CN118286156A - Weight-reducing polypeptide pharmaceutical composition, nasal spray and preparation method thereof - Google Patents
Weight-reducing polypeptide pharmaceutical composition, nasal spray and preparation method thereof Download PDFInfo
- Publication number
- CN118286156A CN118286156A CN202410501532.7A CN202410501532A CN118286156A CN 118286156 A CN118286156 A CN 118286156A CN 202410501532 A CN202410501532 A CN 202410501532A CN 118286156 A CN118286156 A CN 118286156A
- Authority
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- Prior art keywords
- weight
- nasal spray
- poloxamer
- reducing
- parts
- Prior art date
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- Pending
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- 229920001184 polypeptide Polymers 0.000 title claims abstract description 36
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 36
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 36
- 239000007922 nasal spray Substances 0.000 title claims abstract description 29
- 229940097496 nasal spray Drugs 0.000 title claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229920001993 poloxamer 188 Polymers 0.000 claims abstract description 31
- 229940044519 poloxamer 188 Drugs 0.000 claims abstract description 31
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract description 27
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229940041616 menthol Drugs 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 18
- 238000010521 absorption reaction Methods 0.000 claims abstract description 17
- 229940124532 absorption promoter Drugs 0.000 claims abstract description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 4
- DRNXELHHXZJHPN-OCLAHLCRSA-N alpha-D-GlcNS(6S)-(1->4)-beta-D-GlcA-(1->4)-alpha-D-GlcNS(3S,6S)-(1->4)-beta-D-GlcA(2S)-(1->4)-alpha-D-GlcNS(6S)-(1->4)-beta-D-GlcA(2S)-(1->4)-alpha-D-GlcNS(6S)-(1->4)-beta-D-GlcA-O-pNp Chemical compound O[C@H]1[C@H](O)[C@@H](NS(O)(=O)=O)[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O[C@@H]3[C@@H](COS(O)(=O)=O)O[C@H](O[C@H]4[C@H](O)[C@@H](OS(O)(=O)=O)[C@H](O[C@H]5[C@H](O)[C@@H](NS(O)(=O)=O)[C@@H](O[C@H]6[C@H](O)[C@@H](OS(O)(=O)=O)[C@H](O[C@H]7[C@H](O)[C@@H](NS(O)(=O)=O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)C(Oc9ccc(cc9)[N+]([O-])=O)O[C@@H]8C(O)=O)O[C@@H]7COS(O)(=O)=O)O[C@@H]6C(O)=O)O[C@@H]5COS(O)(=O)=O)O[C@@H]4C(O)=O)[C@H](NS(O)(=O)=O)[C@H]3OS(O)(=O)=O)O[C@@H]2C(O)=O)O[C@@H]1COS(O)(=O)=O DRNXELHHXZJHPN-OCLAHLCRSA-N 0.000 claims abstract description 4
- 239000000600 sorbitol Substances 0.000 claims abstract description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims abstract description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims abstract 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 42
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 28
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- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 21
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- 229940116229 borneol Drugs 0.000 claims description 11
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- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 8
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims description 7
- 108010019598 Liraglutide Proteins 0.000 claims description 6
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- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims 1
- 210000004556 brain Anatomy 0.000 abstract description 24
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- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 33
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- 229960004657 indocyanine green Drugs 0.000 description 5
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 5
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
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- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
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- 210000000133 brain stem Anatomy 0.000 description 3
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 3
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- 230000007547 defect Effects 0.000 description 3
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Substances 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 description 3
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Classifications
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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
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
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- 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
- A61K38/26—Glucagons
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Landscapes
- Health & Medical Sciences (AREA)
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Abstract
The invention provides a weight-reducing polypeptide pharmaceutical composition, a nasal spray and a preparation method thereof. The pharmaceutical composition comprises 0.05-0.3 part of weight-reducing polypeptide and 0.05-1 part of absorption promoter, wherein the absorption promoter is at least one of Tween 80, poloxamer 188, HS-15, EDTA, sorbitol, menthol (the purity is more than or equal to 99.0%) and dextroamphaeol (the purity is more than or equal to 99.0%). The invention further develops the pharmaceutical composition into a nasal spray, and related experiments show that the preparation can increase the retention time of the polypeptide medicine in the nasal cavity, promote the absorption of nasal epithelium, increase the efficiency of the medicine entering the brain, and better exert the weight-reducing effect of the polypeptide medicine.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a weight-reducing polypeptide pharmaceutical composition, a nasal spray and a preparation method thereof.
Background
Obesity refers to the accumulation of fat that can be significantly overweight or excessive to the health, with Body Mass Index (BMI) being the criterion for obesity, and the cause of death of millions of people worldwide is closely related to high BMI. Obesity, a chronic metabolic disease, gradually causes dysfunction of various systems of the human body, thereby causing serious complications such as hypertension, diabetes, various cardiovascular diseases, osteoarthropathy, respiratory diseases, and the like. At present, obesity is treated by adopting modes of intervention living, medicines and operation intervention in China, but the intervention living mode is easily interfered by other factors, so that the effect is poor; the intervention effect of the operation is short, rebound is easy to cause, and a plurality of uncertain risks exist in the operation. However, only one of the drugs approved to be marketed for treating obesity in China has a large limitation, so that the safe and effective weight-losing drugs need to be further developed.
The semaglutin is a glucagon-like peptide-1 (Glucagon-LIKE PEPTIDE-1, GLP-1) receptor agonist, has been approved by the FDA for the treatment of type 2 diabetes and obesity, and currently, the developed semaglutin dosage forms are injections and oral tablets. The semaglutin injection can effectively improve blood sugar control and effectively reduce weight, but still has the common defects of the injection: inconvenient use, poor patient compliance, relatively complex preparation process, and the like. However, the oral semaglutin tablet improves the defect of the semaglutin tablet serving as an injection, but has the characteristics of large molecular weight, hydrophilicity and the like, has poor penetrability of gastrointestinal mucosa, is easily influenced by gastrointestinal tract pH and is degraded by enzymes, so that the oral bioavailability of the semaglutin is extremely low. The semaglutin can inhibit appetite, keep satiety, reduce food consumption, thereby achieving the effect of losing weight, hypothalamus and brainstem (medulla oblongata, pontic) in the brain are central centers of appetite regulation, nasal administration is used as a non-invasive administration mode, and after administration, the semaglutin can bypass blood brain barrier, and the medicament can be directly delivered to brain tissues through a nose-brain channel, so that the targeting effect is strong, and the medicament utilization rate is high. The medicine can avoid the defects and risks of oral administration and injection administration, and has the advantages of quick response, convenient administration and the like. Nasal delivery systems have the advantages of convenient delivery, rapid onset of action, central targeting, etc., however, cilia in the nasal cavity have a scavenging effect, poor permeability of hydrophilic compounds, enzymatic degradation and short residence time are major limiting factors for intranasal delivery. How to increase the retention time of the nasal cavity of the medicine and promote the absorption of nasal epithelium, thereby improving the bioavailability in the brain is a technical problem to be solved urgently for nasal administration preparations. In addition, macromolecular drugs in nasal formulations are not easily absorbed, which is also a significant problem in developing nasal formulations.
Disclosure of Invention
The invention aims to provide a semaglutin pharmaceutical composition, a nasal spray and a preparation method thereof, so that semaglutin can rapidly enter the brain through a nose-brain passage, and the effect of reducing weight can be achieved by regulating neurons in the brain to control the organism to ingest food.
In order to solve the technical problems, the invention adopts the following technical scheme:
In a first aspect, the invention provides a weight-reducing polypeptide pharmaceutical composition comprising, in parts by weight: 0.05-0.3 part of weight-reducing polypeptide and 0.05-1 part of absorption promoter, wherein the absorption promoter is at least one selected from Tween 80, poloxamer 188, HS-15, EDTA, sorbitol, menthol (the purity is more than or equal to 99.0 percent) and dextroamphenol (the purity is more than or equal to 99.0 percent).
Preferably, the weight-reducing polypeptide is selected from at least one of telipopeptide, liraglutide, semraglutide.
Preferably, the absorption enhancer is selected from at least one of poloxamer 188, menthol and right borneol; more preferably, the absorption enhancer is selected from poloxamer 188 and one of menthol and right borneol.
In a second aspect, the invention provides application of the weight-reducing polypeptide pharmaceutical composition in preparation of weight-reducing medicines.
Preferably, the weight-reducing medicament is an oral and/or nasal spray.
In a third aspect, the invention provides a nasal spray, which comprises the following raw materials in parts by weight: 0.05 to 0.3 part of weight-reducing polypeptide, 0.5 to 4 parts of sodium alginate, 0.05 to 1 part of absorption accelerator, 1 to 5 parts of propylene glycol and 50 to 200 parts of water.
Preferably, the weight-reducing polypeptide is at least one of telpofungin, liraglutide, semraglutide; preferably, the weight-reducing polypeptide is 0.1 to 0.2 parts.
Preferably, the absorption enhancer is selected from at least one of poloxamer 188, menthol and right borneol; more preferably, the absorption enhancer is selected from poloxamer 188 and one of menthol and right borneol; preferably, the absorption enhancer is 0.1 to 0.5 part.
Preferably, the raw materials comprise the following components in parts by weight: 0.1 to 0.2 part of weight-reducing polypeptide, 0.5 to 2 parts of sodium alginate, 0.1 to 0.5 part of absorption accelerator, 2 to 4 parts of propylene glycol and 50 to 200 parts of water.
In a fourth aspect, the present invention provides a method for preparing the nasal spray, comprising the steps of: the nasal spray is prepared by mixing the components of the nasal spray and preparing into a solution.
The invention has the following advantages: the invention provides a pharmaceutical composition containing semaglutin, and an in-situ gel nasal spray is developed by adding an optimal adhesive and an absorption promoter, and related experiments show that the preparation can increase the retention time of the semaglutin in the nasal cavity, promote the absorption of nasal epithelium, increase the efficiency of drug entering the brain and better exert the weight-reducing effect of the semaglutin.
Drawings
Fig. 1 is a mass diagram of unreacted liquid after the reaction of sodium alginate aqueous solutions with different concentrations with artificial nose liquid in example 1 of the present invention, prescription 1 is 0.25% sodium alginate aqueous solution reacted with artificial nose liquid, prescription 2 is 0.5% sodium alginate aqueous solution reacted with artificial nose liquid, and prescription 3 is 1% sodium alginate aqueous solution reacted with artificial nose liquid. Prescription 4 is 2% sodium alginate aqueous solution and artificial nose liquid reaction.
FIG. 2 is a gel forming chart of the example 1 of the present invention after the aqueous sodium alginate solution with different concentration reacts with the artificial nose solution, the prescription 1 is 0.25% aqueous sodium alginate solution reacts with the artificial nose solution, the prescription 2 is 0.5% aqueous sodium alginate solution reacts with the artificial nose solution, and the prescription 3 is 1% aqueous sodium alginate solution reacts with the artificial nose solution. Prescription 4 is 2% sodium alginate aqueous solution and artificial nose liquid reaction.
FIG. 3 is a graph showing the brain penetration efficiency of a fluorescence-labeled polypeptide by nasal administration of different absorption enhancers to mice in example 2 of the present invention.
FIG. 4 is a graph showing the brain penetration efficiency of the fluorescent labeled polypeptide of example 2 of the present invention when the mice are nasally administered with 3 absorption promoters in a pairwise manner.
Fig. 5 shows the effect of the nasal administration of dexbornyl alcohol and poloxamer 188 at different concentrations in the mice in example 3 of the present invention in promoting the penetration of polypeptides into the brain.
FIG. 6 is a graph showing the weight change of mice in each group of different weight-loss polypeptides in example 4 of the present invention, and the beginning and ending of the experiment.
FIG. 7 is a graph of body weight, food intake and blood glucose of mice in each group of the semaglutin weight loss test of example 5 of the present invention, wherein graph (a) is a graph of the change of body weight of mice with days; panel (b) is a plot of mice feeding versus days; panel (c) is a graph of blood glucose in mice as a function of days.
Detailed Description
The KM mice used in the examples of the present invention were purchased from Liaoning Changsheng biotechnology Co., ltd, the Semiglutide drug substance was purchased from Ji Lin Shengji Jian biotechnology Co., ltd, the liraglutide drug substance was purchased from Suzhou Tianma pharmaceutical group Tianji biopharmaceutical Co., ltd, and the Tierpide drug substance was purchased from Nanjin Rui biomedical technology Co., ltd.
The right camphol adopted in the embodiment of the invention is purchased from Tianjin Sheen Sichu Biochemical technology Co., ltd, and the purity is more than or equal to 99.0%.
In the description of the present invention, it is to be noted that the specific conditions are not specified in the examples, and the description is performed under the conventional conditions or the conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The technical solution of the present invention will be clearly and fully described below with reference to the accompanying drawings and the detailed description, but the following examples are only limited to a part of the study of the present invention, and are only for illustrating the present invention, and should not be construed as limiting the scope of the present invention. Based on this, other embodiments, which can be obtained by a person skilled in the art without making any inventive effort, fall within the scope of protection of the present invention. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 examination of gel formability
The sodium alginate can form gel with soluble calcium salt, and certain calcium ions exist in the nasal cavity of a human body, so that the nasal spray can form in-situ gel by using the sodium alginate as an adhesive. Firstly, examining gel formability in vitro, and preparing artificial nose liquid according to electrolyte of the nose liquid: every 1000ml of water contains 7.91g,KCl 3.68g,CaCl 2 0.51g,NaHCO3 2.56.56 g of NaCl, the mixture is placed at room temperature for standby, sodium alginate aqueous solutions (0.25%, 0.5%, 1% and 2%) with different mass concentrations are prepared, firstly, 500 mu L of the prepared sodium alginate aqueous solution is uniformly dripped on a glass plate, the glass plate is stuck with a plastic ring to enclose the liquid, a small opening is cut to enable the liquid to flow out and gel to not flow out, then the prepared artificial nose liquid with the same volume and the sodium alginate aqueous solution with different mass concentrations are added to react for 20 seconds with full mixing, then the tool is inclined at 45 degrees, unreacted liquid is collected at the small opening, and the mixture is weighed. The smaller the amount of liquid collected, the better the gel formability. And observing the elasticity and hardness of the molding, and finding the prescription with the best gel molding property.
FIG. 1 shows the mass of unreacted components collected after the reaction of aqueous sodium alginate solution with 4 mass concentrations with artificial nose solution, the collected unreacted liquid represents the component which does not fully form gel, the mass of the unreacted component is the least when prescription 3 is adopted, as can be seen from FIG. 2, the gel forming property is poor and almost no complete gel is formed when prescription 1 is selected; when prescription 2 is selected, the gel is generated by reaction, but the shape is too soft, and both prescription 3 and prescription 4 generate complete gel, but the gel formed by prescription 3 has better formability and elasticity, so the gel can be used as the prescription of the subsequent nasal spray.
Example 2 indocyanine green (ICG) -insulin (Ins) coupling experiments
45Mg of insulin is precisely weighed and dissolved in 6mL of 0.01M HCl solution, 6mg of indocyanine green is added for reaction at room temperature and in a dark place for 12 hours, then the activated 3500KD dialysis bag is used for dialysis for 2 days to remove unreacted ICG, the dialysis is carried out immediately, and the concentration of ICG in the prepared ICG-Ins solution is 1mg/mL for later use.
(1) The different absorption promoters of the mice administered through the nasal cavity promote the ICG-Ins solution to enter the brain experiments, and are specifically as follows:
Respectively precisely weighing 5 μl of Tween 80, 188 mg of poloxamer, 5mg of HS-15, 5mg of EDTA, 5mg of sorbitol, 1mg of menthol and 1mg of dextroamphetamol (borneol group in fig. 3), dissolving each absorption enhancer in 1mL of prepared ICG-Ins solution for later use (water-insoluble drugs are firstly dissolved by 100 μl of propylene glycol and then added into the ICG-Ins solution), weighing 16 KM mice, weighing 2 mice in each group, respectively carrying out nasal administration on 7 groups of solutions according to the dosage of 1mg/kg, setting a blank group, carrying out nasal administration on the same dosage of ICG-Ins solution in the blank group, anesthetizing the mice with 4% of chloral hydrate after 15min administration of 8 groups of mice, carrying out cardiac perfusion to remove fluorescence influence in blood, taking the whole brain of the mice after perfusion, and photographing each part of the ventral side and dorsal side of the whole brain of the mice under a vascular imager. The results are shown in fig. 3, and fig. 3 shows the imaging results of 1 mouse in each group.
As can be seen from fig. 3, the effect of promoting the polypeptide to enter the brain by the right camphol, menthol and poloxamer 188 is better, and the effect of tween 80 is also a certain effect, but the effect is not obvious. Further selecting three absorption promoters of the right camphol, the menthol and the poloxamer 188 for carrying out the study of pairwise compounding, and further observing the effect of promoting brainstem.
(2) Experiments for promoting ICG-Ins solution to enter brain by two-by-two combination of nasal administration of mice absorption promoters
Precisely weighing 1mg of dextromethorphan, 188 5mg of poloxamer and 1mg of menthol respectively, dissolving the dextromethorphan and the menthol in 100 mu L of propylene glycol, mixing the two components, dissolving in 1mL of prepared ICG-Ins solution for later use, weighing 6 KM mice, carrying out nasal administration according to the dosage of 1mg/kg of each group of 2 mice, anesthetizing the mice with 4% chloral hydrate of 1mg/kg after 15min, carrying out heart perfusion to eliminate fluorescence influence in blood, taking the whole brain of the mice after perfusion, and photographing and observing the ventral side and the dorsal side of the whole brain of the mice and each partial partition of the whole brain under a vascular imager. The results are shown in fig. 4, and fig. 4 shows the imaging results of 1 mouse in each group.
As can be seen from fig. 4, the combination of poloxamer 188 and right borneol has better comprehensive effect of promoting the polypeptide to enter the whole brain and brainstem, and the poloxamer 188+menthol is the next, but the effect of menthol+right borneol is not as good as that of the experimental group in which poloxamer 188 participates. Therefore, poloxamer 188+dexbornyl alcohol and poloxamer 188+menthol are all expected to be absorption promoters of the semaglutin. Subsequent experiments selected poloxamer 188 and dexbornyl alcohol as the absorption enhancer in nasal sprays.
Example 3 experiments on different doses of poloxamer 188 and dexborneolum to promote the infusion of ICG-Ins solutions into the brain
1Mg of right camphol and three parts of poloxamer 1881 mg, poloxamer 188 5mg and poloxamer 18810mg are respectively precisely weighed, the right camphol is firstly dissolved in 100 mu L of propylene glycol, then propylene glycol solution of the right camphol and poloxamer 188 with different weights are respectively mixed with each other in pairs and then dissolved in 1mL of prepared ICG-Ins solution for standby, 6 KM mice are weighed, 2 mice in each group are subjected to nasal administration according to the dosage of 1mg/kg, after 15min, the mice are anesthetized by 4% chloral hydrate, the fluorescence influence in blood is eliminated by heart perfusion, the whole brain of the mice is taken after perfusion, and the ventral side and the dorsal side of the whole brain of the mice and each part of the whole brain are photographed and observed under a vascular imager in a partitioned mode. The results are shown in fig. 5, and fig. 5 shows the imaging results of 1 mouse in each group.
As shown in fig. 5, the effect of promoting the polypeptide to enter the brain by compounding the right borneol and poloxamer 188 with different concentrations is poorer than that of promoting the polypeptide to enter the brain by 1mg/mL of the right borneol and 5mg/mL of poloxamer 188 in fig. 4, so that the mass ratio of the right borneol to the poloxamer 188 is selected to be 1:4 to 6, preferably 1:5.
Example 4 weight-loss experiments on obese mice with different weight-loss polypeptides
SPF-grade KM (more than 4 weeks old) had 35 mice, which were male. Animals were purchased from Liaoning long-life biotechnology Co., ltd, and after 1 week of adaptation, the mice of the remaining groups were given enough high-fat feed daily for obesity model modeling, with the exception of the blank group (5) free-feeding normal feed, and were free-drinking water. Weighing after 30 days, judging whether the modeling of the obesity model is successful, judging whether the weight of the obesity model mouse is 30% greater than that of a mouse fed by normal feed, judging that the modeling of all mice is successful after weighing, and carrying out the operation process of experimental animals according to the rule of the ethical committee of experimental animals of Shenyang medical university.
Grouping animals: 25 mice were randomly divided into 5 groups according to weight balance, and the standard mice were kept in 5 mice/cage, which were a blank group, an obese model group, a liraglutide group, a telipopeptide group, and a semraglutide group, respectively. The specific groupings and modes of administration are as follows in Table 1:
Table 1 grouping and administration of mice
| Grouping | Feed for feeding | Quantity of | Mode, frequency and dosage of administration |
| Blank control group | Common feed | 5 | Distilled water is administered orally and nasally 1 time each day |
| Obesity model group | High-fat feed | 5 | Distilled water is administered orally and nasally 1 time each day |
| Liraglutide group | High-fat feed | 5 | Nasal administration of semaglutin, 0.021mg/kg/day 1 times daily |
| Tenipotene group | High-fat feed | 5 | Nasal administration of telipopeptide 1 times daily, 0.32mg/kg/day |
| Stavudine group | High-fat feed | 5 | Nasal administration of liraglutide 1 time per day, 0.039mg/kg/day |
The administration dose is converted into the administration dose of mice according to the subcutaneous administration dose of various polypeptides for human on the market, the administration period is 30 days, the body weight of the mice is detected every day during the experiment, the results are shown in fig. 6 and table 2, and three polypeptide medicaments all have weight-reducing effects after 30 days, wherein the weight-reducing effect of the nasal administration of the semaglutinin is the best, so the semaglutinin is selected for the next experimental verification.
Table 2 weight results on day 1 and day 30 for each group of mice
Example 5 weight loss experiments of different absorption promoters formulated obese mice
Animal rules were chosen as in example 6, animals were grouped: the 35 mice were randomly divided into 7 groups according to weight balance, and were fed in standard mice cages, 5 mice/cage, which were blank group, obesity model group, subcutaneous injection group, oral suspension group, menthol+poloxamer 188 group, right borneol+poloxamer 188 group, menthol+right borneol group, respectively. The specific grouping and administration modes are as follows 3:
TABLE 3 grouping and administration of mice
The dosing amount was converted to the dosing amount of mice based on the initial amount of semaglutin for human on the market, the dosing period was 30 days, the body weight of the mice and the feeding amount of each group of mice were measured daily during the experiment, and the blood glucose of the mice was measured and recorded every 3 days. As shown in fig. 7 and table 4, the nasal administration group was effective in controlling weight gain of mice and reducing ingestion, and fluctuation of blood glucose of mice was relatively stable and balanced, and nasal administration was better than the oral suspension group and the subcutaneous injection group in terms of weight reduction effect, except for menthol + poloxamer 188 group, which was the best in terms of right camphol + poloxamer 188 as an absorption enhancer, with the increase in administration time.
Table 4 weight results on day 1 and day 30 for each group of mice
The preparation method of the nasal spray of the right camphol and poloxamer 188 group comprises the following steps:
10mL of purified water is measured and heated to 80 ℃, 100mg of sodium alginate is precisely weighed and added into the water while stirring, after the sodium alginate is fully dissolved, the water is cooled for standby, and 250 mu L of propylene glycol and 10mg of right camphol are precisely weighed. Dissolving dextromethorphan in propylene glycol for standby, precisely weighing 17.5mg of semaglutin and 50mg of poloxamer 188, adding the mixture into the prepared sodium alginate solution, and uniformly mixing the propylene glycol with the sodium alginate solution to prepare the nasal spray containing the semaglutin of dextromethorphan and poloxamer 188.
The preparation method of the menthol and poloxamer 188 nasal spray is the same as that of the right camphol and poloxamer 188.
The preparation method of the nasal spray of menthol and dextromethorphan group comprises the following steps:
10mL of purified water is measured and heated to 80 ℃, 100mg of sodium alginate is precisely weighed and added into the water while stirring, after the sodium alginate is fully dissolved, the solution is cooled for standby, and 250 mu L of propylene glycol, 10mg of dextromethorphan and 10mg of menthol are precisely weighed. Dissolving dextro-camphol and menthol in propylene glycol for standby, precisely weighing 17.5mg of the semaglutin, adding the semaglutin into the prepared sodium alginate solution, and uniformly mixing the propylene glycol with the sodium alginate solution to prepare the nasal spray containing menthol plus the semaglutin of dextro-camphol.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The weight-reducing polypeptide pharmaceutical composition is characterized by comprising the following components in parts by weight: 0.05-0.3 part of weight-reducing polypeptide and 0.05-1 part of absorption promoter, wherein the absorption promoter is at least one selected from Tween 80, poloxamer 188, HS-15, EDTA, sorbitol, menthol (the purity is more than or equal to 99.0 percent) and dextroamphenol (the purity is more than or equal to 99.0 percent).
2. The weight-reducing polypeptide pharmaceutical composition of claim 1, wherein the weight-reducing polypeptide is selected from at least one of telipopeptide, liraglutide, semraglutide.
3. The weight-reducing polypeptide pharmaceutical composition according to claim 1 or 2, wherein the absorption enhancer is selected from at least one of poloxamer 188, menthol, dexamphetamol; preferably, the absorption enhancer is selected from poloxamer 188 and one of menthol and dextromethorphan.
4. Use of a weight-reducing polypeptide pharmaceutical composition according to any one of claims 1 to 3 for the preparation of a weight-reducing medicament.
5. The use according to claim 4, wherein the weight-reducing medicament is an oral and/or nasal spray.
6. The nasal spray is characterized by comprising the following raw materials in parts by weight: 0.05 to 0.3 part of weight-reducing polypeptide, 0.5 to 4 parts of sodium alginate, 0.05 to 1 part of absorption accelerator, 1 to 5 parts of propylene glycol and 50 to 200 parts of water.
7. The nasal spray of claim 6, wherein the weight-reducing polypeptide is at least one of telipopeptide, liraglutide, semraglutide; preferably, the weight-reducing polypeptide is 0.1 to 0.2 parts.
8. The nasal spray of claim 6 or 7, wherein the absorption enhancer is selected from at least one of poloxamer 188, menthol, and dexamphetamine; preferably, the absorption enhancer is selected from poloxamer 188, menthol and one of right borneol; preferably, the absorption enhancer is 0.1 to 0.5 part.
9. The nasal spray according to any one of claims 6 to 8, characterized in that the nasal spray comprises the following raw materials in parts by weight: 0.1 to 0.2 part of weight-reducing polypeptide, 0.5 to 2 parts of sodium alginate, 0.1 to 0.5 part of absorption accelerator, 2 to 4 parts of propylene glycol and 50 to 200 parts of water.
10. A method of preparing a nasal spray according to any one of claims 6 to 9, comprising the steps of: the nasal spray is prepared by mixing the components of the nasal spray and preparing into a solution.
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