WO2012113117A1 - Préparation orale comprenant une protéine ou un polypeptide, son procédé de préparation et son utilisation - Google Patents
Préparation orale comprenant une protéine ou un polypeptide, son procédé de préparation et son utilisation Download PDFInfo
- Publication number
- WO2012113117A1 WO2012113117A1 PCT/CN2011/000815 CN2011000815W WO2012113117A1 WO 2012113117 A1 WO2012113117 A1 WO 2012113117A1 CN 2011000815 W CN2011000815 W CN 2011000815W WO 2012113117 A1 WO2012113117 A1 WO 2012113117A1
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- weight
- parts
- emulsion
- fatty acid
- polyethylene glycol
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 41
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 41
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 39
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 33
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 31
- 239000000839 emulsion Substances 0.000 claims abstract description 81
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- -1 aliphatic ester Chemical class 0.000 claims abstract description 14
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 41
- 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 claims description 34
- 239000002202 Polyethylene glycol Substances 0.000 claims description 31
- 229920001223 polyethylene glycol Polymers 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- 229940079593 drug Drugs 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 210000004369 blood Anatomy 0.000 claims description 21
- 239000008280 blood Substances 0.000 claims description 21
- 229930003427 Vitamin E Natural products 0.000 claims description 19
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 19
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 19
- 239000011709 vitamin E Substances 0.000 claims description 19
- 229940046009 vitamin E Drugs 0.000 claims description 19
- 235000019165 vitamin E Nutrition 0.000 claims description 19
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 18
- 239000012071 phase Substances 0.000 claims description 18
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 16
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- 150000003904 phospholipids Chemical class 0.000 claims description 16
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- 238000000034 method Methods 0.000 claims description 15
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- VQENOYXMFIFHCY-UHFFFAOYSA-N Monoglyceride citrate Chemical compound OCC(O)COC(=O)CC(O)(C(O)=O)CC(O)=O VQENOYXMFIFHCY-UHFFFAOYSA-N 0.000 claims description 12
- JRTVEUGOGWTHTR-UHFFFAOYSA-N dodecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCC JRTVEUGOGWTHTR-UHFFFAOYSA-N 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 235000011187 glycerol Nutrition 0.000 claims description 11
- 239000008347 soybean phospholipid Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 claims description 10
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- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
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- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 8
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- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 8
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- 101000993800 Sus scrofa Insulin Proteins 0.000 claims description 5
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- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 3
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- 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
- 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
-
- 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
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
-
- 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
- A61P3/08—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
Definitions
- the present invention is in the field of pharmacy and formulation, and relates to an oral preparation containing a protein or a polypeptide, a preparation method thereof and use thereof. Background technique
- Insulin in, parathyroid hormone, ca lci tonin, growth hormone, incretin-like peptide-1 (GLP-1) and other protein or peptide drugs clinical An important drug in treatment.
- GLP-1 incretin-like peptide-1
- other protein or peptide drugs clinical An important drug in treatment.
- a common feature of these drugs is that oral administration is almost ineffective and requires frequent injections.
- Protein shield polypeptides limit their use due to the lack of oral administration routes in the clinic.
- the degradation of proteases in the gastrointestinal tract and the intestinal epithelial barrier function limit the oral bioavailability of these drugs.
- researchers have used strategies such as covalent modification, enzyme inhibitors, absorption enhancers, microsphere microspheres, and W/0 (water-in-oil) emulsions to address the low oral bioavailability of protein peptides. .
- Car ino GP et al (2000) J. Control. Release. 65: 261-269; Kathryn Wehi tehead, et al (2004) J. Control. Release. 98: 37-45; Yan Pan, et al (2002) Int J.
- covalent modification may reduce the activity of the drug, and may change the pharmacology and toxicology of the drug molecule, resulting in high preparation cost and serious safety hazard; the enzyme inhibitor can effectively prevent the hydrolysis of the protease,
- enzyme inhibitors also affect the digestion of food proteins. Long-term use will cause digestion and absorption disorders and even pancreatic enlargement or hyperplasia; absorption enhancers may cause irreversible damage to the cell membrane while increasing intestinal permeability. Long-term use can lead to membrane poisoning; micro-sphere microsphere preparation engineering often requires the participation of organic solvents, and requires high-speed centrifugation and other steps, increasing the complexity of the process.
- the drug used has a molecular weight of less than 700 Daltons, and the drug can be bioavailable up to 2% after oral administration, with protein
- P. Constantinides obtained a combination of high HLB (hydrophilic-lipophilic balance) surfactants and low HLB surfactants to obtain different hydrophilic molecules including RGD, descending hormone, and insulin.
- the W/0 formulation was emulsified, but its oral bioavailability effect was not reported publicly.
- Mao-Bo Cheng et al. prepared an oral W/0 microemulsion preparation containing guanidine kinase (Mao-Bo Cheng, et al (2008) J. Control. Release. 129: 41-48).
- microemulsion as a carrier to achieve the encapsulation of proteins or peptide drugs.
- these preparations have poor emulsifying effect, large difference in particle size, and stratification of the emulsion after emulsification (after dilution); or the clear area is narrow and cannot be uniformly dispersed after dilution, thereby limiting its oral biology. Utilization effect. It may even cause emulsion demulsification, protein peptide molecules encapsulated in the inner aqueous phase will be released quickly, degraded by proteases in the gastrointestinal tract, or incompatible with substances such as medium chain fatty acid esters.
- the protein peptide molecules are flocculated and precipitated, resulting in loss of drug activity and difficulty in being absorbed by the body. Moreover, after oral administration of these products, the drug has a slow onset of action, and it usually takes 4 hours or even 8 hours to reach the peak plasma concentration, which is greatly different from the existing drugs, which brings inconvenience to clinical application (G. Sharma , et al (2010) EUR. J. PHARM. BIOPHARM. 76: 159-169; Amani El sayed, et al (2009) EUR. J. PHARM. BIOPHARM. 73: 269 - 279 ) 0 SUMMARY
- the inventors have surprisingly found through a large amount of trials and creative labor that the compatibility of the obtained protein or polypeptide-containing emulsion is obtained by selecting a high HLB surfactant and a medium chain fatty acid ester (especially when a phospholipid is added). It is very stable and the emulsion maintains excellent bioavailability while maintaining excellent emulsifying properties. Moreover, when the emulsion is diluted by water, it can be uniformly dispersed, and the generated droplet size distribution is relatively uniform, which does not cause the emulsion to be unclear. Moreover, the emulsion of the invention can be quickly absorbed after oral administration, and has a blood concentration or a peak effect time similar to that of the similar injection drug, which will greatly facilitate clinical application.
- An aspect of the invention relates to an emulsion comprising a protein or polypeptide, an aqueous phase, an oil phase, an emulsifier, characterized in that the oil phase contains a medium chain fatty acid ester (for example, a medium chain) a fatty acid glyceride), and the emulsifier comprises an emulsifier having an HLB value greater than 12; Specifically, the oil phase is a medium chain fatty acid ester (for example, a medium chain fatty acid glyceride), and the emulsifier is an emulsifier having an HLB value of more than 12.
- the protein or polypeptide is an active ingredient (medicinal ingredient) or an active ingredient of the emulsion.
- the protein or polypeptide may be isolated from a living organism, or may be obtained by genetic engineering means such as genetic recombination or chemical synthesis.
- the protein or polypeptide is calcitonin, insulin, GLP-1, parathyroid hormone, parathyroid hormone 1-84, parathyroid hormone 1- 34, or growth hormone.
- the calcitonin comprises salmon, salmon, and human calcitonin; the insulin, including pig, cow, human, and recombinant insulin; the GLP-1, including recombinant and synthetic GLP-1; the parathyroid hormone, including human parathyroid hormone 1-84, recombinant and/or synthetic parathyroid hormone 1-34; the long hormones, including pig, cow, human body and recombination Growth hormone.
- the medium chain fatty acid ester is a medium chain fatty acid glyceride, a pegylated medium chain fatty acid glyceride, an acetylated medium chain fatty acid glyceride, a medium chain fatty acid Propylene glycol ester, medium chain fatty acid butylene glycol ester, or medium chain fatty acid polyethylene glycol ester.
- the medium chain fatty acid glyceride may be one or more of a medium chain fatty acid monoglyceride, a medium chain fatty acid diglyceride, and a medium chain fatty acid triglyceride.
- the medium chain fatty acid in the medium chain fatty acid glyceride may be bonded to any one or more hydroxyl positions in the glycerol molecule, and when forming a medium chain fatty acid diglyceride or a medium chain fatty acid triglyceride, the hydroxyl group in the glycerol molecule
- the bound medium chain fatty acid molecules can be the same or different.
- the medium chain fatty acid means a fatty acid having 6 to 12 carbon atoms, which may be saturated or unsaturated, and may be linear or branched.
- the medium chain fatty acid is octanoic acid and/or citric acid.
- the medium chain fatty acid ester is a carbon number a monoglyceride, a diglyceride, and/or a triglyceride of a fatty acid of 6 to 12; more specifically, a glyceryl caprylate, a polyglyceryl octanoate/capric glyceride, a caprylic acid glyceride, a hydrazine One or more of the acid glycerides.
- the emulsion according to any one of the present invention, wherein the emulsifier having an HLB value of more than 12 is selected from the group consisting of poloxamer 188, poloxamer 407, Tween 20, Tween 80, and polyethylene glycol.
- the emulsifier having an HLB value of more than 12 is selected from the group consisting of poloxamer 188, poloxamer 407, Tween 20, Tween 80, and polyethylene glycol.
- the medium-chain fatty acid glycerol for example, medium-chain fatty acid glycerol
- the emulsifier having an HLB value of more than 12 is from 20 to 2000 parts by weight; specifically, the protein or polypeptide is from 0.01 to 0.5 parts by weight. 01 ⁇
- the weight of the protein is 0. 01 - 0. 3 parts by weight, the protein or the polypeptide is 0. 01 - 0.
- the emulsifier having an HLB value of more than 12 is 50 - 1 000 parts by weight;
- the medium chain fatty acid ester (for example, a medium chain fatty acid glyceride) is from 100 to 300 parts by weight, and the emulsifier having an HLB value of more than 12 is from 50 to 500 parts by weight.
- the emulsion further contains a phospholipid, and the molar ratio of the phospholipid to the protein or polypeptide is from 10:1 to 1 000:1.
- the molar ratio of the phospholipid to the protein or polypeptide is preferably from 20:1 to 500:1, more preferably from 60:1 to 200:1.
- the phospholipid is preferably soy lecithin and/or egg yolk lecithin.
- the emulsion according to any one of the present invention which further comprises a pharmaceutically acceptable excipient such as a dispersion medium, an isotonic agent, an antioxidant, a lyoprotectant, or a pH adjuster.
- a pharmaceutically acceptable excipient such as a dispersion medium, an isotonic agent, an antioxidant, a lyoprotectant, or a pH adjuster.
- dispersion medium is selected from the group consisting of Chitosan, silica, magnesium aluminum silicate, sodium carboxymethyl cellulose, crosslinked cellulose sodium, croscarmellose sodium, magnesium sulfate, magnesium stearate, polyethylene glycol 400, and One or more of glycerin.
- the antioxidant is selected from the group consisting of L-cysteine hydrochloride, sodium sulfite, sodium hydrogen sulfite, propyl gallate, glutathione, sodium metabisulfite, One or more of potassium metabisulfite, and vitamin E.
- lyoprotectant is selected from one or more of sucrose, lactose, trehalose, glucose, glycine, arginine, and xylitol.
- pH adjusting agent is selected from the group consisting of hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate One or more of disodium hydrogen phosphate, and sodium dihydrogen phosphate.
- Microemulsion is an isotropic, transparent, thermodynamically stable dispersion consisting of water, oil, or emulsifier, usually having a particle size of less than 500 nm.
- An emulsion according to any one of the invention which is administered orally.
- the emulsion according to any one of the present invention the components and contents thereof are as follows: Recombinant human insulin 0. 008 - 0. 012 parts by weight Hydrochloric acid
- physiological saline 0. 4 - 0. 6 parts by weight of medium chain fatty acid triglycerides (eg Crodamol ⁇ & ⁇
- the present invention also relates to the use of the emulsion for the preparation of a medicament for treating or preventing diabetes, or lowering blood sugar.
- the invention further relates to a method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion.
- the components and levels of the emulsion are as follows:
- Polyethylene glycol dodecyl stearate for example
- Vitamin E 0.1 The emulsion according to any one of the present invention, the components and contents thereof are as follows:
- Poloxamer 188 eg Lutrol F68, BASF
- soy lecithin eg Epikuron 170
- the present invention also relates to the use of the emulsion in the preparation of a medicament for treating or preventing diabetes, or lowering blood sugar.
- the invention further relates to a method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion.
- the components and levels of the emulsion are as follows:
- Polyethylene glycol octanoate / glyceryl citrate for example
- Poloxamer 188 eg Lutrol F68, BASF 0.2 parts by weight
- Soy lecithin eg Epikuron 170
- PTH 1-34 0.0008-0.0012 parts by weight PBS buffer 0.4-0.6 parts by weight glyceryl caprylate (eg Miglyol ® 812,
- Polyethylene glycol dodecyl stearate for example
- Tocopheryl succinate polyethylene glycol ester eg TPGS
- the present invention also relates to the use of the emulsion in the preparation of a medicament for treating or preventing osteoporosis.
- the invention further relates to a method of treating or preventing osteoporosis comprising the step of administering an effective amount of the emulsion.
- the components and levels of the emulsion are as follows:
- Caprylic glyceryl citrate (eg Miglyol ® 812,
- Polyethylene glycol dodecyl stearate for example
- Tocopheryl succinate polyethylene glycol ester eg TPGS
- Vitamin E 0.1 parts by weight.
- GLP-1 0.08-0.12 parts by weight Deionized water 55 - 65 parts by weight Caprylic glyceryl citrate (eg Miglyol ® 812,
- Poloxamer 188 eg Lutrol F68, BASF
- Soybean egg fat eg Epikuron 170
- Glycerol 8- 12 parts by weight Polyethylene glycol 400 6-8 parts by weight
- the present invention also relates to the use of the emulsion in the preparation of a medicament for treating or preventing diabetes, or lowering blood sugar.
- the invention further relates to a method of treating or preventing diabetes, or lowering blood glucose, comprising the step of administering an effective amount of the emulsion.
- the components and levels of the emulsion are as follows:
- Poloxamer 188 eg Lutrol F68, BASF 1.5 parts by weight
- Soybean egg fat (eg Epikuron 170,
- An emulsion according to any one of the invention which is a lyophilized emulsion (lyophilized formulation).
- a lyophilized preparation of the above emulsion can be prepared, for example, by adding an appropriate amount of a lyoprotectant to the above emulsion, and then removing the moisture by freeze-drying (for example, temperature - 40 ° C, working vacuum of 30 Pa). Thereby obtaining a dried protein or polypeptide lyophilized emulsion. After the freezing, the emulsion does not contain a water phase, and can be formed into a final dosage form such as a tablet or a capsule.
- the method of preparing the emulsion of the present invention for example 1 using the following steps:
- step 1) Add the product of step 1) to the product of step 2) at 4 - 37 ° C, and continue stirring at 200 - 800 rpm until a clear and clear homogeneous preparation is formed, and finally a protein or peptide containing drug is obtained.
- the component dissolved in the aqueous phase further comprises a pH adjusting agent and/or an isotonic agent.
- step B it is possible to prepare the phospholipid complex for those skilled in the art.
- the following method is used: the phospholipid and the protein are respectively dissolved in the organic phase and the aqueous phase, and after mixing, freeze-dried (-40 to -150 ° C, or even lower; pressure is lower than -100 Pa, lower than -200 Pa , or less than -300 Pa; lyophilization time of 12 hours or more, such as 12 - 24 hours, or more than 24 hours, such as 24-48 hours), to obtain a protein phospholipid complex.
- the phospholipids and eggs The white matter or polypeptide molar ratio is from 10:1 to 1000:1.
- the molar ratio of the phospholipid to the protein or polypeptide is more preferably from 20:1 to 500:1, further preferably from 60:1 to 200:1.
- the phospholipid is preferably soy egg yolk and/or egg yolk lecithin.
- the organic phase is dichloromethane, acetone, or dimethyl sulfoxide, preferably dimethyl sulfoxide.
- the mixed mixture further includes deionized water; optionally, a dispersing shield and/or an antioxidant.
- the preparation method further comprises the step 4): lyophilizing the emulsion prepared in the step 3) to obtain a lyophilized emulsion.
- the lyophilization step described in step B) and step 4) may employ the lyoprotectant described herein.
- the term "mice l les" refers to a molecularly ordered aggregate of a hydrophobic group as a core and a hydrophilic group as a shell formed by association of several solute molecules or ions in a solution. Micellar is a colloidal dispersion system and belongs to a class of associative colloids. When the amphiphilic polymer substance is dispersed in a solution to a critical micelle concentration (CMC), the molecular association self-assembles to form a micelle.
- CMC critical micelle concentration
- a nonionic surfactant having an HLB value (hydrophilic-lipophilic balance) of 12 or more is used as an emulsifier
- a medium-chain fatty acid ester is an oil phase
- an aqueous solution containing a protein-peptide drug is an aqueous phase, and is prepared.
- the remarkable feature of the invention is that the problem of emulsifying performance of the protein polypeptide emulsion is solved, the oral bioavailability of the protein or polypeptide drug can be significantly increased, the application prospect is very promising, and the preparation process is simple, and is suitable for industrial production, the dosage form of the product. It may be an emulsion, a micelle solution, a self-emulsifying administration system, a paste substance or a solid powder.
- Fig. 1 Phase diagram of blood glucose in rats after ileal administration.
- Fig. 2 PTH1-34 blood concentration.
- Fig. 3 PTH1-34 efficacy test.
- the four columnar figures from left to right represent the oral group, the injection group, the control group, and the sham operation group.
- Example 1 Preparation of Oral Insulin Formulation (Sample 1)
- Poloxamer 188 (Lutrol F68, BASF) 0.2 g
- Soybean Eggs ( Epikuron 170, Degussa ) 0 ⁇ 5 grams
- the preparation method of the preparation is as follows:
- porcine insulin soy lecithin complex is added to the product in step 3) at room temperature, and the mixture is stirred at a speed of 200 r/min for 15 min;
- step 5 After mixing the above weight of silica, crosslinked cellulose sodium and stearic acid at room temperature, the product of step 4) is added dropwise at a speed of 200 r/min, and then the rotation speed is increased to 300 r/min, and After 30 minutes of lyophilization (temperature - 40 ° C, working vacuum of 30 Pa), the oral preparation of insulin was finally obtained as a sample.
- Sample 1 can be formulated into a final dosage form such as a tablet or a capsule.
- Example 2 Preparation of an oral insulin preparation (Sample 2)
- step 3 A solution was added dropwise to the product of step 2) at room temperature, and the mixture was stirred until clear and clear at 200 r/min, and finally an insulin oral preparation was obtained as sample 2.
- Example 3 Preparation of recombinant human parathyroid hormone 1-34 oral preparation (Sample 3)
- caprylic caproic acid glyceride polyethylene glycol dodecyl stearate, tocopherol succinate polyethylene glycol ester, Tween 20, vitamin E at 60 ° C To clear and clear;
- step 3 At room temperature, add the A solution dropwise to the product of step 2), stir the mixture for 15 min at lOOr/min, and finally obtain the PTH 1-34 oral preparation as sample 3.
- Example 4 Preparation of GLP-1 Oral Formulation (Sample 4)
- Soybean egg fat (Epikuron 170, Degussa) 7 g
- Vitamin E 0.3 g
- the preparation method of the preparation is as follows:
- GLP-1 soybean phospholipid complex 1) The above weight of GLP-1 is dissolved in 5 g of deionized water at room temperature, and the above-mentioned weight of soybean lecithin is dissolved in 30 ml of dichlorosilane. After mixing the two phases, it is placed in liquid nitrogen for 30 min, and the freezing is performed. Dry, the obtained product is GLP-1 soybean phospholipid complex;
- step 3 At room temperature, at 500r / min, the GLP-1 soy lecithin complex is added to the product of step 2), stirring is continued for 5min, to obtain colostrum B;
- Example 4 Stability study of samples 2, 3, and 4.
- the stability of the oral preparation samples 2, 3, and 4 was determined by visually observing whether the preparation exhibited flocculent substances or produced an "oil-water" interface.
- the stability of insulin in samples 1, 2 was studied by high performance liquid chromatography.
- the color meter used was the Agilent 1200.
- the mobile phase is a linear gradient elution, in which mobile phase A is acetonitrile and mobile phase B is 0.05 mol/L sodium dihydrogen phosphate (pH 3.0): 0 - lOmin mobile phase A is increased from 20% to 50%, mobile phase B Change from 80% to 50%; 11 - 15min mobile phase A changes from 50% to 80%, mobile phase B changes from 50% to 20%; 21 - 25min mobile phase A changes from 80% to 20%, mobile phase B Change from 20% to 80%.
- the flow rate is 1.0 mL/min
- the detection wavelength is 214 nm
- the column temperature is 40° (:.
- sample 2 preparation, sample 3 preparation, and sample 4 preparation of C did not produce macroscopic flocculent substances, nor did they produce an "oil-water" interface.
- the resulting preparation was placed in a refrigerator at 4 ° C, and the drug content was determined at 0 days, 3 months, and 6 months after the placement.
- HPLC HPLC method was used to determine the content of active pharmaceutical ingredients. The results are shown in Table 1.
- Example 2 Samples prepared in Example 3 2, 3, placed in a refrigerator at 4 ° C, and measured the particle size and appearance of the emulsion at 0 days, the third month, and the sixth month.
- the particle size was measured with a Malvern Zetasizer 3000HSA particle size analyzer. Before the measurement, samples 2 and 3 were diluted 5, 30, and 100 times with Millipore ultrapure water, and the appearance of each dilution was visually determined. The results are shown in Table 2 below.
- Test group 1 Male SD rats weighing 180-220 g, 6 rats, were administered the sample 1 prepared in Example 1.
- Test group 2 Male SD rats having a body weight of 180-220 g, 6 rats, were administered the sample 2 prepared in Example 2.
- Control group Male Sprague-Dawley rats weighing 180-220 g, 6 doses For insulin aqueous solution, subcutaneous injection.
- mice Male Sprague-Dawley rats weighing 180-220 g were fasted for 12 h and the test was started; the animals were anesthetized with 50 mg of sodium pentobarbital before the experiment. After the animals were anesthetized, they were tied in a supine position, and a small opening was made in the abdomen, and the ileum was administered by a dispenser. After administration, the incision was sutured, and at the time of 0.5, 1, 2, 3, and 4 h, blood was taken from the tail vein, blood glucose was measured using a Roche blood glucose meter, and the average blood glucose level of 6 rats in each group was calculated.
- test group 1 is administered as sample 1, according to insulin, the dose is 0.3 mg/kg; the test group 2 is administered as sample 2, and the insulin is administered at a dose of 1 mg/kg; 02mg/ ⁇ The drug was administered in a dose of 0. 02mg / kg.
- Figure 1 shows that both Sample 1 and Sample 2 are effective in reducing blood glucose in rats.
- the blood glucose concentration was reduced to the lowest value 1 hour after the administration.
- Example 9 Gavage absorption test of PTH1-34 mouth Yueliang preparation
- Test group Male Sprague-Dawley rats weighing from 180 to 220 g, 12, and the sample prepared in Example 3, were administered to the stomach.
- Control group Male SD rats weighing 180-220 g, 10 rats, were administered PTH1-34 PBS solution and injected subcutaneously.
- the test group was administered with stomach, and the control group was treated with PTH1-34.
- Serum PTH 1-34 concentration with PTH 1-34 Sensitivity EIA kit (Alpco Di agnos t ic, Cat. No. 31-IPTHUU-E01) detected that the kit reacts exclusively with exogenous PTH1-34, but does not react with the rat itself, so it can be detected.
- PTH1-34 which is ⁇ 1-34 into the blood of rats after administration. There were 12 animals in the gavage group and 10 animals in the injection group. After administration, the PTH1-34 plasma concentration changes as shown in Figure 2.
- FIG. 2 shows that after intragastric administration, PTH1-34 can rapidly enter the rat body, and the plasma concentration peak time is very similar (the peak time of the blood concentration in the experimental group is 18.3 ⁇ 1. 2 minutes, control The bioavailability of the intragastric administration group relative to the injection group was 6.73%.
- Example 10 Efficacy test of PTH1-34 oral preparation
- Oral group Six female rats of 2 months old were selected, and the bilateral ovaries of the female rats were excised, and the sample prepared in Example 3 was administered and administered by oral gavage.
- Injection group Six female rats of 2 months old were selected, and the bilateral ovaries of the female rats were excised, and the sample prepared in Example 3 was administered, PTH1-34 PBS injection, subcutaneously.
- Control group Six female rats of 2 months old were selected, and the bilateral ovaries of the female rats were excised, and the sample 3 prepared in Example 3 was administered without administration.
- Sham-operated group Five female rats of 2 months old were selected, the ovaries were preserved, and the same size of fat near the egg nest was removed, and no drug was administered.
- Two-month-old female rats were randomly divided into the castration group (castrated animals, bilateral ovaries by surgery, including the oral group, the injection group, the control group) and the sham operation group for 6 weeks, followed by oral administration.
- the group and the injection group were continuously administered for 8 weeks, administered 6 days a week, once a day, and the rats were fasted for 10 hours before administration.
- BMD Bone mineral density
- BMC bone mineral content
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Abstract
L'invention porte sur une émulsion pour administration orale comprenant une protéine ou un polypeptide, sur son procédé de préparation et sur son utilisation. L'émulsion comprend une protéine ou un polypeptide, une phase aqueuse, une phase huileuse et un émulsifiant, la phase huileuse comprenant un ester aliphatique à chaîne moyenne et l'émulsifiant comprenant un émulsifiant ayant une valeur de rapport hydrophile/lipophile (HLB) supérieure à 12. L'émulsion permet d'améliorer la biodisponibilité. L'émulsion peut être uniformément dispersée et produit des gouttes d'émulsion ayant une taille uniforme des grains lorsqu'elle est diluée avec de l'eau.
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CN102125520A (zh) * | 2011-02-24 | 2011-07-20 | 美迪思生物科技(北京)有限公司 | 含亲水性生物大分子的乳剂、其制备方法及用途 |
CN102552174B (zh) * | 2011-11-18 | 2015-07-22 | 中山大学 | 一种高载药量高包封率多肽/蛋白类药物纳米粒的制备方法 |
CN103861090B (zh) * | 2012-12-18 | 2017-06-13 | 美迪思生物科技(北京)有限公司 | 含蛋白或多肽的疏水溶液、其制备方法及用途 |
CN103655487B (zh) * | 2013-11-15 | 2015-05-06 | 西安力邦制药有限公司 | 一种注射用前列地尔冻干乳剂 |
CN110639425B (zh) * | 2019-10-22 | 2021-09-17 | 湖北文理学院 | 复合乳化剂的制备方法 |
CN113952301A (zh) * | 2021-11-17 | 2022-01-21 | 胡振华 | 中链脂肪酸作为促吸收剂制备药物组合物乳剂的应用 |
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CN1456351A (zh) * | 2003-05-26 | 2003-11-19 | 上海医药工业研究院 | 一种口服多肽类药物自乳化附聚物及其制备方法 |
CN101422431A (zh) * | 2007-12-28 | 2009-05-06 | 上海医药工业研究院 | 胰岛素经鼻给药制剂 |
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CN101422431A (zh) * | 2007-12-28 | 2009-05-06 | 上海医药工业研究院 | 胰岛素经鼻给药制剂 |
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