CN112138167A - Oral pharmaceutical composition of teriparatide or abamectin - Google Patents
Oral pharmaceutical composition of teriparatide or abamectin Download PDFInfo
- Publication number
- CN112138167A CN112138167A CN201910498364.XA CN201910498364A CN112138167A CN 112138167 A CN112138167 A CN 112138167A CN 201910498364 A CN201910498364 A CN 201910498364A CN 112138167 A CN112138167 A CN 112138167A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- small intestine
- teriparatide
- absorption
- promoting
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Abstract
The invention belongs to the field of biological medicine, and particularly relates to an oral pharmaceutical composition of teriparatide or abamectin, which comprises the following components in percentage by weight: teriparatide or Abaprotide, and a pharmaceutical composition for promoting small intestine absorption, wherein the pharmaceutical composition for promoting small intestine absorption comprises sodium dodecyl sulfate, carbomer, chitosan, and sodium citrate; the pharmaceutical composition for promoting small intestine absorption provided by the invention can be prepared into a composite auxiliary material, and the auxiliary material and the teriparatide or the abamectin composition can improve the absorption of the effective components in the small intestine.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an oral pharmaceutical composition of teriparatide or abamectin.
Background
Teriparatide is a synthetic polypeptide hormone, a 1-34 amino acid fragment of human parathyroid hormone PTH, which is the biologically active N-terminal region of the endogenous parathyroid hormone PTH containing 84 amino acids. The immunological and biological characteristics of the medicine are completely the same as those of endogenous parathyroid hormone PTH and bovine parathyroid hormone PTH (bPTH). Teriparatide stimulates bone formation and resorption, reduces the incidence of fractures in postmenopausal women, and increases or decreases bone density depending on the mode of administration. Continuous infusion results in a sustained increase in parathyroid hormone PTH concentration and therefore greater bone resorption than daily injections which cause only a transient increase in serum parathyroid hormone PTH. In addition, teriparatide does not inhibit platelet aggregation response of either the adenosine diphosphate-induced pathway or the collagen-induced pathway.
Abarotide was originally developed by Ipsen pharmaceutical, France, and was licensed to the U.S. Radius Health biopharmaceutical company for marketing and sale in the United states. The Abarotide is a polypeptide artificially synthesized with 34 amino acids, is an analogue of parathyroid hormone-related protein, regulates metabolism and promotes bone formation by selectively activating a signal pathway of parathyroid hormone type 1 receptors, and is used for treating postmenopausal women at risk of osteoporosis. And the product is approved by the Food and Drug Administration (FDA) to be marketed in 2017, 4 and 28 months, and has the trade name of Tymlos.
Neither teriparatide nor abamectin is orally available, which results in poor patient compliance, and thus, it is of great importance to alter the route of administration of somatostatin and its analogs.
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, carbomer, chitosan and sodium citrate, and the researches show that the medicine composition for promoting small intestine absorption can be prepared into a composite auxiliary material, and the auxiliary material and the teriparatide or the abamectin composition can improve the absorption and other effects of the effective components in the small intestine.
The invention is realized by the following technical scheme.
A pharmaceutical composition comprising: the composition is prepared from teriparatide or abalopeptide and a pharmaceutical composition for promoting small intestine absorption, wherein the pharmaceutical composition for promoting small intestine absorption is composed of sodium dodecyl sulfate, carbomer, chitosan and sodium citrate.
The pharmaceutical composition is prepared into an oral preparation.
The medicinal composition for promoting the small intestine absorption is used for ensuring the absorption of teriparatide or abamectin in the small intestine.
The pharmaceutical composition for promoting the small intestine absorption is used for promoting the absorption of teriparatide or abamectin in the small intestine.
Wherein the weight ratio of the sodium dodecyl sulfate to the carbomer to the chitosan to the sodium citrate is 15-25: 5-8: 5-8: 50-80.
Wherein the weight ratio of the teriparatide or the abamectin to the pharmaceutical composition for promoting the intestinal absorption is as follows: 1:5-860.
An oral preparation is prepared from teriparatide or abamectin, sodium dodecyl sulfate, carbomer, chitosan and sodium citrate.
Wherein the weight ratio of the sodium dodecyl sulfate to the carbomer to the chitosan to the sodium citrate is 15-25: 5-8: 5-8: 50-80.
Wherein the weight ratio of the teriparatide or the abamectin to the pharmaceutical composition for promoting the 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.
Drawings
1. FIG. 1 is a PD test of Exenatide in STZ rats
Wherein: the abscissa is time (h) and the ordinate is blood glucose lowering efficiency (%).
Wherein: the solid circular solid line indicates 2ml/kg of physiological saline for intestinal injection, the solid square dotted line indicates 1 μ g/kg of subcutaneous Exenatide, the solid circular dotted line indicates 250 μ g/kg of subcutaneous Exenatide, the solid triangular dotted line indicates 1mg/kg of subcutaneous Exenatide, the hollow triangular solid line indicates the pharmaceutical composition for intestinal administration test 1 + Exenatide (dose of Exenatide 30 μ g/kg), the hollow circular solid line indicates the pharmaceutical composition for intestinal administration test 1 + Exenatide (dose of Exenatide 40 μ g/kg), the hollow square solid line indicates the pharmaceutical composition for intestinal administration test 1 + Exenatide (dose of Exenatide50 μ g/kg), and the hollow diamond solid line indicates the pharmaceutical composition for intestinal administration test 1 + Exenatide (dose of Exenatide60 μ g/kg).
2. FIG. 2 is an iv PK assay of Exenatide in rats
Wherein: the abscissa is time (min) and the ordinate is the concentration of Exenatide (ng/ml) in rat plasma.
3. FIG. 3 is the ei PK test of Exenatide/test 1 pharmaceutical composition on rats
Wherein: the abscissa is time (min) and the ordinate is the concentration of Exenatide (ng/ml) in rat plasma.
4. FIG. 4 is an iv PK assay for Exenatide on beagle dogs
Wherein: the abscissa is time (min) and the ordinate is the concentration of Exenatide (ng/ml) in plasma of beagle dogs.
5. FIG. 5 is a po PK test on beagle dogs for Exenatide/test 1 pharmaceutical compositions
Wherein: the abscissa is time (min) and the ordinate is the concentration of Exenatide (ng/ml) in plasma of beagle dogs.
6. FIG. 6 is a PD test of Exenatide on Alloxan beagle dogs
Wherein: the abscissa is time (h) and the ordinate is beagle blood glucose (mM).
Wherein: the solid circular solid line is the postprandial blood glucose profile of Alloxan beagle dogs, the solid square solid line is the postprandial blood glucose profile of Alloxan beagle dogs swallowed Exenatide/test 1 pharmaceutical composition, and the solid diamond solid line is the postprandial serum profile of normal beagle dogs.
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.
The pharmaceutical composition for promoting the absorption of the small intestine comprises: sodium dodecyl sulfate, carbomer, chitosan and sodium citrate in a weight ratio of: 20: 6.5: 6.5: 65.
mixing Exenatide and the pharmaceutical composition according to the weight ratio of 1:5 fully and uniformly 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, 3h, 6h and 9h for testing of blood glucose, administered subcutaneously (sc) or via small intestine catheter (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 figure 1.
Mixing Exenatide and the medicinal composition for promoting small intestine absorption of the test 1 according to the weight ratio of 1: 5;
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, the Exenatide is injected (ei) by the small intestine catheter for 200 mug/kg or the Exenatide added with the pharmaceutical composition of the invention, the blood is collected at the tail part after 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after the administration, the blood sample is anticoagulated by 10mM EDTA, the blood sample is centrifuged at 3000rpm at 4 ℃ for 5min, and the plasma is collected and quickly 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 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 1.47ng/ml. h, the bioavailability of intestinal administration was about 0.79%. The test results are shown in fig. 2 and 3.
Mixing Exenatide 0.7mg and test 1 small intestine absorption promoting pharmaceutical composition 200mg, lyophilizing, and making into No. 3 enteric capsule;
mixing Exenatide 0.7mg and test 1 small intestine absorption promoting pharmaceutical composition 400mg, lyophilizing, and making into No. 0 enteric capsule;
mixing Exenatide 0.7mg and test 1 intestinal absorption promoting pharmaceutical composition 600mg, lyophilizing, and making into No. 00 enteric-coated capsule;
mixing Exenatide 0.7mg and test 1 small intestine absorption promoting 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. See fig. 4 and 5.
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 1.36ng/ml. hour for 0.7mg of oral Exenatide/test 1 drug composition. The bioavailability of the oral Exenatide/test 1 pharmaceutical composition is about 0.83%.
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 increases slightly with the increase in the weight of the test 1 pharmaceutical composition, the magnitude of the increase is limited. The capsule No. 3 is suitable in quantity by combining the consideration of two aspects of oral convenience and drug effectiveness.
Table 1 Exenatide/test 1 po PD test of intestinal absorption-promoting pharmaceutical composition on beagle dogs
Mixing Exenatide 0.7mg and test 1 small intestine absorption promoting pharmaceutical composition 200mg, lyophilizing, and making into No. 3 enteric 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 4 time points (2 h, 4h, 6h before and after feeding) every day for 5 days;
and (3) molding test: injecting 60mg/kg Alloxan solution into vein in fasting state, collecting blood samples at 4 time points (2 h, 4h and 6h before and after feeding) every day after one week, and continuously collecting for 5 days; 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 4 time points (2 h, 4h, 6h before and after feeding).
The results show that the Exenatide/test 1 intestinal absorption-promoting pharmaceutical composition can obviously inhibit the postprandial blood glucose increase on Alloxan modeled beagle dogs. See fig. 6.
And (4) test conclusion: the tests show that the medicinal composition for promoting the absorption of the small intestine has good effect of promoting the absorption of the effective components which can not be orally taken in the intestine, and can be used as a novel medicinal auxiliary material.
Test example 5 the pharmaceutical composition of the present invention can significantly improve the bioavailability of teriparatide (teriparatide) administered to the small intestine
The pharmaceutical composition of the invention comprises: the weight ratio of the sodium dodecyl sulfate to the carbomer to the chitosan to the sodium citrate is as follows: 20: 6.5: 6.5: 65.
mixing teriparatide and the pharmaceutical composition of the invention according to the weight ratio of 1: 5;
test animals: adult male SD rats;
small intestine PK assay: on an adult SD rat in a fasting state, the injection is carried out by a small intestine catheter according to the administration volume of 1ml/kg, so that the teriparatide dosage is 200 mug/kg, the teriparatide is divided into another group, 200 mug/kg of the teriparatide of the pharmaceutical composition is added in small intestine catheter injection (ei), 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after the administration, tail blood collection is carried out, blood samples are anticoagulated by 10mM EDTA, and are centrifuged at 4 ℃ and 3000rpm for 5min, and plasma is collected.
Intravenous PK assay: animals were fasted and injected intravenously with 1. mu.g/kg teriparatide, 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 teriparatide is administered at 200. mu.g/kg via the small intestine and that the blood concentration is below the lower limit of ELISA detection. After the pharmaceutical composition is added, the bioavailability of the small intestine administration can reach 2.08%.
The pharmaceutical composition for promoting small intestine absorption: the weight ratio of the sodium dodecyl sulfate to the carbomer to the chitosan to the sodium citrate is as follows: 20: 6.5: 6.5: 68.
the abacavir peptide and the pharmaceutical composition are fully and uniformly mixed according to the weight ratio of 1:5 for later use;
test animals: adult male SD rats;
small intestine PK assay: on an adult SD rat in a fasting state, the administration volume of 1ml/kg is administered through a small intestine catheter, so that the dosage of the abalones peptide is 200 mug/kg, the abalones peptide (200 mug/kg) of the pharmaceutical composition for promoting the intestinal absorption is added into the rat in a small intestine catheter injection (ei) in another group, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after the administration, tail blood is collected, blood samples are anticoagulated by 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma is collected and 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 when the abacavir peptide is injected into the small intestine at 200 mug/kg, the blood concentration is lower than the lower detection limit of ELISA. After the medicinal composition for promoting the small intestine to absorb the abamectin is added, the bioavailability of the abamectin for small intestine administration can reach 1.66%.
Claims (9)
1. A pharmaceutical composition characterized in that it comprises: the composition is prepared from teriparatide or abalopeptide and a pharmaceutical composition for promoting small intestine absorption, wherein the pharmaceutical composition for promoting small intestine absorption is composed of sodium dodecyl sulfate, carbomer, 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 teriparatide or abamectin in the small intestine.
4. A pharmaceutical composition according to claim 1 or 2 for promoting the absorption of teriparatide or abamectin in the small intestine.
5. A pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of sodium lauryl sulfate, carbomer, chitosan, sodium citrate is 15-25: 5-8: 5-8: 50-80.
6. A pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of teriparatide or abamectin to the pharmaceutical composition for promoting intestinal absorption is: 1:5-860.
7. An oral formulation characterized by: the oral preparation is prepared from teriparatide or abamectin, sodium dodecyl sulfate, carbomer, chitosan and sodium citrate.
8. An oral formulation according to claim 7, wherein the weight ratio of sodium lauryl sulphate, carbomer, chitosan, sodium citrate is from 15 to 25: 5-8: 5-8: 50-80.
9. An oral formulation according to claim 7, wherein the weight ratio of teriparatide or abamectin to the pharmaceutical composition for promoting intestinal absorption is: 1:5-860.
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| CN116211827A (en) * | 2023-03-17 | 2023-06-06 | 浙江大学 | Teriparatide solid lipid nanoparticle and preparation method and application thereof |
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| WO2012130193A1 (en) * | 2011-03-31 | 2012-10-04 | Zentiva, K.S. | Non-covalent soluble complexes of teriparatide with polysaccharides and a dosage form of teriparatide for oral administration |
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| WO2012130193A1 (en) * | 2011-03-31 | 2012-10-04 | Zentiva, K.S. | Non-covalent soluble complexes of teriparatide with polysaccharides and a dosage form of teriparatide for oral administration |
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| 金朝辉等: "口服吸收促进剂研究进展概述", 《华西医学》, vol. 23, no. 4, 31 December 2008 (2008-12-31), pages 940 - 942 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116211827A (en) * | 2023-03-17 | 2023-06-06 | 浙江大学 | Teriparatide solid lipid nanoparticle and preparation method and application thereof |
| CN116211827B (en) * | 2023-03-17 | 2024-04-05 | 浙江大学 | Teriparatide solid lipid nanoparticle and preparation method and application thereof |
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