CN112972691A - Oral pharmaceutical composition of insulin or insulin analogue - Google Patents
Oral pharmaceutical composition of insulin or insulin analogue Download PDFInfo
- Publication number
- CN112972691A CN112972691A CN201911287370.7A CN201911287370A CN112972691A CN 112972691 A CN112972691 A CN 112972691A CN 201911287370 A CN201911287370 A CN 201911287370A CN 112972691 A CN112972691 A CN 112972691A
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- CN
- China
- Prior art keywords
- insulin
- 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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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 102000004877 Insulin Human genes 0.000 title claims abstract description 33
- 108090001061 Insulin Proteins 0.000 title claims abstract description 33
- 229940125396 insulin Drugs 0.000 title claims abstract description 33
- 239000004026 insulin derivative Substances 0.000 title claims abstract description 12
- 239000008203 oral pharmaceutical composition Substances 0.000 title description 3
- 210000000813 small intestine Anatomy 0.000 claims abstract description 65
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 56
- 230000001737 promoting effect Effects 0.000 claims abstract description 33
- 238000010521 absorption reaction Methods 0.000 claims abstract description 32
- 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
- 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
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 17
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 13
- 108010073961 Insulin Aspart Proteins 0.000 claims description 12
- 108010057186 Insulin Glargine Proteins 0.000 claims description 12
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 claims description 12
- 229960004717 insulin aspart Drugs 0.000 claims description 12
- 229960002869 insulin glargine Drugs 0.000 claims description 12
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 230000031891 intestinal absorption Effects 0.000 claims description 6
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 3
- 108010065920 Insulin Lispro Proteins 0.000 claims description 3
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 claims description 3
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 3
- 229960002068 insulin lispro Drugs 0.000 claims description 3
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 claims description 2
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Classifications
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- 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
- 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
- A61K38/28—Insulins
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- 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
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- 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
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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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
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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Abstract
The invention belongs to the field of biological medicine, and particularly relates to a pharmaceutical composition with a blood sugar reducing effect, which comprises the following components in part by weight: insulin and/or insulin analogs, and a pharmaceutical composition for promoting small intestine absorption, wherein the pharmaceutical composition for promoting small intestine absorption comprises sodium dodecyl sulfate, chitosan, and sodium citrate; the pharmaceutical composition for promoting the absorption of the small intestine has the advantages that the pharmaceutical composition is prepared into a composite auxiliary material, and the auxiliary material and the insulin and/or insulin analogue 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 insulin or an analogue thereof.
Background
Insulin is an important means for treating diabetes, plays an irreplaceable role since being discovered and used for treating diabetes in 1921, and the discovery of insulin enables the treatment of diabetes to open a brand-new page, so that the lives of tens of thousands of diabetic patients are saved, and the discovery of insulin can be epoch-making and is a milestone for treating diabetes. However, the insulin is not universal, and has limitations and some unfavorable places, for example, the common insulin needs to be injected 30min before meal, some patients have increased body mass, insulin allergy, large blood sugar fluctuation, hypoglycemia easily occurs when the dosage is increased, fasting blood sugar rises when the dosage is reduced, and the conventional insulin cannot truly simulate the secretion of human physiological insulin. Therefore, in response to the above situation, scientists developed new insulin-insulin analogues, the emergence of which provides more new options for the treatment of diabetes. In the intensive research on the structure and components of insulin, human beings discovered that the modification of a peptide chain can change the physicochemical property and biological characteristics of insulin, so that insulin analogues more suitable for the physiological needs of human bodies than the traditional human insulin can be developed in the end of 90 s in the 20 th century. In 1996, the first insulin analog in the world, insulin lispro (eutrinol), was introduced by the american etiquette company. The first long-acting insulin analog, insulin glargine (time to come), was marketed by penorubin, france, 2000. A number of insulin analogues produced by different companies have been produced in the meantime.
Insulin and its analogs are available on the market as injections, and for diabetic patients, the injections have the defects of inconvenient use, pain and the like, so that the change of the administration route of insulin and its analogs has great significance.
Disclosure of Invention
Based on the reasons, the applicant obtains a novel medicine composition for promoting small intestine absorption through multiple creative researches, the composition is composed of sodium dodecyl sulfate, chitosan and sodium citrate, and the researches show that the medicine composition for promoting small intestine absorption can be prepared into a composite auxiliary material, and the auxiliary material and insulin and/or insulin analogue 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 having hypoglycemic effects, the pharmaceutical composition comprising: insulin and/or insulin analogs, and a pharmaceutical composition for promoting small intestine absorption, wherein the pharmaceutical composition for promoting small intestine absorption comprises sodium dodecyl sulfate, chitosan, and sodium citrate.
The pharmaceutical composition is prepared into an oral preparation.
The insulin analogues include: recombinant human insulin, insulin aspart, insulin glargine, insulin lispro, insulin glulisine, insulin aspart and insulin deglutamide.
The pharmaceutical composition for promoting small intestine absorption is used for ensuring the absorption of insulin and/or insulin analogues in the small intestine.
The pharmaceutical composition for promoting small intestine absorption is used for promoting the absorption of insulin and/or insulin analogues in the small intestine.
Wherein the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is 15-25: 5-8: 50-80.
Wherein the weight ratio of the insulin and/or insulin analogue to the pharmaceutical composition for promoting intestinal absorption is as follows: 1:5-860.
An oral preparation with hypoglycemic effect is prepared from insulin and/or insulin analog, sodium laurylsulfate, chitosan and sodium citrate.
The oral preparation with the hypoglycemic effect is characterized in that the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is (15-25): 5-8: 50-80.
The oral preparation with the hypoglycemic effect is characterized in that the weight ratio of the insulin and/or the insulin analogue to the pharmaceutical composition for promoting the absorption of the small intestine is as follows: 1:5-860.
The invention discloses a medicinal composition for promoting small intestine absorption, which obtains a novel auxiliary material, and the auxiliary material can be used for: drugs (active ingredients or active ingredients) that cannot be orally administered but can be injected can be orally administered, thereby changing the mode of administration of the drug (active ingredients or active ingredients).
The intestinal absorption-promoting pharmaceutical composition of the present invention can promote the absorption of a drug (active ingredient or active ingredient) that is easily decomposed in the gastrointestinal tract in the intestine.
The pharmaceutical composition for promoting intestinal absorption of the present invention can promote the absorption of a drug (active ingredient or active ingredient) that is not easily absorbed in the gastrointestinal tract in the intestine.
Since the pharmaceutical composition for promoting small intestine absorption of the invention is used for promoting the absorption of the drug (effective component or active component) in the small intestine, and the drug is required to be released in the small intestine to exert the efficacy, when the pharmacodynamic test and the pharmacokinetic test are carried out, rodents adopt small intestine catheters for administration, and mammals adopt enteric capsules for oral administration.
The invention combines the drug combination and the drug (effective component or active component) which can promote the intestinal absorption on rodents one by one to carry out the bioavailability detection, and simultaneously, part of the polypeptide is selected to carry out the detection of the drug effect and the pharmacokinetics on different animals.
Concrete examples of the test
The technical means of the present invention will be described below with reference to specific test examples, but the scope of the present invention is not limited thereto.
The contents of the test examples in the specification are only lists of implementation forms of the inventive concept, and the protection scope of the invention should not be considered to be limited to the specific forms set forth in the test examples, and the protection scope of the invention is equivalent to the technical means which can be thought of by those skilled in the art according to the inventive concept. While the following embodiments of the invention have been described, the invention is not limited to the specific embodiments and applications described above, which are intended to be illustrative, instructive, and not limiting. Those skilled in the art, having the benefit of this disclosure, may effect numerous modifications thereto without departing from the scope of the invention as defined by the appended claims.
The following tests are conclusion tests of research personnel based on multiple creative tests and on the technical scheme to be protected by the invention. In the quantitative tests in the following test examples, three replicates were set, and the data are the mean value or the mean value ± standard deviation of the three replicates.
Experiment 1 significantly improved the efficacy of Exenatide (Exendin4, EXE4) administered to the small intestine
The medicine composition is as follows: the surfactant is sodium dodecyl sulfate, the chitin and the derivatives thereof are chitosan, the metal ion chelating agent is sodium citrate, and the weight ratio is 20: 6.5: 65.
mixing Exenatide and the pharmaceutical composition according to the weight ratio of 1:5, fully and uniformly mixing for later use;
test animals: injecting 45mg/kg STZ into the abdominal cavity of SD male rats to construct a hyperglycemia model;
small intestine efficacy test: blood samples were taken at 0h and 9h for testing of blood glucose, either by subcutaneous injection (sc) or via small intestinal tract (ei).
The result shows that the blood sugar reducing effect of Exenatide administered in small intestine is very weak under the condition that the pharmaceutical composition is not added, and when the dosage reaches 1mg/kg, the blood sugar reducing efficiency after 9 hours is only about 70 percent and is far lower than about 50 percent of that of the subcutaneous dosage of 1 mug/kg. After the pharmaceutical composition is added, the blood sugar reducing effect of subcutaneous 1 mug/kg can be achieved by the administration dosage of 50 mug/kg. (see table 1 below).
TABLE 1
Experiment 2 significantly improves the bioavailability of Exenatide administered to the small intestine
Mixing Exenatide and the test 1 pharmaceutical composition according to the weight ratio of 1:5, fully and uniformly mixing for later use;
test animals: adult male SD rats;
small intestine PK assay: on an adult SD rat in a fasting state, the Exenatide is administrated by a small intestine catheter according to the administration volume of 1ml/kg to ensure that the dose of Exenatide is 200 mug/kg, the Exenatide is divided into another group, 200 mug/kg of Exenatide of the pharmaceutical composition in the test 1 is added in small intestine catheter injection (ei), blood is collected from the tail after 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after administration, the blood sample is anticoagulated by 10mM EDTA, and is centrifuged at 3000rpm at 4 ℃ for 5min to collect plasma for quick freezing.
To avoid hypoglycemia in the animals, 1g/kg glucose was administered prior to administration.
The ELISA detection method comprises the following steps: coating with mouse monoclonal antibody of anti-target polypeptide, blocking with 1% BSA, adding blood sample or standard substance diluted with 0.1% BSA for incubation, capturing rabbit polyclonal antibody of anti-target polypeptide labeled by Biotin, incubating with HRP-conjugated streptavidin, finally developing TMB, terminating HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the plasma according to the standard curve obtained by the standard substance.
The AUC was calculated from the PK profile, and the bioavailability for small intestine dosing was calculated as 100% bioavailability for intravenous (iv).
The results show that the AUC of the PK curve of Exenatide after 1 mu g/kg of iv injection is 0.93ng/ml.h, and the blood concentration of Exenatide after 200 mu g/kg of iv injection is lower than the lower detection limit of ELISA. Whereas, the AUC of the PK profile after addition of the test 1 pharmaceutical composition was 1.33ng/ml. h, the bioavailability of intestinal administration was about 0.71%. The test results are shown in Table 2.
TABLE 2
Experiment 3 significantly improves the bioavailability of oral Exenatide
Mixing Exenatide 0.7mg and test 1 pharmaceutical composition 200mg, lyophilizing, and making into No. 3 enteric-coated capsule;
mixing Exenatide 0.7mg and test 1 pharmaceutical composition 400mg, lyophilizing, and making into No. 0 enteric-coated capsule;
mixing Exenatide 0.7mg and test 1 pharmaceutical composition 600mg, lyophilizing, and making into No. 00 enteric-coated capsule;
mixing Exenatide 0.7mg and test 1 pharmaceutical composition 200mg, lyophilizing, and making into No. 3 common capsule;
mixing Exenatide 0.7mg and mannitol 200mg, lyophilizing, and making into No. 3 enteric-coated capsule;
test animals: adult male beagle dog
Oral PK assay: in the state of empty stomach of animals, blood samples are collected at 0.5, 1, 1.5, 2, 2.5 and 3 hours after the enteric capsule is orally taken. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma was collected and snap frozen.
Intravenous PK assay: animals were fasted and blood samples were collected by intravenous injection of 0.3. mu.g/kg Exenatide at 5, 15, 30, 60, 90, 120 min. Blood samples were anticoagulated with 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma was collected and snap frozen.
To avoid hypoglycemia in the animals, 1g/kg glucose was administered prior to administration.
The ELISA detection method comprises the following steps: coating with mouse monoclonal antibody of anti-target polypeptide, blocking with 1% BSA, adding blood sample or standard substance diluted with 0.1% BSA for incubation, capturing rabbit polyclonal antibody of anti-target polypeptide labeled by Biotin, incubating with HRP-conjugated streptavidin, finally developing TMB, terminating HCl, and reading at 450 nm. And calculating the concentration of the target polypeptide in the plasma according to the standard curve obtained by the standard substance.
The AUC was calculated from the PK profile, and the bioavailability for small intestine dosing was calculated as 100% bioavailability for intravenous (iv).
The PK data for beagle dogs showed that the AUC for Exenatide at 0.3. mu.g/kg was about 0.82ng/ml. hour for intravenous injection and about 1.37ng/ml. hour for 0.7mg of oral Exenatide/test 1 drug composition. The bioavailability of the oral Exenatide/test 1 pharmaceutical composition is about 0.76%. The test results are shown in Table 3.
TABLE 3
Exenatide cannot successfully enter blood without the assistance of the pharmaceutical composition, and the blood entering efficiency is remarkably improved after the pharmaceutical composition is added. Although the blood entry efficiency of Exenatide increased slightly with increasing weight of the test 1 pharmaceutical composition, the magnitude of the increase was limited (table 4 below). The capsule No. 3 is suitable in quantity by combining the consideration of two aspects of oral convenience and drug effectiveness.
TABLE 4
Test 4 Exenatide/test 1 pharmaceutical composition can obviously inhibit the postprandial blood glucose rise of Alloxan beagle dogs, Exenatide 0.7mg and test 1 pharmaceutical composition 200mg are fully mixed, freeze-dried and filled into No. 3 enteric capsules for later use;
test animals: adult male beagle dogs;
animal physical examination and adaptation: collecting animal fasting blood sample to detect blood biochemical index, after determining that all the blood biochemical indexes are normal, placing the animal in a quieter room to adapt for 1 week, and requiring that the feeding time and the feeding amount are consistent every day;
data acquisition before modeling: blood samples were collected at 2 time points (before and after feeding for 6 hours) every day for 5 days;
and (3) molding test: in a fasting state, 60mg/kg of Alloxan solution is injected into the vein, and blood samples are collected at 2 time points (before feeding and 6 hours after feeding) every day for 5 days continuously after one week; and judging whether the model is qualified or not according to the acquired data. If the test is qualified, starting the drug effect test;
and (3) pharmacodynamic test: the test capsules were swallowed before feeding and blood samples were collected at 2 time points (before feeding, 6h after feeding).
The results show that the Exenatide/test 1 pharmaceutical composition can obviously inhibit the postprandial blood glucose increase on Alloxan-modeled beagle dogs. The test results are shown in Table 5.
TABLE 5
Test example 5 the pharmaceutical composition for promoting intestinal absorption of the present invention can significantly improve the bioavailability of recombinant insulin (rInsulin) administered into the small intestine
The pharmaceutical composition for promoting small intestine absorption: the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is as follows: 20: 6.5: 68.
fully and uniformly mixing the rInsulin 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 dosage of the rInsulin is 200 mug/kg, the rInsulin is divided into another group, the rInsulin with 200 mug/kg is injected into the small intestine catheter (ei) or added with the pharmaceutical composition for promoting the absorption of the small intestine (the rInsulin is 200 mug/kg), 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 were fasted, injected intravenously with 1. mu.g/kg rInsulin 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 the rInsulin is injected by 200 mug/kg via small intestine, and the blood concentration is lower than the lower detection limit of ELISA. After the pharmaceutical composition for promoting small intestine absorption is added, the bioavailability of the rInsulin small intestine administration can reach 0.80%.
Experiment 6 the pharmaceutical composition for promoting the absorption of small intestine of the invention can obviously improve the bioavailability of insulin glargine fed into small intestine
The invention discloses a medicinal composition for promoting small intestine absorption: the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is as follows: 3: 1: 10.
fully and uniformly mixing insulin glargine 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 insulin glargine is 200 mug/kg, the insulin glargine is divided into another group, 200 mug/kg of insulin glargine is injected (ei) through the small intestine catheter or the insulin glargine added with the pharmaceutical composition for promoting the absorption of the small intestine is taken at 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after the administration, the tail part is taken as blood, the blood sample is anticoagulated by 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma is collected and quickly frozen.
Intravenous PK assay: animals in fasted state were injected intravenously with 1. mu.g/kg of insulin glargine 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 insulin glargine is injected by 200 mug/kg through small intestine, and the blood concentration is lower than the lower detection limit of ELISA. After the medicinal composition for promoting the small intestine to absorb insulin is added, the bioavailability of the insulin glargine fed through the small intestine can reach 0.55 percent.
Experiment 7 the pharmaceutical composition for promoting the absorption of the small intestine can obviously improve the bioavailability of insulin aspart fed into the small intestine
The invention discloses a medicinal composition for promoting small intestine absorption: the weight ratio of the sodium dodecyl sulfate to the chitosan to the sodium citrate is as follows: 25: 8: 80.
mixing insulin aspart and the pharmaceutical composition according to the weight ratio of 1:5 sufficiently for standby;
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 insulin aspart is 200 mug/kg, the insulin aspart is divided into another group, 200 mug/kg of insulin aspart or insulin aspart added with the medicinal composition for promoting the absorption of small intestine is injected (ei) through the small intestine catheter, blood is collected at the tail part after 0h, 0.5h, 1h, 1.5h, 2h, 2.5h and 3h after the administration, blood samples are anticoagulated by 10mM EDTA, centrifuged at 4 ℃ and 3000rpm for 5min, and plasma is collected and quickly frozen.
Intravenous PK assay: animals are in fasting state, 1 mug/kg insulin aspart is injected into vein, 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 200 mug/kg of insulin aspart is injected by small intestine, and the blood concentration is lower than the lower detection limit of ELISA. After the medicinal composition for promoting the small intestine to promote the small intestine to absorb is added, the bioavailability of the insulin aspart fed through the small intestine can reach 0.68 percent.
Claims (10)
1. A pharmaceutical composition having hypoglycemic effect, characterized in that it comprises: insulin and/or insulin analogs, and a pharmaceutical composition for promoting small intestine absorption, wherein the pharmaceutical composition for promoting small intestine absorption comprises sodium dodecyl sulfate, chitosan, and sodium citrate.
2. The pharmaceutical composition with hypoglycemic effect according to claim 1, wherein the pharmaceutical composition is prepared into an oral preparation.
3. A pharmaceutical composition with hypoglycemic effect according to claim 1, wherein the insulin analogue comprises: recombinant human insulin, insulin aspart, insulin glargine, insulin lispro, insulin glulisine, insulin detemir and insulin deglutamide.
4. A pharmaceutical composition with hypoglycemic effect according to any of claims 1-3 for use in ensuring absorption of insulin and/or insulin analogues in the small intestine.
5. A pharmaceutical composition having a hypoglycemic effect according to any one of claims 1-3, for use in promoting the absorption of insulin and/or insulin analogues in the small intestine.
6. The pharmaceutical composition with hypoglycemic effect according to any of claims 1-3, wherein the weight ratio of sodium lauryl sulfate, chitosan, sodium citrate is 15-25: 5-8: 50-80.
7. A pharmaceutical composition with hypoglycemic effect according to any of claims 1-3, wherein the weight ratio of insulin and/or insulin analogue to the pharmaceutical composition promoting intestinal absorption is: 1:5-860.
8. An oral preparation with hypoglycemic effect, which is characterized in that: the oral preparation is prepared from insulin and/or insulin analogues, sodium dodecyl sulfate, chitosan and sodium citrate.
9. The oral preparation with hypoglycemic effect of claim 8, wherein the weight ratio of sodium lauryl sulfate, chitosan, sodium citrate is 15-25: 5-8: 50-80.
10. The oral preparation with hypoglycemic effect according to claim 8, wherein the weight ratio of insulin and/or insulin analog to the pharmaceutical composition for promoting intestinal absorption is: 1:5-860.
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Non-Patent Citations (2)
| Title |
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| 刘利等: "胰岛素口服给药途径的研究进展", 《现代食品与药品杂志》, vol. 17, no. 6, 31 December 2017 (2017-12-31), pages 62 - 66 * |
| 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 * |
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