CN112138141A - Oral pharmaceutical composition of somatostatin or analogue thereof - Google Patents
Oral pharmaceutical composition of somatostatin or analogue thereof Download PDFInfo
- Publication number
- CN112138141A CN112138141A CN201910498794.1A CN201910498794A CN112138141A CN 112138141 A CN112138141 A CN 112138141A CN 201910498794 A CN201910498794 A CN 201910498794A CN 112138141 A CN112138141 A CN 112138141A
- Authority
- CN
- China
- Prior art keywords
- somatostatin
- pharmaceutical composition
- small intestine
- absorption
- promoting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000012113 quantitative test Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
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Abstract
The invention belongs to the field of biological medicine, and particularly relates to an oral pharmaceutical composition of somatostatin or an analogue thereof, which comprises the following components in percentage by weight: somatostatin and/or somatostatin analogue, 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 medicinal composition for promoting the absorption of the small intestine has the function of preparing a composite auxiliary material, and the auxiliary material and the somatostatin and/or the somatostatin analogue can improve the absorption of the effective components in the small intestine and the like after being combined.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an oral pharmaceutical composition of somatostatin or an analogue thereof.
Background
Somatostatin (somatostatin, growth hormone release-inhibition hormone, GHRIH, or somatotatin) is a tetradecapeptide cleaved from a macromolecular peptide of 116 amino acids, which has a cyclic structure, with a disulfide bond between the 3 rd and 14 th cysteines; somatostatin is a neurohormone with a wide range of actions, and has the main effects of inhibiting the basal secretion of pituitary Growth Hormone (GH) and inhibiting GH secretion response of adenohypophysis caused by various stimuli, including exercise, meal, stress, hypoglycemia and the like. In addition, somatostatin inhibits secretion of LH, FSH, TSH, PRL and ACTH. Somatostatin acts by reducing intracellular cAMP and Ca2 upon binding to membrane receptors of adenohypophysial somatotropin cells. Somatostatin is found in a wide range of tissues other than the hypothalamus, such as the cerebral cortex, striatum, amygdala, hippocampus, and spinal cord, sympathetic nerves, gastrointestinal tract, pancreatic islets, kidney, thyroid and parathyroid glands. The GHRIH28 consisting of 28 amino acids is purified from brain and stomach and intestine and is formed by extending the end of GHRIH14N outwards. The extrapituitary action of somatostatin is complex and it may act as a transmitter or modulator in the nervous system; somatostatin has certain inhibition effect on gastrointestinal motility and secretion of digestive tract hormone; it also inhibits the secretion of insulin, glucagon, renin, parathyroid hormone and calcitonin.
Somatostatin and its analogs cannot be taken orally, which causes poor patient compliance, and therefore, it is of great significance to change the administration route 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 provided by the invention can be prepared into a composite auxiliary material, and after the auxiliary material is combined with somatostatin and/or somatostatin analogues, the effects of improving the absorption of the effective components in the small intestine and the like can be realized.
The invention is realized by the following technical scheme.
A pharmaceutical composition comprising: the somatostatin and/or somatostatin analogue and the medicine composition for promoting small intestine absorption are prepared, wherein the medicine composition for promoting small intestine absorption consists of sodium dodecyl sulfate, carbomer, chitosan and sodium citrate.
The pharmaceutical composition is prepared into an oral preparation.
Somatostatin analogs include: octreotide.
The medicinal composition for promoting the small intestine absorption is used for ensuring the somatostatin and/or somatostatin analogue to be absorbed in the small intestine.
The medicinal composition for promoting the small intestine absorption is used for promoting the absorption of the somatostatin and/or the somatostatin analogue 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 somatostatin and/or the somatostatin analogue to the pharmaceutical composition for promoting intestinal absorption is as follows: 1:5-860.
An oral preparation is prepared from somatostatin and/or its analog, sodium laurylsulfate, 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 somatostatin and/or the somatostatin analogue 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.
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.
Experimental example 5 the pharmaceutical composition of the present invention can significantly improve the bioavailability of Octreotide (Octreotide) administered in 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: 21: 7: 6: 69.
mixing octreotide and the pharmaceutical composition of the invention 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 administration is carried out through a small intestine catheter according to the administration volume of 1ml/kg, so that the dosage of octreotide is 200 mug/kg, the octreotide is divided into another group, 200 mug/kg of the octreotide 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, centrifugation is carried out for 5min at 4 ℃ and 3000rpm, and plasma is collected and quickly frozen.
Intravenous PK assay: animals were fasted, 1 μ g/kg octreotide was injected intravenously, 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 octreotide is administered at 200. mu.g/kg via the small intestine, the blood concentration is lower than the lower detection limit of ELISA. After the pharmaceutical composition is added, the bioavailability of the small intestine administration can reach 1.71%.
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.
fully and uniformly mixing somatostatin-14 and the pharmaceutical composition 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 is carried out through a small intestine catheter according to the administration volume of 1ml/kg, so that the dose of somatostatin-14 is 200 mug/kg, the other group is divided, 200 mug/kg of somatostatin-14 or the somatostatin-14 added with the pharmaceutical composition for promoting the absorption of the small intestine is injected into the small intestine catheter (ei) (200 mug/kg of somatostatin-14), 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, the centrifugation is carried out for 5min at 4 ℃ and 3000rpm, and plasma is collected and quickly frozen.
Intravenous PK assay: animals are in fasted state, injected with 1 mug/kg somatostatin-14 intravenously, and blood samples are collected at 5, 15, 30, 60, 90 and 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 somatostatin-14 is injected via small intestine at 200. mu.g/kg, and the blood concentration is lower than the lower detection limit of ELISA. After the medicinal composition for promoting the small intestine to absorb is added, the bioavailability of the somatostatin-14 administered in the small intestine can reach 0.70 percent.
Experiment 7 the pharmaceutical composition for promoting intestinal absorption of the invention can significantly improve the bioavailability of somatostatin-28
The invention discloses a medicinal 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: 3: 1: 1: 10.
fully and uniformly mixing somatostatin-28 and the pharmaceutical composition for promoting small intestine absorption 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 is carried out through a small intestine catheter according to the administration volume of 1ml/kg, so that the dose of somatostatin-28 is 200 mug/kg, the somatostatin-28 is divided into another group, the small intestine catheter is injected (ei) with 200 mug/kg of somatostatin-28 or the somatostatin-28 added with the pharmaceutical composition for promoting the absorption of the small intestine is injected for 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after the administration, the tail part is blood-collected, the blood sample is anticoagulated by 10mM EDTA, centrifuged for 5min at 4 ℃ and 3000rpm, and plasma is collected for quick freezing.
Intravenous PK assay: animals are in fasted state, injected with 1 microgram/kg somatostatin-28 intravenously, and blood samples are collected at 5, 15, 30, 60, 90 and 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 somatostatin-28 was injected via small intestine at 200. mu.g/kg and the blood concentration was below the lower limit of ELISA detection. After the medicinal composition for promoting the small intestine to absorb is added, the bioavailability of the somatostatin-28 administered in the small intestine can reach 0.40 percent.
Claims (10)
1. A pharmaceutical composition characterized in that it comprises: the somatostatin and/or somatostatin analogue and the medicine composition for promoting small intestine absorption are prepared, wherein the medicine composition for promoting small intestine absorption consists 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, wherein the somatostatin analogue comprises: octreotide.
4. A pharmaceutical composition according to any one of claims 1-3 for use in ensuring the absorption of somatostatin and/or somatostatin analogues in the small intestine.
5. A pharmaceutical composition according to any one of claims 1-3 for use in promoting absorption of somatostatin and/or somatostatin analogues in the small intestine.
6. A pharmaceutical composition according to any one of claims 1 to 3, wherein the weight ratio of sodium lauryl sulfate, carbomer, chitosan, sodium citrate is from 15 to 25: 5-8: 5-8: 50-80.
7. A pharmaceutical composition according to any one of claims 1 to 3 wherein the weight ratio of somatostatin and/or somatostatin analogue to the intestinal absorption-promoting pharmaceutical composition is: 1:5-860.
8. An oral formulation characterized by: the oral preparation is prepared from somatostatin and/or somatostatin analogue, sodium dodecyl sulfate, carbomer, chitosan and sodium citrate.
9. An oral formulation according to claim 8, wherein the weight ratio of sodium lauryl sulfate, carbomer, chitosan, sodium citrate is from 15 to 25: 5-8: 5-8: 50-80.
10. An oral formulation according to claim 8, wherein the weight ratio of somatostatin and/or somatostatin analogue to the intestinal absorption-promoting pharmaceutical composition is: 1:5-860.
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| 刘利等: "胰岛素口服给药途径的研究进展", 《现代食品与食品杂志》 * |
| 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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