CN113058039A - Oral medicine composition of thymalfasin or thymopentin - Google Patents
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Abstract
The invention belongs to the field of biological medicine, and particularly relates to an oral pharmaceutical composition of thymalfasin or thymopentin, which comprises the following components in percentage by weight: thymalfasin or thymopentin and a drug composition for promoting small intestine absorption, wherein the drug composition for promoting small intestine absorption is composed of sodium dodecyl sulfate, chitosan and sodium citrate; the medicinal composition for promoting the absorption of small intestine has the function of preparing a composite auxiliary material, and the auxiliary material can improve the absorption of the effective components in the small intestine after being combined with thymalfasin or thymopentin.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an oral pharmaceutical composition of thymalfasin or thymopentin.
Background
Thymalfasin is a chemically synthesized polypeptide consisting of twenty-eight amino acids, and the action mechanism of thymalfasin for treating chronic hepatitis B and enhancing immune system reactivity is not completely elucidated. A plurality of in vitro experiments show that the product promotes the maturation of T lymphocytes by stimulating the mitogen of peripheral blood lymphocytes, increases the levels of interferon alpha and interferon gamma, as well as lymphokines such as interleukin 2 and interleukin 3 secreted by the T cells after the activation of antigen or mitogen, and simultaneously increases the level of a T cell surface lymphokine receptor. The product can also enhance the mixed lymphocyte reaction of allogeneic and autologous human by activating CD4 cells. The product can increase the aggregation of pre-NK cells, and interferon can enhance cytotoxicity. In vivo experiments show that the product can improve the expression level of interleukin 2 receptor of mouse lymphocytes after the activation of the concanavalin A and simultaneously improve the secretion level of interleukin 2.
The thymopentin is composed of five amino acids of arginine, lysine, aspartic acid, valine and tyrosine. Thymopentin is suitable for: the malignant tumor patients have low immunity caused by radiotherapy and chemotherapy. In the domestic and foreign literature, thymopentin is used in the following cases, but the safety and effectiveness of the administration of more than 1mg dose are not available in domestic. (1) Can be used for treating chronic hepatitis B of 18 years old or older. After 18 years of age, the thymus begins to shrink and cellular immune function declines. (2) Various primary or secondary T cell deficiency diseases. (3) Certain autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus). (4) Various diseases with low cellular immune function. (5) And (3) adjuvant treatment of tumors.
Thymalfasin or thymopentin can not be orally taken, which causes poor patient compliance, so that the change of the administration route of the somatostatin and the analogues thereof has important significance.
Disclosure of Invention
Based on the reasons, the applicant obtains a novel medicine composition for promoting small intestine absorption through multiple creative researches, the composition is composed of sodium dodecyl sulfate, chitosan and sodium citrate, and the researches show that the medicine composition for promoting small intestine absorption provided by the invention can be prepared into a composite auxiliary material, and the auxiliary material and thymalfasin or thymopentin can improve the absorption of the effective components in the small intestine and the like after being combined.
The invention is realized by the following technical scheme.
A pharmaceutical composition comprising: thymalfasin or thymopentin and a drug composition for promoting small intestine absorption, wherein the drug composition for promoting small intestine absorption is composed of sodium dodecyl sulfate, chitosan and sodium citrate.
The pharmaceutical composition is prepared into an oral preparation.
The medicinal composition for promoting small intestine absorption is used for ensuring the absorption of thymalfasin or thymopentin in small intestine.
The medicinal composition for promoting small intestine absorption is used for promoting absorption of thymalfasin or thymopentin in the small intestine.
Wherein the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is 15-25: 5-8: 50-80.
Wherein the weight ratio of thymalfasin or thymopentin to the pharmaceutical composition for promoting intestinal absorption is as follows: 1:5-860.
An oral preparation is prepared from thymalfasin or thymopentin, sodium dodecyl sulfate, chitosan, and sodium citrate.
Wherein the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is 15-25: 5-8: 50-80.
Wherein the weight ratio of thymalfasin or thymopentin to the pharmaceutical composition for promoting intestinal absorption is as follows: 1:5-860.
The invention discloses a medicinal composition for promoting small intestine absorption, which obtains a novel auxiliary material, and the auxiliary material can be used for: drugs (active ingredients or active ingredients) that cannot be orally administered but can be injected can be orally administered, thereby changing the mode of administration of the drug (active ingredients or active ingredients).
The intestinal absorption-promoting pharmaceutical composition of the present invention can promote the absorption of a drug (active ingredient or active ingredient) that is easily decomposed in the gastrointestinal tract in the intestine.
The pharmaceutical composition for promoting intestinal absorption of the present invention can promote the absorption of a drug (active ingredient or active ingredient) that is not easily absorbed in the gastrointestinal tract in the intestine.
Since the pharmaceutical composition for promoting small intestine absorption of the invention is used for promoting the absorption of the drug (effective component or active component) in the small intestine, and the drug is required to be released in the small intestine to exert the efficacy, when the pharmacodynamic test and the pharmacokinetic test are carried out, rodents adopt small intestine catheters for administration, and mammals adopt enteric capsules for oral administration.
The invention combines the drug combination and the drug (effective component or active component) which can promote the intestinal absorption on rodents one by one to carry out the bioavailability detection, and simultaneously, part of the polypeptide is selected to carry out the detection of the drug effect and the pharmacokinetics on different animals.
Concrete examples of the test
The technical means of the present invention will be described below with reference to specific test examples, but the scope of the present invention is not limited thereto.
The contents of the test examples in the specification are only lists of implementation forms of the inventive concept, and the protection scope of the invention should not be considered to be limited to the specific forms set forth in the test examples, and the protection scope of the invention is equivalent to the technical means which can be thought of by those skilled in the art according to the inventive concept. While the following embodiments of the invention have been described, the invention is not limited to the specific embodiments and applications described above, which are intended to be illustrative, instructive, and not limiting. Those skilled in the art, having the benefit of this disclosure, may effect numerous modifications thereto without departing from the scope of the invention as defined by the appended claims.
The following tests are conclusion tests of research personnel based on multiple creative tests and on the technical scheme to be protected by the invention. In the quantitative tests in the following test examples, three replicates were set, and the data are the mean value or the mean value ± standard deviation of the three replicates.
Experiment 1 significantly improved the efficacy of Exenatide (Exendin4, EXE4) administered to the small intestine
The medicine composition is as follows: the surfactant is sodium dodecyl sulfate, the chitin and the derivatives thereof are chitosan, the metal ion chelating agent is sodium citrate, and the weight ratio is 20: 6.5: 65.
mixing Exenatide and the pharmaceutical composition according to the weight ratio of 1:5, fully and uniformly mixing for later use;
test animals: injecting 45mg/kg STZ into the abdominal cavity of SD male rats to construct a hyperglycemia model;
small intestine efficacy test: blood samples were taken at 0h and 9h for testing of blood glucose, either by subcutaneous injection (sc) or via small intestinal tract (ei).
The result shows that the blood sugar reducing effect of Exenatide administered in small intestine is very weak under the condition that the pharmaceutical composition is not added, and when the dosage reaches 1mg/kg, the blood sugar reducing efficiency after 9 hours is only about 70 percent and is far lower than about 50 percent of that of the subcutaneous dosage of 1 mug/kg. After the pharmaceutical composition is added, the blood sugar reducing effect of subcutaneous 1 mug/kg can be achieved by the administration dosage of 50 mug/kg. (see table 1 below).
TABLE 1
Experiment 2 significantly improves the bioavailability of Exenatide administered to the small intestine
Mixing Exenatide and the test 1 pharmaceutical composition according to the weight ratio of 1:5, fully and uniformly mixing for later use;
test animals: adult male SD rats;
small intestine PK assay: on an adult SD rat in a fasting state, the Exenatide is administrated by a small intestine catheter according to the administration volume of 1ml/kg to ensure that the dose of Exenatide is 200 mug/kg, the Exenatide is divided into another group, 200 mug/kg of Exenatide of the pharmaceutical composition in the test 1 is added in small intestine catheter injection (ei), blood is collected from the tail after 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after administration, the blood sample is anticoagulated by 10mM EDTA, and is centrifuged at 3000rpm at 4 ℃ for 5min to collect plasma for quick freezing.
To avoid hypoglycemia in the animals, 1g/kg glucose was administered prior to administration.
The ELISA detection method comprises the following steps: coating with mouse monoclonal antibody of anti-target polypeptide, blocking with 1% BSA, adding blood sample or standard substance diluted with 0.1% BSA for incubation, capturing rabbit polyclonal antibody of anti-target polypeptide labeled by Biotin, incubating with HRP-conjugated streptavidin, finally developing TMB, terminating HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the plasma according to the standard curve obtained by the standard substance.
The AUC was calculated from the PK profile, and the bioavailability for small intestine dosing was calculated as 100% bioavailability for intravenous (iv).
The results show that the AUC of the PK curve of Exenatide after 1 mu g/kg of iv injection is 0.93ng/ml.h, and the blood concentration of Exenatide after 200 mu g/kg of iv injection is lower than the lower detection limit of ELISA. Whereas, the AUC of the PK profile after addition of the test 1 pharmaceutical composition was 1.33ng/ml. h, the bioavailability of intestinal administration was about 0.71%. The test results are shown in Table 2.
TABLE 2
Experiment 3 significantly improves the bioavailability of oral Exenatide
Mixing Exenatide 0.7mg and test 1 pharmaceutical composition 200mg, lyophilizing, and making into No. 3 enteric-coated capsule;
mixing Exenatide 0.7mg and test 1 pharmaceutical composition 400mg, lyophilizing, and making into No. 0 enteric-coated capsule;
mixing Exenatide 0.7mg and test 1 pharmaceutical composition 600mg, lyophilizing, and making into No. 00 enteric-coated capsule;
mixing Exenatide 0.7mg and test 1 pharmaceutical composition 200mg, lyophilizing, and making into No. 3 common capsule;
mixing Exenatide 0.7mg and mannitol 200mg, lyophilizing, and making into No. 3 enteric-coated capsule;
test animals: adult male beagle dog
Oral PK assay: in the state of empty stomach of animals, blood samples are collected at 0.5, 1, 1.5, 2, 2.5 and 3 hours after the enteric capsule is orally taken. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma was collected and snap frozen.
Intravenous PK assay: animals were fasted and blood samples were collected by intravenous injection of 0.3. mu.g/kg Exenatide at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma was collected and snap frozen.
To avoid hypoglycemia in the animals, 1g/kg glucose was administered prior to administration.
The ELISA detection method comprises the following steps: coating with mouse monoclonal antibody of anti-target polypeptide, blocking with 1% BSA, adding blood sample or standard substance diluted with 0.1% BSA for incubation, capturing rabbit polyclonal antibody of anti-target polypeptide labeled by Biotin, incubating with HRP-conjugated streptavidin, finally developing TMB, terminating HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the plasma according to the standard curve obtained by the standard substance.
The AUC was calculated from the PK profile, and the bioavailability for small intestine dosing was calculated as 100% bioavailability for intravenous (iv).
The PK data for beagle dogs showed that the AUC for Exenatide at 0.3. mu.g/kg was about 0.82ng/ml. hour for intravenous injection and about 1.37ng/ml. hour for 0.7mg of oral Exenatide/test 1 drug composition. The bioavailability of the oral Exenatide/test 1 pharmaceutical composition is about 0.76%. The test results are shown in Table 3.
TABLE 3
Exenatide cannot successfully enter blood without the assistance of the pharmaceutical composition, and the blood entering efficiency is remarkably improved after the pharmaceutical composition is added. Although the blood entry efficiency of Exenatide increased slightly with increasing weight of the test 1 pharmaceutical composition, the magnitude of the increase was limited (table 4 below). The capsule No. 3 is suitable in quantity by combining the consideration of two aspects of oral convenience and drug effectiveness.
TABLE 4
Test 4 Exenatide/test 1 pharmaceutical composition can obviously inhibit the postprandial blood glucose increase of Alloxan beagle dogs
Mixing Exenatide 0.7mg and test 1 pharmaceutical composition 200mg, lyophilizing, and making into No. 3 enteric-coated capsule;
test animals: adult male beagle dogs;
animal physical examination and adaptation: collecting animal fasting blood sample to detect blood biochemical index, after determining that all the blood biochemical indexes are normal, placing the animal in a quieter room to adapt for 1 week, and requiring that the feeding time and the feeding amount are consistent every day;
data acquisition before modeling: blood samples were collected at 2 time points (before and after feeding for 6 hours) every day for 5 days;
and (3) molding test: in a fasting state, 60mg/kg of Alloxan solution is injected into the vein, and blood samples are collected at 2 time points (before feeding and 6 hours after feeding) every day for 5 days continuously after one week; and judging whether the model is qualified or not according to the acquired data. If the test is qualified, starting the drug effect test;
and (3) pharmacodynamic test: the test capsules were swallowed before feeding and blood samples were collected at 2 time points (before feeding, 6h after feeding).
The results show that the Exenatide/test 1 pharmaceutical composition can obviously inhibit the postprandial blood glucose increase on Alloxan-modeled beagle dogs. The test results are shown in Table 5.
TABLE 5
Experimental example 5 the pharmaceutical composition for promoting absorption in small intestine of the present invention can significantly improve the bioavailability of thymalfasin administered in small intestine
The pharmaceutical composition for promoting small intestine absorption: the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is as follows: 20: 6.5: 68.
mixing thymalfasin with the pharmaceutical composition according to the weight ratio of 1:12.5, and keeping the mixture for later use;
test animals: adult male SD rats;
small intestine PK assay: on an adult SD rat in a fasting state, the thymalfasin is administrated through a small intestine catheter according to the administration volume of 1ml/kg, the dose of the thymalfasin is 200 mug/kg, the thymalfasin is divided into another group, the thymalfasin of the pharmaceutical composition for promoting intestinal absorption is added into the small intestine catheter (ei), the blood is collected at the tail part after 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after administration, the blood sample is anticoagulated by 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma is collected and quickly frozen.
Intravenous PK assay: animals were fasted, injected intravenously with 1. mu.g/kg of Abarotide, and blood samples were collected at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma was collected and snap frozen.
The ELISA detection method comprises the steps of coating a mouse monoclonal antibody resisting target polypeptide, blocking by 1% BSA, adding a blood sample or a standard substance diluted by 0.1% BSA for incubation, capturing rabbit polyclonal antibody resisting the target polypeptide marked by Biotin, incubating streptavidin coupled with HRP, finally developing TMB, stopping HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the plasma according to the standard curve obtained by the standard substance.
The AUC was calculated from the PK profile, and the bioavailability for small intestine dosing was calculated as 100% bioavailability for intravenous (iv).
The results show that thymalfasin was injected in the small intestine at 200. mu.g/kg, and the blood level was below the lower limit of ELISA detection. After the pharmaceutical composition for promoting small intestine absorption is added, the bioavailability of thymalfasin administered in small intestine can reach 0.59%.
Claims (9)
1. A pharmaceutical composition characterized in that it comprises: thymalfasin or thymopentin and a drug composition for promoting small intestine absorption, wherein the drug composition for promoting small intestine absorption is composed of sodium dodecyl sulfate, chitosan and sodium citrate.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for oral administration.
3. A pharmaceutical composition according to claim 1 or 2 for use in ensuring the absorption of thymalfasin or thymopentin in the small intestine.
4. A pharmaceutical composition according to claim 1 or 2 for promoting absorption of thymalfasin or thymopentin in the small intestine.
5. A pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of sodium lauryl sulfate, chitosan, sodium citrate is 15-25: 5-8: 50-80.
6. A pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of thymalfasin or thymopentin to the intestinal absorption-promoting pharmaceutical composition is: 1:5-860.
7. An oral formulation characterized by: the oral preparation is prepared from thymalfasin or thymopentin, sodium dodecyl sulfate, chitosan, and sodium citrate.
8. The oral preparation of claim 7, wherein the weight ratio of sodium lauryl sulfate, chitosan and sodium citrate is 15-25: 5-8: 50-80.
9. The oral dosage form of claim 7, wherein the weight ratio of thymalfasin or thymopentin to the intestinal absorption-promoting pharmaceutical composition is: 1:5-860.
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Citations (4)
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| CN101683519A (en) * | 2008-08-25 | 2010-03-31 | 海南中和多肽药物研发有限公司 | Composition of thymic peptide alpha 1 and thymopeptide-5 and preparation method thereof |
| CN103977407A (en) * | 2014-05-29 | 2014-08-13 | 深圳市健元医药科技有限公司 | Oral nanoparticle polypeptide composition tablets and preparation method thereof |
| CN105288583A (en) * | 2015-11-13 | 2016-02-03 | 海南森瑞谱生命科学药业股份有限公司 | Oral thymopentin preparation and preparation method thereof |
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- 2019-12-14 CN CN201911287463.XA patent/CN113058039A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108246A (en) * | 2006-07-20 | 2008-01-23 | 成都地奥九泓制药厂 | Thymus gland pentapeptide oral intestine-dissolved formulated product and method of preparing the same and use thereof |
| CN101683519A (en) * | 2008-08-25 | 2010-03-31 | 海南中和多肽药物研发有限公司 | Composition of thymic peptide alpha 1 and thymopeptide-5 and preparation method thereof |
| CN103977407A (en) * | 2014-05-29 | 2014-08-13 | 深圳市健元医药科技有限公司 | Oral nanoparticle polypeptide composition tablets and preparation method thereof |
| CN105288583A (en) * | 2015-11-13 | 2016-02-03 | 海南森瑞谱生命科学药业股份有限公司 | Oral thymopentin preparation and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| 刘利等: "胰岛素口服给药途径的研究进展", 《现代食品与药品杂志》 * |
| 金朝辉等: "口服吸收促进剂研究进展概述", 《华西医学》 * |
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Application publication date: 20210702 |