and exact curative effect, broad market prospects, with good economic and social benefits. |
mechanism of action | thymopentin has the function of inducing and promoting the differentiation, maturation and activation of T lymphocytes and its subsets, regulate the proportion of T lymphocytes, so that CD4 /CD8 tends to be normal; Regulation and enhancement of human cellular immune function, can promote the maturation of T lymphocytes in peripheral blood after mitogen activation, increases the secretion of various lymphokines (e. G., Alpha, Gamma Interferon, interleukin 2 or interleukin 3) by T cells after activation of various antigens or mitogens, increases the level of lymphokine receptors on T cells. It also enhances the lymphocyte response through activation of T helper cells. In addition, it may affect the chemotaxis of NK precursor cells that become more cytotoxic upon exposure to interferon, contributing to their therapeutic effects. In addition, the thymus five peptide can enhance the ability of the human body to resist radiation. Therefore, it has the role of regulating and enhancing the body's cellular immune function. |
physiological function | thymopentin has the same function of regulating the immune system as Thymosin, which can induce the differentiation of pre-T lymphocytes, mature, regulating the immune activity of mature T lymphocytes. For a variety of immune disorders, such as congenital thymus, thymectomy, senile thymic atrophy hypofunction, infection, tumor and autoimmune diseases due to the proportion of different T lymphocyte subsets and functional changes caused by low immune function, the drug has to make the immune response to normal regulation. |
pharmacological action | thymopoietin is an endogenous polypeptide in thymus tissue, containing 49 amino acids, it can promote the differentiation of thymus and peripheral T cells, regulate the immune function and other biological activities. The thymopentin (TP5), which is composed of the 32 to 36 amino acids of the active center of thymopoietin, contains only five amino acid residues, but can effectively maintain the biological activity of thymopoietin. Since its launch in Italy under the trade name Timunox in 1985, TP5 has been used as an immunomodulator in clinical use including chronic hepatitis B, AIDS, and severe acute respiratory syndrome (SARS). Such as disease treatment and prevention. [Pharmacological effects] 1. Induce and promote T cell differentiation and maturation. Regulation of T lymphocyte subsets to make CD4/CD8 normal. 3. Enhanced macrophage phagocytosis. 4. Enhance red blood cell mediated immune function. 5. Increase the viability of natural killer (NK) cells. 6. Increase the production level of interleukin-2 (IL-2) and the expression level of its receptor. 7. Enhanced interferon-gamma production by peripheral blood mononuclear cells. 8. Enhance the activity of SOD in serum. |
preparation method | TP-5 there are two main preparation methods: liquid phase synthesis method and solid phase synthesis method. 1. Liquid-phase synthesis of TP-5:(1) TP-5 was synthesized by a liquid-phase method combining Boc (tert-butoxycarbonyl) and Fmoc (9-fluorenylmethoxycarbonyl) strategies: the protected amino acids are HCl · H-Tyr(Bzl)-OBzl, Boc-Val-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Boc)-OH and Fmoc-Arg(Pbf)-OH, the condensation reagent was BOP-HOBt, the condensation time was 2 h, the reaction solvent was chloroform, and the base neutralization reagent was N-methylmorpholine (NMM). Finally, the protective group removal system was carried out by using trifluoromethanesulfonic acid/trifluoroacetic acid (TFMSA/TFA)+ anisole, and the reaction was carried out at 0 ℃ for 2 h. (2) liquid phase synthesis of TP-5 by Boc amino group protection strategy and carbon chain step-by-step growth method: amino group was protected by Boc-HCl/dioxane system, DCC-HOBt condensation to obtain fully protected Boc-Arg(Tos)-Lys(Z)-Asp(OBz1)-Val-Tyr(Bz1)-OMe, after saponification, using TFA/TFMSA + anisole, anisole sulfide and O-methylphenol, reaction at room temperature for 1H, the side chain was removed to obtain white crystals, and the total yield was 30% after purification. (3) using the liquid phase minimum protection strategy to synthesize TP-5 step by step: Amino acid protection strategy: HC1 · Tyr-OMe, Boc-Val-OH, Boc-Asp(OBz1)-OH, Boc-Lys(2C1Z)-OH, Z-Arg-OH, DCC-HOBt condensation to form dipeptide, tripeptide and tetrapeptide, HBTU condensation to form a protective pentapeptide, and finally using Pd/C hydrogen to remove the side chain protection to obtain the target product. On the premise of no larger side reaction, the side chain functional group is not protected as much as possible, and the strong acid cleavage of HF can be avoided. The conditions are relatively mild and more suitable for industrialization. 2. The solid-phase synthesis of tp-5 is mainly composed of Boc/Bzl and Fmoc/OtBu two synthetic protection strategies. (1)Boc solid phase synthesis method: the main strategy of Boc synthesis method is to use the Boc which can be removed by TFA as the α-amino group, and the side chain protection is benzyl alcohol. Synthesis of a Boc-amino acid derivative covalently cross-linked to Merrifield or MBHA resin, removal of Boc with TFA, neutralization of the free amino terminus with triethylamine, followed by activation by DCC, coupling of the next amino acid, finally, the HF method or TFMSA method is used for deprotection. (2)Fmoc solid phase synthesis method: the fundamental difference between Fmoc method and Boc method lies in the use of alkali removable Fmoc as a protective group of α-amino group, the side chain is protected by tert-butoxy group which can be removed by TFA, etc., and the resin is 90% TFA-resectable p-alkoxybenzyl alcohol resin and 1%TFA-resectable dialkoxybenzyl alcohol resin, the final deprotection avoids strong acid treatment. The advantage of Fmoc as an amino protecting group is that it is stable to acids and is not affected by treatment with reagents such as TFA, Only mild alkali treatment is needed, and β 2 elimination reaction can be removed without neutralization with tertiary amine, and the Fmoc group has characteristic ultraviolet absorption, which is easy to detect and carry out, and brings convenience to automated synthesis. However, the price of Fmoc protected amino acids is expensive, and the synthesis cost is correspondingly higher. In TP-5 Fmoc solid-phase synthesis, using Wang resin, DMF as solvent, DIC-HOBt condensation, side chain protection strategy: Fmoc-Arg(Pbf)-OH, Fmoc-Lys(Boc)-OH, fmoc-Asp (OtBu)-OH, Fmoc-Val-OH and Fmoc-Tyr(tBu)-OH. |
Use | 1. For chronic hepatitis B patients over 18 years of age. 2. Various primary or secondary T lymphocyte deficiency diseases. 3. Some autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, etc.). 4. Various diseases with low cellular immune function. 5. Adjuvant therapy of tumor. (2016-04-25) It has the function of immune activation, promoting T cell differentiation, regulating neuromuscular conduction, and treating myasthenia gravis. Adverse reactions and contraindications: occasional skin itching, rash, periorbital edema, medication local pain, erythema damage, severe Leukopenia. enhancer of immune function, for the treatment of primary or secondary immunodeficiency |
Drug Description | . Subcutaneous injection (1) primary immunodeficiency: At the beginning of the day 0.5~1 mg/kg, for 2 consecutive weeks; Maintain the amount of 0.5~1 mg/kg, 2~3 times a week. (2) Secondary Immunodeficiency: once 50mg, 3 times a week, for 3 to 6 weeks. Intramuscular injection (1) primary immunodeficiency: the beginning of the day 0.5~1 mg/kg, for 2 consecutive weeks; Maintenance of a dose of 0.5~1 mg/kg, 2 to 3 times a week. (2) To improve the immune function of patients with malignant tumor: radiotherapy, chemotherapy at the same time, 1 times a day, 1 mg/kg,28 days for a course of treatment. The drug was well tolerated, individual visible Nausea, Fever, dizziness, chest tightness, weakness and other adverse reactions, a small number of patients with occasional drowsiness. 2. Patients with chronic hepatitis B may have a transient increase in ALT level. If there is no sign of liver failure, the product can still be used. [Taboo] 1. The goods have allergic reactions or organ transplant disabled. Patients who have used immunosuppressive therapy (eg, organ transplant recipients) are contraindicated. Note: 1. This product plays a therapeutic role by enhancing the immune function of patients, so it should not be used for patients receiving immunosuppressive therapy (such as organ transplant recipients), unless the benefits of treatment are significantly greater than the risks. 2. Liver function should be checked regularly during treatment. It is not known whether the drug is harmful to the embryo, or whether it affects fertility. Therefore, this medicine can only be used in pregnant women when necessary. At present, although this product has not been confirmed by human milk, but for lactating women should be particularly cautious. In patients under 18 years of age, the safety and efficacy of this drug has not been established. There are no reports of overdose (treatment or accident) in humans. Animal toxicity experiments showed that no adverse reactions occurred below the 10mg/kg dose (the maximum amount currently used). Drug interactions 1. This product is used in combination with many commonly used drugs, including interferon, anti-inflammatory drugs, antibiotics, hormones, analgesics, antihypertensive drugs, diuretics, drugs for the treatment of cardiovascular diseases, central nervous system drugs, contraceptives, there was no interference. 2. The combination of this product and interferon has a synergistic effect on improving immune function. |
production method | preparation of thymopoietin-II. Raw material treatment and concentration with calf thymus as raw material, 0.1mol/L NH4HCO3 was added, and the basic protein solution was obtained by stirring and extracting, and the denatured heterologous protein was removed by heating to 70 ° C., the precipitate was removed, and the supernatant was concentrated. Calf thymus [0.1 mol/L NH4HCO3]→ basic protein solution [70 ℃, dehybridized protein] → concentrated solution separation, chromatography and purification through SephadexG-50 and hydroxyl phosphorus lime column chromatography, after QAE-Sephadex column chromatography, refined, ready-to-get thymopoietin-II concentrated solution [Sephadex G-50]→ [hydroxyphosphorus lime column] chromatography solution [QAE-Sephadex column] → thymopoietin-II thymopoietin-II extraction raw material processing, ultrafiltration, with fresh bovine spleen as raw material, adding 0.1 mol/L NH4HCO3, homogenate extraction, alkaline soluble protein was obtained. The filtrate was concentrated by ultrafiltration with H10 × 100, heated to 70 ° C. In a water bath, and centrifuged for 15 min, leaving the supernatant. Fresh Bovine spleen [0.1 mol/L NH4HCO3]→ basic protein solution [ultrafiltration, concentration] →[70 ℃, centrifugation for 15min] the supernatant was purified by column and the supernatant was adjusted to pH 5.2, cation exchange resin (50 mg/ml) was added, stirred, filtered, and the filtrate was adjusted to pH 9.5. Cation exchange resin (50 mg/ml) was added, stirred, and filtered to give a filtrate. Supernatant [pH5.2, cation column] → filtrate [pH9.5, cation column] → filtrate gel filtration, purification filtrate was filtered through Sephadex G-75 gel to obtain active TP and ubiquitin, after anion exchange resin chromatography (NH4HCO3, ionic strength change 0.1-0.8mol/L), TP-III, hetero-protein and ubiquitin were obtained. Filtrate [Sephadex G-75 gel filtration] → active TP and ubiquitin [anion resin chromatography] → TP-III, hetero-protein and ubiquitin. |