CN112138148B - Oral pharmaceutical composition of growth hormone or analogue thereof - Google Patents
Oral pharmaceutical composition of growth hormone or analogue thereof Download PDFInfo
- Publication number
- CN112138148B CN112138148B CN201910498350.8A CN201910498350A CN112138148B CN 112138148 B CN112138148 B CN 112138148B CN 201910498350 A CN201910498350 A CN 201910498350A CN 112138148 B CN112138148 B CN 112138148B
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- pharmaceutical composition
- small intestine
- growth hormone
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- absorption
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- 102000018997 Growth Hormone Human genes 0.000 title claims abstract description 41
- 108010051696 Growth Hormone Proteins 0.000 title claims abstract description 41
- 239000000122 growth hormone Substances 0.000 title claims abstract description 41
- 239000008203 oral pharmaceutical composition Substances 0.000 title abstract description 4
- 210000000813 small intestine Anatomy 0.000 claims abstract description 84
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 71
- 230000001737 promoting effect Effects 0.000 claims abstract description 45
- 238000010521 absorption reaction Methods 0.000 claims abstract description 36
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229920001661 Chitosan Polymers 0.000 claims abstract description 14
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 14
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 14
- 229960001631 carbomer Drugs 0.000 claims abstract description 14
- 229940045110 chitosan Drugs 0.000 claims abstract description 14
- 239000001509 sodium citrate Substances 0.000 claims abstract description 14
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims abstract description 14
- 229960001790 sodium citrate Drugs 0.000 claims abstract description 11
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Inorganic Chemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Zoology (AREA)
- Hospice & Palliative Care (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Psychiatry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of biological medicine, and in particular relates to an oral pharmaceutical composition of growth hormone or analogues thereof, which comprises the following components: the preparation method comprises the steps of preparing a growth hormone and/or a growth hormone analogue and a small intestine absorption promoting pharmaceutical composition, wherein the small intestine absorption promoting pharmaceutical composition consists of sodium dodecyl sulfate, carbomer, chitosan and sodium citrate; the pharmaceutical composition for promoting the absorption of the small intestine is prepared into a composite auxiliary material, and the auxiliary material and the growth hormone and/or the growth hormone analogue composition can improve the absorption of the active ingredient in the small intestine and the like.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an oral pharmaceutical composition of growth hormone or an analogue thereof.
Background
Recombinant human growth hormone is produced by recombinant DNA technology and its effects include: regulating endocrine system to restore to near pubertal level, balancing emotion fluctuation, and promoting breast development, increasing lifting, increasing elasticity and postponing climacteric; improving oocyte quality and ovarian reactivity, and improving endometrial receptivity; can activate and maintain the normal work of immune system, improve immunity and disease resistance, and reduce illness of human body; activating active electrons and oscillating molecules of cells to enable the cells at the bottom layer of the skin to regrow, wherein the active electrons adsorb water molecules to increase the water content of the skin, lighten deep-skin wrinkles, lighten skin color, whiten skin, tender skin and have elasticity, and restore youth skin texture; promoting muscle growth, preventing muscular atrophy, and thus consuming body fat, especially central fat (fat in intestine, liver, abdominal cavity and subcutaneous fat in abdomen, waist) of human body, and restoring arrangement of muscle and fat to adolescence state; is the most effective substance with resuscitation function, supports normal gland function, improves the endocrine index of sexual desire and opens micro-blood vessels; the change of baldness and white hair, the pituitary gland secretes chemical information to revive hair follicle cells, so that nutrients are fully increased, enzymes are increased (white hair causes = reduced enzymes), and the hair follicle which is dying is directly stimulated to resume growth; regulating central nerve, promoting brain cell metabolism, improving memory, improving sleep, and relieving insomnia, mental stress, and anxiety. Has adjuvant therapeutic effect on Alzheimer's disease and senile dementia; promoting regeneration of visceral cells such as heart, liver, kidney and islet, recovering functional activities of liver, kidney and islet, and carrying hepatitis B virus; three yang in size; glutamic pyruvic transaminase is ultrahigh; the blood sugar is ultrahigh; the urinary protein ultra-high liver disease, kidney disease and diabetes have auxiliary curative effects; can promote wound healing, regenerate burned skin, and reduce local edema and scar formation; promoting absorption and storage of calcium by bone cells, and preventing and treating osteoporosis; can strengthen physical strength, enable people to be energetic, and work for a long time without tiredness; can improve spleen qi of people, lead the confidence of people to be quite high, lead the emotion to be high, and lead people to be in a young spirit and face.
Recombinant human growth hormone on the market is an injection, and has the defects of inconvenient use, pain and the like for patients, so that the change of the administration route of the growth hormone and analogues thereof has important significance.
Disclosure of Invention
Based on the reasons, the applicant obtains a novel pharmaceutical composition for promoting small intestine absorption, which consists of sodium dodecyl sulfate, carbomer, chitosan and sodium citrate through a plurality of creative researches, and the research shows that the pharmaceutical composition for promoting small intestine absorption has the effect of preparing a composite auxiliary material, wherein the auxiliary material and the composition of growth hormone and/or growth hormone analogues can improve the absorption of the active ingredient in small intestine.
The invention is realized by the following technical scheme.
A pharmaceutical composition comprising: the growth hormone and/or the growth hormone analogue and the small intestine absorption promoting pharmaceutical composition are prepared, wherein the small intestine absorption promoting pharmaceutical composition consists of sodium dodecyl sulfate, carbomer, chitosan and sodium citrate.
The growth hormone of the invention is recombinant human growth hormone.
The pharmaceutical composition is prepared into an oral preparation.
The growth hormone analogues include: sermorelin, ghrelin-2, ghrelin-6, gonadorelin, growth hormone secretagogues, growth hormone releasing hormone and the like.
The pharmaceutical composition for promoting the absorption of the small intestine is used for guaranteeing the absorption of growth hormone and/or growth hormone analogues in the small intestine.
The pharmaceutical composition for promoting small intestine absorption is used for promoting the absorption of growth hormone and/or growth hormone analogue in 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 growth hormone and/or the growth hormone analogue to the small intestine absorption promoting pharmaceutical composition is as follows: 1:5-860.
An oral preparation is prepared from growth hormone and/or growth hormone analogue, 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 growth hormone and/or the growth hormone analogue to the small intestine absorption promoting pharmaceutical composition is as follows: 1:5-860.
The small intestine absorption promoting pharmaceutical composition of the invention obtains a novel auxiliary material which can be used for: drugs (active ingredients or active ingredients) which cannot be orally administered but can be injected only can be orally administered, thereby changing the administration mode of the drugs (active ingredients or active ingredients).
The small intestine absorption promoting pharmaceutical composition of the present invention can promote the absorption of a drug (active ingredient or active ingredient) which is easily decomposed in the gastrointestinal tract in the intestine.
The small intestine absorption promoting pharmaceutical composition of the present invention can promote the absorption of a drug (active ingredient or active ingredient) which is not easily absorbed in the gastrointestinal tract in the intestine.
Because the pharmaceutical composition for promoting small intestine absorption of the invention promotes the absorption of medicines (active ingredients or active ingredients) in small intestine and requires release in small intestine to exert the efficacy, rodents are administrated by small intestine catheters and mammals are administrated orally by enteric capsules when pharmacodynamic tests and drug substitution tests are carried out.
The invention matches the pharmaceutical composition for promoting intestinal absorption and the medicine (active ingredient or active ingredient) one by one on rodents for bioavailability detection, and simultaneously selects part of polypeptides for detecting the drug effect and pharmacokinetics on different animals.
Drawings
1. FIG. 1 shows PD test of Exenatide on STZ rats
Wherein: the abscissa is time (h), and the ordinate is the blood glucose lowering efficiency (%).
Wherein: the solid circular solid line is 2ml/kg of physiological saline injected into the small intestine, the solid square dashed line is 1 μg/kg of subcutaneous Exenatide, the solid circular dashed line is 250 μg/kg of subcutaneous Exenatide, the solid triangular dashed line is 1mg/kg of subcutaneous Exenatide, the solid triangular solid line is 30 μg/kg of pharmaceutical composition +Exenatide for small intestine administration test 1, the solid hollow circular solid line is 40 μg/kg of pharmaceutical composition +Exenatide for small intestine administration test 1, the solid hollow square line is 50 μg/kg of pharmaceutical composition +Exenatide for small intestine administration test 1, and the solid hollow diamond line is 60 μg/kg of pharmaceutical composition +Exenatide for small intestine administration test 1.
2. FIG. 2 shows the iv PK test of Exenatide on rats
Wherein: the abscissa is time (min) and the ordinate is Exenatide concentration (ng/ml) in rat plasma.
3. FIG. 3 shows the ei PK assay of Exenatide/test 1 pharmaceutical compositions on rats
Wherein: the abscissa is time (min) and the ordinate is Exenatide concentration (ng/ml) in rat plasma.
4. FIG. 4 is an iv PK test of Exenatide on beagle dogs
Wherein: the abscissa is time (min) and the ordinate is Exenatide concentration (ng/ml) in beagle plasma.
5. FIG. 5 is a po PK test of Exenatide/test 1 pharmaceutical compositions on beagle dogs
Wherein: the abscissa is time (min) and the ordinate is Exenatide concentration (ng/ml) in beagle plasma.
6. FIG. 6 is a PD test on an Alloxan beagle by Exenatide
Wherein: the abscissa is time (h) and the ordinate is beagle glucose (mM).
Wherein: solid circular solid lines are postprandial glycemic profiles for Alloxan beagle dogs, solid square solid lines are postprandial glycemic profiles for Alloxan beagle dogs following swallowing of Exenatide/test 1 pharmaceutical composition, and solid diamond solid lines are postprandial serum profiles for normal beagle dogs.
Specific test examples
The following will explain the embodiments of the present invention by way of specific examples, but the scope of the present invention is not limited thereto.
The description of the test examples in this specification is merely an illustration of implementation forms of the inventive concept and the scope of protection of the invention should not be construed as being limited to the specific forms set forth in the test examples, as well as equivalent technical means which can be conceived by those skilled in the art based on the inventive concept. Although the following embodiments of the present invention are described, the present invention is not limited to the specific embodiments and fields of application described above, which are illustrative, instructive, and not limiting. Those skilled in the art, having the benefit of this disclosure, may effect numerous forms of the invention without departing from the scope of the invention as claimed.
The following test is a conclusion test of summarized research and development personnel based on the technical scheme to be protected by the invention on the basis of multiple creative tests. In the following test examples, three repeated experiments were set, and the data are the average value or the average value.+ -. Standard deviation of the three repeated experiments.
Test 1 significantly improves the efficacy of small intestine administered Exenatide (Exendin 4, EXE 4)
The pharmaceutical composition for promoting intestinal absorption comprises the following components: sodium dodecyl sulfate, carbomer, chitosan and sodium citrate in the weight ratio: 20:6.5:6.5:65.
fully and uniformly mixing Exenatide and the medicinal composition according to the weight ratio of 1:5 for later use;
test animals: SD male rats were intraperitoneally injected with 45mg/kg STZ to construct a hyperglycemic model;
small intestine drug efficacy test: blood samples were taken at 0h,3h,6h and 9h for blood glucose testing either subcutaneously (sc) or via small intestine catheter (ei).
The results show that the Exenatide administered into the small intestine has weak hypoglycemic effect under the condition that the pharmaceutical composition is not added, and the hypoglycemic efficiency after 9 hours is only about 70 percent when the dosage reaches 1mg/kg, which is far lower than about 50 percent of the dosage which can reach 1 mug/kg subcutaneously. And after the pharmaceutical composition is added, the subcutaneous blood glucose reducing effect of 1 mug/kg can be achieved by the administration dosage of 50 mug/kg. See fig. 1.
Test 2 significantly improves the bioavailability of Exenatide administered to the small intestine
Fully and uniformly mixing Exenatide and the test 1 small intestine absorption promoting pharmaceutical composition according to the weight ratio of 1:5 for later use;
test animals: adult male SD rats;
small intestine PK assay: on adult SD rats in the fasting state, the administration was carried out through a small intestine catheter at a dose of 200. Mu.g/kg by a dose volume of 1ml/kg, and the other group was injected (ei) with 200. Mu.g/kg of Exenatide or Exenatide added with the pharmaceutical composition of the present invention by a small intestine catheter, 0h,0.5h,1h,1.5h,2h,2.5h and 3h after administration, blood was collected from the tail, blood was anticoagulated with 10mM EDTA, centrifuged at 3000rpm at 4℃for 5min, and plasma quick-freezing was collected.
To avoid hypoglycemia in the animals, 1g/kg of glucose was administered prior to administration.
ELISA detection method: coating with anti-target polypeptide mouse monoclonal antibody, blocking with 1% BSA, adding blood sample or 0.1% BSA diluted standard substance for incubation, capturing Biotin labeled anti-target polypeptide rabbit polyclonal antibody, incubating HRP coupled streptavidine, finally TMB developing, HCl stopping, and reading at 450 nm. And calculating the concentration of the target polypeptide in the blood plasma according to a standard curve obtained by the standard substance.
AUC was calculated from PK profile and bioavailability for small intestine administration was calculated as 100% of bioavailability for intravenous injection (iv).
The results showed that the AUC of the PK profile after iv injection of Exenatide at 1. Mu.g/kg was 0.93ng/ml.h, and that the blood concentration had been below the ELISA lower limit of detection after small intestine injection at 200. Mu.g/kg. Whereas the AUC of the PK profile after addition of the test 1 pharmaceutical composition could reach 1.47ng/ml.h, the bioavailability for small intestine administration was about 0.79%. The test results are shown in fig. 2 and 3.
Test 3 significantly improves the bioavailability of oral Exenatide
Mixing Exenatide 0.7mg and test 1 small intestine absorption promoting pharmaceutical composition 200mg thoroughly, lyophilizing, and making into No. 3 enteric capsule;
mixing Exenatide 0.7mg with test 1 small intestine absorption promoting pharmaceutical composition 400mg, lyophilizing, and making into No. 0 enteric capsule;
mixing Exenatide 0.7mg and test 1 pharmaceutical composition for promoting intestinal absorption 600mg thoroughly, lyophilizing, and making into No. 00 enteric capsule;
mixing Exenatide 0.7mg and test 1 small intestine absorption promoting pharmaceutical composition 200mg thoroughly, lyophilizing, and making into common capsule No. 3;
mixing Exenatide 0.7mg and mannitol 200mg thoroughly, lyophilizing, and making into enteric capsule No. 3;
test animals: adult male beagle dogs
Oral PK assay: blood samples were collected at 0.5,1,1.5,2,2.5,3h after oral administration of the enteric capsule in the fasting state of the animal. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma flash frozen.
Venous PK test: the animals were given a fasting state and blood samples were collected by intravenous injection of 0.3 μg/kg Exenatide at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma flash frozen. See fig. 4 and 5.
To avoid hypoglycemia in the animals, 1g/kg of glucose was administered prior to administration.
ELISA detection method: coating with anti-target polypeptide mouse monoclonal antibody, blocking with 1% BSA, adding blood sample or 0.1% BSA diluted standard substance for incubation, capturing Biotin labeled anti-target polypeptide rabbit polyclonal antibody, incubating HRP coupled streptavidine, finally TMB developing, HCl stopping, and reading at 450 nm. And calculating the concentration of the target polypeptide in the blood plasma according to a standard curve obtained by the standard substance.
AUC was calculated from PK profile and bioavailability for small intestine administration was calculated as 100% of bioavailability for intravenous injection (iv).
The PK data for beagle dogs showed that the AUC for intravenous injection of 0.3 μg/kg Exenatide was about 0.82ng/ml. Hour, and the AUC for oral Exenatide/test 1 pharmaceutical composition 0.7mg was about 1.36ng/ml. Hour. The bioavailability of the oral Exenatide/test 1 pharmaceutical composition was about 0.83%.
Exenatide cannot successfully enter blood without the assistance of the pharmaceutical composition, and blood entering efficiency is remarkably improved after the pharmaceutical composition is added. Although Exenatide blood entry efficiency increased slightly with increasing weight of the test 1 pharmaceutical composition, the magnitude of the increase was limited. The capsule number 3 is suitable for taking the convenience of oral administration and the effectiveness of the medicine into consideration.
Table 1 Exenatide/test 1 po PD test of pharmaceutical compositions for promoting intestinal absorption on beagle dogs
Test 4 Exenatide/test 1 intestinal absorption promoting pharmaceutical composition can obviously inhibit the postprandial blood glucose increase of Alloxan beagle
Mixing Exenatide 0.7mg and test 1 small intestine absorption promoting pharmaceutical composition 200mg thoroughly, lyophilizing, and making into No. 3 enteric capsule;
test animals: adult male beagle dogs;
physical examination and adaptation of animals: collecting an animal fasting blood sample, detecting blood biochemical indexes, and after determining that all the indexes are normal, placing the animal in a quieter room for 1 week, wherein the daily feeding time and the feeding amount are required to be consistent;
data acquisition before molding: blood samples were collected at 4 time points per day (2 h, 4h, 6h before feeding, after feeding) for 5 days continuously;
and (3) molding test: in a fasting state, 60mg/kg of Alloxan solution is injected intravenously, blood samples are collected at 4 time points (2 h, 4h and 6h before feeding and after feeding) every day after one week, and continuous collection is carried out for 5 days; and judging whether the model is qualified or not according to the acquired data. If the test is qualified, starting a drug effect test;
efficacy test: the test capsules were swallowed before feeding and blood samples were taken at 4 time points (2 h, 4h, 6h before feeding, after feeding).
The results show that Exenatide/test 1 intestinal absorption-promoting pharmaceutical composition can significantly inhibit postprandial blood glucose elevation in Alloxan-molded beagle dogs. See fig. 6.
Conclusion of the test: the test shows that the medicine composition for promoting the intestinal absorption has good effect of promoting the absorption of the effective components which cannot be orally taken in the intestines, 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 small intestine-administered growth hormone (rhGH)
The medicine composition comprises the following components: the weight ratio of the sodium dodecyl sulfate, carbomer, chitosan and sodium citrate is as follows: 20:6.5:6.5:65.
fully and uniformly mixing the growth hormone 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 adult SD rats in the fasting state, a dose of 200. Mu.g/kg of growth hormone was administered via a small intestine catheter at a dose of 1ml/kg, and 200. Mu.g/kg of growth hormone was added to the pharmaceutical composition of the present invention by small intestine catheter injection (ei) in groups of small intestine catheters, 0h,0.5h,1h,1.5h,2h,2.5h and 3h after administration, tail blood sampling, anticoagulation of blood samples by 10mM EDTA, centrifugation at 3000rpm for 5min at 4℃and plasma quick freezing were collected.
Venous PK test: the animals were given a fasting state and blood samples were collected by intravenous injection of 1 μg/kg growth hormone at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma flash frozen.
ELISA detection method comprises coating with mouse monoclonal antibody against target polypeptide, blocking with 1% BSA, adding blood sample or 0.1% BSA diluted standard substance for incubation, capturing rabbit polyclonal antibody against target polypeptide labeled by Biotin, incubating HRP coupled strepavidin, and finally TMB developing, terminating with HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the blood plasma according to a standard curve obtained by the standard substance.
AUC was calculated from PK profile and bioavailability for small intestine administration was calculated as 100% of bioavailability for intravenous injection (iv).
The results showed that the growth hormone was administered at 200. Mu.g/kg via the small intestine and the blood concentration was below the ELISA lower limit of detection. And after the pharmaceutical composition is added, the bioavailability of the small intestine administration can reach 0.32 percent.
Experiment 6 the pharmaceutical composition for promoting intestinal absorption of the present invention can significantly improve the bioavailability of ghrelin-2 administered into the small intestine
Pharmaceutical composition for promoting intestinal absorption: the weight ratio of the sodium dodecyl sulfate, carbomer, chitosan and sodium citrate is as follows: 20:6.5:6.5:68.
fully and uniformly mixing the growth hormone releasing peptide-2 with 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 adult SD rats in the fasting state, the administration was performed through a small intestine catheter at a dose of 1ml/kg, so that the ghrelin-2 dose was 200. Mu.g/kg, and the other group was subjected to small intestine catheter injection (ei) of 200. Mu.g/kg of ghrelin-2 or to addition of ghrelin-2 (ghrelin-2 of 200. Mu.g/kg) of the small intestine absorption-promoting pharmaceutical composition of the present invention, 0h,0.5h,1h,1.5h,2h,2.5h and 3h after administration, tail blood collection, anticoagulation of blood samples by 10mM EDTA, centrifugation at 3000rpm for 5min at 4℃and plasma quick-freezing were collected.
Venous PK test: the animals were given a fasting state and blood samples were collected by intravenous injection of 1 μg/kg ghrelin-2 at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma flash frozen.
ELISA detection method comprises coating with mouse monoclonal antibody against target polypeptide, blocking with 1% BSA, adding blood sample or 0.1% BSA diluted standard substance for incubation, capturing rabbit polyclonal antibody against target polypeptide labeled by Biotin, incubating HRP coupled strepavidin, and finally TMB developing, terminating with HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the blood plasma according to a standard curve obtained by the standard substance.
AUC was calculated from PK profile and bioavailability for small intestine administration was calculated as 100% of bioavailability for intravenous injection (iv).
The results showed that ghrelin-2 was injected into the small intestine at 200. Mu.g/kg and the blood concentration was below the ELISA detection limit. And after the pharmaceutical composition for promoting the absorption of the small intestine is added, the bioavailability of the ghrelin-2 for small intestine administration can reach 1.20 percent.
Experiment 7 the pharmaceutical composition for promoting intestinal absorption of the present invention can significantly improve the bioavailability of ghrelin-6 administered into the small intestine
The invention relates to a pharmaceutical composition for promoting intestinal absorption, which comprises the following components: the weight ratio of the sodium dodecyl sulfate, carbomer, chitosan and sodium citrate is as follows: 3:1:1:10.
fully and uniformly mixing the growth hormone releasing peptide-6 with the pharmaceutical composition for promoting intestinal absorption according to the weight ratio of 1:5 for later use;
test animals: adult male SD rats;
small intestine PK assay: on adult SD rats in the fasting state, the administration was carried out through a small intestine catheter at an administration volume of 1ml/kg, so that the dose of ghrelin-6 was 200. Mu.g/kg, and the other group was injected (ei) with 200. Mu.g/kg ghrelin-6 or with ghrelin-6 added with the pharmaceutical composition for promoting intestinal absorption of the present invention, 0h,0.5h,1h,1.5h,2h,2.5h and 3h after administration, blood was collected from the tail, the blood was anticoagulated with 10mM EDTA, centrifuged at 4℃and 3000rpm for 5min, and quick-frozen plasma was collected.
Venous PK test: the animals were given a fasting state and blood samples were collected by intravenous injection of 1 μg/kg ghrelin-6 at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma flash frozen.
ELISA detection method comprises coating with mouse monoclonal antibody against target polypeptide, blocking with 1% BSA, adding blood sample or 0.1% BSA diluted standard substance for incubation, capturing rabbit polyclonal antibody against target polypeptide labeled by Biotin, incubating HRP coupled strepavidin, and finally TMB developing, terminating with HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the blood plasma according to a standard curve obtained by the standard substance.
AUC was calculated from PK profile and bioavailability for small intestine administration was calculated as 100% of bioavailability for intravenous injection (iv).
The results showed that ghrelin-6 was injected into the small intestine at 200. Mu.g/kg and the blood concentration was below the ELISA detection limit. And after the pharmaceutical composition for promoting the absorption of the small intestine is added, the bioavailability of the ghrelin-6 small intestine can reach 1.50 percent.
Test 8 the pharmaceutical composition of the present invention can significantly improve the bioavailability of small intestine-administered Sermrelin (Sermorelin)
The medicine composition comprises the following components: the weight ratio of the sodium dodecyl sulfate, carbomer, chitosan and sodium citrate is as follows: 3:1:1:10.
fully and uniformly mixing Sercore with 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 adult SD rats in the fasting state, a dose of Serore was made 200. Mu.g/kg by administration via a small intestine catheter at a dose of 1ml/kg, and the Serore of the pharmaceutical composition of the present invention was added 200. Mu.g/kg by small intestine catheter injection (ei) in another group, 0h,0.5h,1h,1.5h,2h,2.5h and 3h after administration, blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma quick-frozen was collected.
Venous PK test: the animals were on an empty stomach and blood samples were collected by intravenous injection of 1. Mu.g/kg Sercore at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma flash frozen.
ELISA detection method comprises coating with mouse monoclonal antibody against target polypeptide, blocking with 1% BSA, adding blood sample or 0.1% BSA diluted standard substance for incubation, capturing rabbit polyclonal antibody against target polypeptide labeled by Biotin, incubating HRP coupled strepavidin, and finally TMB developing, terminating with HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the blood plasma according to a standard curve obtained by the standard substance.
AUC was calculated from PK profile and bioavailability for small intestine administration was calculated as 100% of bioavailability for intravenous injection (iv).
The results showed that the Sercore was administered at 200. Mu.g/kg via the small intestine with blood concentrations below the ELISA lower limit of detection. And after the pharmaceutical composition is added, the bioavailability of the small intestine administration can reach 1.22 percent.
Experiment 9 significantly improves the bioavailability of small intestine-administered Gonadorelin (Gonadorelin)
The medicine composition comprises the following components: the weight ratio of the sodium dodecyl sulfate, carbomer, chitosan and sodium citrate is as follows: 20:6.5:6.5:65.
the weight ratio of Gonadorelin to the above pharmaceutical composition is 1:8, fully and uniformly mixing for later use;
test animals: adult male SD rats;
small intestine PK assay: on adult SD rats in the fasting state, the administration was carried out through a small intestine catheter at a dose of 1ml/kg, so that the Gonadorelin dose was 200. Mu.g/kg, and the Gonadorelin was 200. Mu.g/kg added to the small intestine catheter injection (ei) in another group, 0h,0.5h,1h,1.5h,2h,2.5h and 3h after administration, blood samples were anticoagulated with 10mM EDTA, centrifuged at 4℃and 3000rpm for 5min, and quick-frozen plasma was collected.
Venous PK test: the animals were given a fasting state and blood samples were collected by intravenous injection of 1 μg/kg Gonadorelin at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 3000rpm for 5min at 4℃and plasma flash frozen.
ELISA detection method comprises coating with mouse monoclonal antibody against target polypeptide, blocking with 1% BSA, adding blood sample or 0.1% BSA diluted standard substance for incubation, capturing rabbit polyclonal antibody against target polypeptide labeled by Biotin, incubating HRP coupled strepavidin, and finally TMB developing, terminating with HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the blood plasma according to a standard curve obtained by the standard substance.
AUC was calculated from PK profile and bioavailability for small intestine administration was calculated as 100% of bioavailability for intravenous injection (iv).
The results showed that Gonadorelin was administered at 200 μg/kg via the small intestine with blood concentrations below ELISA detection limits. And after the pharmaceutical composition is added, the bioavailability of the small intestine administration can reach 1.79 percent.
Claims (3)
1. The pharmaceutical composition is characterized by being prepared from a growth hormone and/or a growth hormone analogue and a small intestine absorption promoting pharmaceutical composition, wherein the small intestine absorption promoting pharmaceutical composition consists of 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 parts; the pharmaceutical composition is prepared into an oral preparation; wherein the weight ratio of the growth hormone and/or the growth hormone analogue to the small intestine absorption promoting pharmaceutical composition is as follows: 1:5-860; wherein the growth hormone analogue is: one or more of Sermurelin, ghrelin-2, ghrelin-6 and gonadorelin.
2. A pharmaceutical composition according to claim 1 for use in ensuring absorption of growth hormone and/or growth hormone analogues in the small intestine.
3. A pharmaceutical composition according to claim 1 for use in promoting absorption of growth hormone and/or growth hormone analogue in the small intestine.
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