WO2021185265A1 - 口服药物组合物 - Google Patents
口服药物组合物 Download PDFInfo
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- WO2021185265A1 WO2021185265A1 PCT/CN2021/081224 CN2021081224W WO2021185265A1 WO 2021185265 A1 WO2021185265 A1 WO 2021185265A1 CN 2021081224 W CN2021081224 W CN 2021081224W WO 2021185265 A1 WO2021185265 A1 WO 2021185265A1
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- Prior art keywords
- compound
- pharmaceutical composition
- oral pharmaceutical
- acid
- cellulose
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- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229950011186 semaglutide Drugs 0.000 description 1
- 108010060325 semaglutide Proteins 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940045845 sodium myristate Drugs 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- JUQGWKYSEXPRGL-UHFFFAOYSA-M sodium;tetradecanoate Chemical compound [Na+].CCCCCCCCCCCCCC([O-])=O JUQGWKYSEXPRGL-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- 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
- A61K47/16—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
-
- 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
- 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
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/08—Solutions
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Definitions
- the invention relates to an oral pharmaceutical composition of peptide amide compounds.
- the invention also relates to a preparation method and application of the oral pharmaceutical composition.
- Polypeptide drugs can be used for the treatment of many diseases because of their wide indications, high safety, remarkable selectivity and effectiveness. With the development of biotechnology, a large number of peptide drugs have entered the market. Currently, the commercially available peptide preparations are mainly injections and nasal sprays, and these administration methods cause great inconvenience to patients. For patients, oral administration is more convenient and does not directly damage the skin or mucous membranes, which can alleviate the suffering of patients and improve patient compliance. However, the oral administration of polypeptide drugs is restricted by a series of barriers, which are easily degraded and destroyed by proteolytic enzymes in the digestive tract.
- peptide drugs are susceptible to degradation by proteases activated by gastric acid, leading to reduced activity of peptide drugs.
- Enteric coating technology is usually used to protect the peptides, which is complicated and costly.
- WO2019/015644 discloses a class of peptide amide compounds with novel structures and good analgesic effects.
- the general formula is as follows: Such compounds have obvious agonistic effects on human kappa-opioid receptors.
- compound A Chemical name: 7-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)-2-acetyl-2,7-diazaspiro[3.5]non Alkyl (7-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)-2-acetyl-2,7-diazaspiro[3.5]nonane).
- the present invention develops an oral polypeptide drug composition.
- the composition is prepared by co-preparing a polypeptide drug with a specific absorption enhancer and other inactive ingredients, which can promote the permeability of the polypeptide drug in the gastrointestinal tract and improve the The oral bioavailability of polypeptide drugs enables oral administration, thereby improving patient compliance.
- the invention provides a simple intragastric drug delivery technology, which simplifies the process to a large extent, and can greatly improve the oral bioavailability of the polypeptide compound A.
- An object of the present invention is to provide an oral pharmaceutical composition of Compound A:
- the present invention significantly improves the oral bioavailability of compound A, and is more conducive to the development of compound A as a medicine.
- Another object of the present invention is to provide a method for preparing the oral pharmaceutical composition.
- Another object of the present invention is to provide the use of the oral pharmaceutical composition.
- the present invention provides an oral pharmaceutical composition comprising:
- the absorption enhancer is selected from N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof, 4-[(4-chloro-2-hydroxy-benzyl Acyl)amino)butyric acid or its pharmaceutically acceptable salt, lauroyl-L-carnitine or its hydrochloride, sodium caprylate, sodium caprate, capric acid, one of caprylic acid capric acid polyethylene glycol glyceride or Multiple;
- the pharmaceutically acceptable salt is selected from sodium salt, potassium salt or calcium salt.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof.
- the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof is 1:20-1:80, preferably 1:40 -1:60, more preferably 1:40.
- the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof is 1:20.
- the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof is 1:30.
- the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof is 1:40.
- the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof is 1:80.
- the absorption enhancer is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate.
- the absorption enhancer is potassium N-[8-(2-hydroxybenzoyl)amino]caprylate.
- the absorption enhancer is calcium N-[8-(2-hydroxybenzoyl)amino]caprylate.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof;
- a filler preferably the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogen phosphate, pregelatinized starch, and calcium hydrogen phosphate dihydrate;
- the binder preferably the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- Disintegrant preferably the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch ;
- pH regulator preferably the pH regulator is selected from one or more of citric acid, anhydrous citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogen phosphate, and calcium carbonate ;
- Surfactant preferably the surfactant is selected from polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate One or more
- Lubricant preferably the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof.
- the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:20-1:200, It is preferably 1:40 to 1:80, and more preferably 1:40.
- the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:20.
- the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:40.
- the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:80.
- the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:100.
- the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:200.
- the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 3:200.
- the absorption enhancer is sodium 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyrate.
- the absorption enhancer is potassium 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyrate.
- the absorption enhancer is calcium 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyrate.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
- a filler preferably the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogen phosphate, pregelatinized starch, and calcium hydrogen phosphate dihydrate;
- the binder preferably the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- Disintegrant preferably the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch ;
- pH regulator preferably the pH regulator is selected from one or more of citric acid, anhydrous citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogen phosphate, and calcium carbonate ;
- Surfactant preferably the surfactant is selected from polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate One or more
- Lubricant preferably the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate.
- the lubricant is magnesium stearate.
- the filler is microcrystalline cellulose and/or anhydrous calcium hydrogen phosphate.
- the adhesive is povidone.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: lubricant is 1:(20-200 ): (0.2-2).
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: lubricant is 1:200:2.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: magnesium stearate is 1:(20 -200): (0.2-2).
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: magnesium stearate is 1:200: 2.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: filler: binder is 1: (20-200):200:5.
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: filler: binder is 1: 200:200:5.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: microcrystalline cellulose: povidone is 1:(20-200):200:5.
- the weight ratio of compound A: 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: microcrystalline cellulose: povidone is 1:200:200:5.
- the oral pharmaceutical composition includes:
- the oral pharmaceutical composition includes:
- compound A 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: microcrystalline cellulose: povidone: stearic acid
- the weight ratio of magnesium is (1-3):(20-200):200:5:(1-5).
- compound A 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: microcrystalline cellulose: povidone: stearic acid
- the weight ratio of magnesium is 1:200:200:5:(4-5), for example, 1:200:200:5:4.06. .
- compound A 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: microcrystalline cellulose: povidone: stearic acid
- the weight ratio of magnesium is 3:200:200:5:4.
- the oral pharmaceutical composition includes:
- compound A 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: povidone: anhydrous calcium hydrogen phosphate: stearin
- povidone anhydrous calcium hydrogen phosphate: stearin
- the weight ratio of magnesium acid is (1-3):(20-200):5:200:(1-5).
- compound A 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: povidone: anhydrous calcium hydrogen phosphate: stearin
- the weight ratio of magnesium acid is 3:200:5:200:4.
- the oral pharmaceutical composition includes:
- the oral pharmaceutical composition includes:
- the oral pharmaceutical composition includes:
- compound A 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof: propylene glycol monolaurate: polyethylene glycol 300:
- the weight ratio of anhydrous calcium hydrogen phosphate: magnesium stearate is (1-3):(20-200):(3-9):(3-9):200:(1-5), for example 3:200 :3:3:200:1.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from lauroyl-L-carnitine or its hydrochloride.
- the weight ratio of compound A to lauroyl-L-carnitine or its hydrochloride is 1:10-1:150, such as 1:10, 1:15, 1:20, 1: 30, 1:50, 1:75, 1:100 or 1:150.
- the oral pharmaceutical composition includes:
- Absorption enhancer selected from lauroyl-L-carnitine.
- the weight ratio of compound A to lauroyl-L-carnitine is 1:10-1:50, preferably 1:10-1:20, and more preferably 1:10.
- the weight ratio of compound A to lauroyl-L-carnitine is 1:10.
- the weight ratio of compound A to lauroyl-L-carnitine is 1:20.
- the weight ratio of compound A to lauroyl-L-carnitine is 1:50.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from lauroyl-L-carnitine hydrochloride.
- the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:15 to 1:150, preferably the amount of lauroyl-L-carnitine hydrochloride is 75-150 mg, More preferably, the amount of lauroyl-L-carnitine hydrochloride is 75 mg.
- the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:15.
- the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:20.
- the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:30.
- the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:75.
- the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:100.
- the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:150.
- the absorption enhancer in the oral pharmaceutical composition when the absorption enhancer in the oral pharmaceutical composition is selected from lauroyl-L-carnitine or its hydrochloride, the pharmaceutical composition does not contain enteric excipients.
- the dosage form of the pharmaceutical composition is not enteric-coated tablets or enteric-coated capsules .
- the dosage form of the pharmaceutical composition is a gastric soluble capsule, a gastric soluble tablet or Stomach dissolving granules.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from lauroyl-L-carnitine or its hydrochloride
- a filler preferably the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogen phosphate, pregelatinized starch, and calcium hydrogen phosphate dihydrate;
- the binder preferably the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- Disintegrant preferably the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch ;
- pH regulator preferably the pH regulator is selected from one or more of citric acid, anhydrous citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogen phosphate, and calcium carbonate ;
- Surfactant preferably the surfactant is selected from polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate One or more
- Lubricant preferably the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: lauroyl-L-carnitine: pH adjuster is 1:(10-50):24.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: lauroyl-L-carnitine: citric acid is 1:(10-50):24.
- the weight ratio of compound A: lauroyl-L-carnitine: citric acid is 1:50:24.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A to sodium caprate is 1:50-1:200, preferably 1:100-1:200, most preferably 1:100.
- the weight ratio of compound A to sodium caprate is 1:50.
- the weight ratio of compound A to sodium caprate is 1:100.
- the weight ratio of compound A to sodium caprate is 1:200.
- the oral pharmaceutical composition includes:
- a filler preferably the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogen phosphate, pregelatinized starch, and calcium hydrogen phosphate dihydrate;
- the binder preferably the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- Disintegrant preferably the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch ;
- Glycerides preferably the glycerides are selected from one or more of glyceryl monocaprylate and glyceryl tricaprylate.
- surfactant preferably the surfactant is selected from caprylic acid capric acid polyethylene glycol glyceride, polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolauric acid One or more of esters and sodium lauryl sulfate;
- Lubricant preferably the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate.
- the binder is povidone.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: sodium caprate: povidone is 1: (50-200): 50, such as 1:50:50, 1:100:50 or 1:200:50 .
- the oral pharmaceutical composition includes:
- a filler preferably the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogen phosphate, pregelatinized starch, and calcium hydrogen phosphate dihydrate;
- the binder preferably the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- the binder is selected from one or more of povidone, copovidone, and cellulose derivatives; the cellulose derivative is selected from hydroxypropyl cellulose, hydroxypropyl cellulose, and cellulose derivatives.
- Disintegrant preferably the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch ;
- Glycerides preferably the glycerides are selected from one or more of glyceryl monocaprylate and glyceryl tricaprylate.
- surfactant preferably the surfactant is selected from caprylic acid capric acid polyethylene glycol glyceride, polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolauric acid One or more of esters and sodium lauryl sulfate;
- Lubricant preferably the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, and glyceryl behenate.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from caprylic acid capric acid polyethylene glycol glyceride.
- the weight ratio of compound A to caprylic acid polyethylene glycol glyceride is 1:600-1:3600, preferably 1:2400-1:3600, most preferably 1:2400.
- the weight ratio of compound A to caprylic acid capric acid polyethylene glycol glyceride is 1:600.
- the weight ratio of compound A to caprylic acid capric acid polyethylene glycol glyceride is 1:1200.
- the weight ratio of compound A to caprylic acid capric acid polyethylene glycol glyceride is 1:1800.
- the weight ratio of compound A to caprylic acid capric acid polyethylene glycol glyceride is 1:2400.
- the weight ratio of compound A to caprylic acid capric acid polyethylene glycol glyceride is 1:3600.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from caprylic acid capric acid polyethylene glycol glyceride
- Hydrophobic medium preferably the hydrophobic medium is selected from one or more of coconut oil, castor oil, and olive oil;
- surfactant preferably the surfactant is selected from polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate One or more of the surfactant, preferably the surfactant is selected from polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate One or more
- Glycerides preferably the glycerides are selected from one or more of glyceryl monocaprylate and glyceryl tricaprylate.
- the oral pharmaceutical composition includes:
- An absorption enhancer selected from caprylic acid capric acid polyethylene glycol glyceride
- Hydrophobic medium preferably the hydrophobic medium is selected from one or more of coconut oil, castor oil, and olive oil;
- surfactant preferably the surfactant is selected from polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate One or more of the surfactant, preferably the surfactant is selected from polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate One or more
- Glycerides other than caprylic acid capric acid polyethylene glycol glycerides preferably the glycerides are selected from one or more of monocaprylic acid glycerides and tricaprylic acid glycerides.
- the oral pharmaceutical composition includes:
- the weight ratio of compound A: caprylic acid capric acid polyethylene glycol glyceride: capric acid is 1: (3000-6000): (50-200), for example, 1:3000: (50-100 ) Or 1:(4000-6000): 200, such as 1:3000:50, 1:3000:75, 1:3000:100, 1:4000:200 or 1:6000:200.
- the oral pharmaceutical composition is a solution, suspension, granule, powder, capsule, tablet or other oral dosage form.
- the oral pharmaceutical composition is a gastric soluble capsule, a gastric soluble tablet or a gastric soluble granule.
- compound (A) is present in the oral pharmaceutical composition in a therapeutically effective amount or unit dose. In some embodiments of the invention, compound (A) is present in the oral drug in a dose of less than 1 mg, 1-3 mg, 3-5 mg, 5-10 mg, 10-25 mg, 25-32 mg, 32-100 mg, or greater than 100 mg In the composition.
- the oral pharmaceutical composition described above is prepared by mixing Compound A, an absorption enhancer, and other inactive ingredients directly, and then filling the capsule or tablet.
- the oral pharmaceutical composition described above is prepared by wet granulating Compound A, an absorption enhancer and other inactive ingredients, and then filling a capsule or tablet.
- the aforementioned oral pharmaceutical composition is prepared as follows: Compound A, absorption enhancer and hydrophilic inactive ingredients are wet-granulated and dispersed in a hydrophobic medium, and capsules are filled.
- the oral pharmaceutical composition can also be prepared as a solution, suspension, granule, powder or other oral dosage form using conventional preparation techniques.
- the capsule may be a hard capsule or a soft capsule.
- the present invention also provides the use of the oral pharmaceutical composition in the preparation of a medicament for treating diseases or conditions related to the kappa opioid receptor.
- the present invention also provides a method for treating diseases or conditions associated with kappa opioid receptors in a subject, which comprises administering to the subject any of the oral pharmaceutical compositions described above.
- the disease or condition associated with the kappa opioid receptor is selected from pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma.
- the pain is selected from neuropathic pain, somatic pain, visceral pain, and skin pain.
- the disease or condition is selected from arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, pain after surgery, pain after medical treatment, eye Head pain, otitis pain, explosive cancer pain, and pain associated with GI disorders (gastrointestinal disorders).
- the oral pharmaceutical composition can be used to treat acute and chronic pain and pruritus.
- the oral pharmaceutical composition is administered to the subject in a manner of 1, 2, or 3 times a day.
- the subject is a mammal, such as bovine, equine, swine, canine, feline, rodent, primate; among them, particularly preferred
- the subjects are humans.
- the raw materials/reagents used in the examples are commercially available or self-made, and the prescriptions in the examples are the dosage of a single preparation.
- the "0# capsule” in the following examples refers to the shell that can be used to prepare gastric soluble hard capsules, and its specification is 0#.
- Compound A was prepared by referring to the method published in WO2019/015644.
- Example 1 The compound A physiological saline solution obtained in Example 1 was orally administered to male Beagle dogs (3 per preparation) for a single oral administration at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours Venous blood was taken, and the absolute bioavailability (F%) (relative to the compound A intravenous dose) was calculated using the area under the curve obtained from the point where the plasma concentration of compound A was taken as a function of time.
- Example 2 After the capsules obtained in Example 2 were orally administered to male Beagle dogs (3 in each formulation) each 5 samples, at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours Venous blood was taken, and the absolute bioavailability (F%) (relative to the compound A intravenous dose) was calculated using the area under the curve obtained from the point where the plasma concentration of compound A was taken as a function of time.
- each one sample was administered at 0, 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 8, Venous blood was taken at 10, 12, and 24 h, and the absolute bioavailability (F%) was calculated based on the area under the curve obtained from the compound A plasma concentration as a function of time (relative to the compound A intravenous dose).
- the weight ratio of compound A to SNAC in the range of 1:20-1:80 can significantly improve the bioavailability of compound A, and the absolute bioavailability is better when the weight ratio of compound A to SNAC is 1:40.
- Example 6 After the capsules obtained in Example 6 were orally administered to male Beagle dogs (3 in each formulation) each 5 pieces of samples, at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, Venous blood was taken at 28, 48 and 72h, and the compound
- Example 7-9 After the capsules obtained in Examples 7-9 were orally administered to male Beagle dogs (3 in each formulation) each 1 sample, at 0, 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 8, Venous blood was taken at 10, 12, and 24 h, and the absolute bioavailability (F%) was calculated based on the area under the curve obtained from the compound A plasma concentration as a function of time (relative to the compound A intravenous dose).
- the weight ratio of compound A to 4-CNAB in the range of 1:20-1:80 can significantly improve the bioavailability of compound A, and the absolute bioavailability is better when the weight ratio of compound A to 4-CNAB is 1:40.
- the preparation samples prepared by different processes in Examples 10-15 were orally administered to male Beagle dogs (3 for each preparation) each 1 tablet/tablet sample, and then the test was performed at 0, 0.083, 0.25, 0.5, 1, 2 Venous blood was taken at, 4, 6, 8, 12, 24, 28, and 48h, and the absolute bioavailability (F%) was calculated from the area under the curve obtained by using the compound A plasma concentration as a function of time. Compound A intravenous dose).
- the preparation samples obtained in Examples 22-24 were orally administered to male Beagle dogs (3 in each preparation) each with 1 sample, at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10 Venous blood was taken at, 12 and 24 h, and the absolute bioavailability (F%) was calculated from the area under the curve obtained from the compound A plasma concentration as a function of time (relative to the compound A intravenous dose).
- the sodium caprate in the prescription improves the bioavailability of compound A in a dose-response manner.
- the weight ratio of compound A to sodium caprate is 1:50, the bioavailability does not change significantly, when the weight ratio of compound A to sodium caprate is The bioavailability increased significantly at 1:100 and 1:200.
- the preparation samples obtained in Examples 25-29 were orally administered to male Beagle dogs (3 for each preparation) each 10ml sample, at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, Venous blood was taken at 12 and 24 h, and the absolute bioavailability (F%) (relative to the intravenous dose of compound A) was calculated using the area under the curve obtained from the point where the plasma concentration of compound A was taken as a function of time.
- Both the solution and the capsule of adding caprylic acid capric acid polyethylene glycol glyceride to the prescription can significantly improve the bioavailability of compound A, and the bioavailability of compound A is similar to that of 1mg and 5mg.
- the preparation samples obtained in Examples 33-35 were orally administered to male Beagle dogs (3 for each preparation) each 10ml sample, at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, Venous blood was taken at 12 and 24 h, and the absolute bioavailability (F%) (relative to the intravenous dose of compound A) was calculated by using the area under the curve obtained by taking the compound A plasma concentration as a function of time.
- the bioavailability of compound A is significantly improved when the weight ratio of compound A: caprylic acid capric acid polyethylene glycol glyceride: sodium caprate is 1:3000:50-100, and the bioavailability is even greater when the weight ratio is 1:3000:100 good.
- the preparation samples obtained in Examples 36-37 were orally administered to male Beagle dogs (3 for each preparation) each 10ml sample, and then at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, Venous blood was taken at 12 and 24 h, and the absolute bioavailability (F%) (relative to the intravenous dose of compound A) was calculated by using the area under the curve obtained by taking the compound A plasma concentration as a function of time.
- Prescription compound A caprylic acid capric acid polyethylene glycol glyceride: capric acid when the weight ratio is 1:(4000-6000):200, the bioavailability of compound A is significantly improved, when the weight ratio is 1:6000:200 Better.
- the preparation samples obtained in Examples 43-45 were orally administered to male Beagle dogs (3 for each preparation) and 1 sample for each one, at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10 Venous blood was taken at, 12 and 24 h, and the absolute bioavailability (F%) was calculated from the area under the curve obtained from the compound A plasma concentration as a function of time (relative to the compound A intravenous dose).
- the bioavailability of the gastric-coated capsule is 4 times that of the enteric-coated capsule preparation.
- the preparation samples obtained in Examples 42-47 were orally administered to male Beagle dogs (3 for each preparation) and 1 sample for each of them, at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10 Venous blood was taken at, 12 and 24 h, and the absolute bioavailability (F%) was calculated from the area under the curve obtained from the compound A plasma concentration as a function of time (relative to the compound A intravenous dose).
- Example 1 2.60 ⁇ 0.49 1.81 ⁇ 0.01
- Example 42 117 ⁇ 49 11.8 ⁇ 6.1
- Example 43 90.1 ⁇ 107 8.32 ⁇ 9.3
- Example 44 125 ⁇ 33 8.30 ⁇ 1.3
- Example 45 25.4 ⁇ 25 12.4 ⁇ 8.9
- Example 46 16.5 ⁇ 8.3 9.17 ⁇ 5.3
- Example 47 24.1 ⁇ 20 6.04 ⁇ 4.1
- the bioavailability of compound A is significantly improved when the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:15 to 1:150, and the bioavailability is better when the weight ratio is 1:15 and 1:75.
- the preparation samples obtained in Examples 24 and 48-52 were orally administered to male Beagle dogs (3 for each preparation), and each sample was administered at 0, 0.25, 0.5, 1, 2, 4, 6, and 8. Venous blood was taken at, 10, 12, and 24 h, and the absolute bioavailability (F%) (relative to the intravenous dose of compound A) was calculated by using the area under the curve obtained from the compound A plasma concentration as a function of time.
- Fatty acid salts with different aliphatic chain lengths have different effects on the bioavailability.
- fatty acid salts with aliphatic chain length of C 6 -C 16 only the fatty acid salt with a fatty chain length of C 10 has significant effect on the bioavailability of compound A. Enhance the effect.
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Abstract
一种肽酰胺类化合物(化合物A)的口服药物组合物。还涉及制备所述口服药物组合物的方法,和所述口服药物组合物在制备治疗与κ阿片样物质受体相关的疾病或病况的药物中的用途。
Description
本发明涉及一种肽酰胺类化合物的口服药物组合物。本发明还涉及所述口服药物组合物的制备方法和用途。
多肽类药物因其适应证广、安全性高、具有显著的选择性和有效性,可用于多种疾病的治疗。随着生物技术的发展,已有大量多肽药物进入市场。目前,市售肽类制剂以注射剂和鼻喷剂为主,这些给药方式给患者带来极大的不便。对于患者来说,口服给药方式更简便,不直接损伤皮肤或黏膜,能够减轻患者痛苦从而提高患者依从性。但是多肽类药物口服受一系列屏障限制,在消化道内易被蛋白水解酶降解破坏,由于分子量较大很难穿过小肠内壁上皮细胞层,导致口服生物利用度低,限制了其临床使用。例如,已上市的索马鲁肽片绝对生物利用度仅0.4-1%。为了达到起效所需的血药浓度,口服剂量较高,对于某些成本较高或治疗窗较窄的多肽药物难以实现口服给药。因此,改善多肽药物的口服生物利用度是实现多肽药物口服给药的关键。
多数多肽类药物由于其易受胃内酸激活的蛋白酶的降解导致多肽药物的活性降低,通常采用肠溶包衣技术对多肽进行保护,工艺复杂且成本较高。
WO2019/015644公布了一类结构新颖、镇痛效果佳的肽酰胺类化合物,通式如下:
此类化合物对人κ-阿片受体具有明显激动作用。其中具体公开了化合物A:
化学名称:7-(D-苯丙氨酰基-D-苯丙氨酰基-D-亮氨酰基-D-赖氨酰基)-2-乙酰基-2,7-二氮杂螺[3.5]壬烷(7-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)-2-acetyl-2,7-diazaspiro[3.5]nonane)。
发明内容
本发明开发了一种口服多肽类药物组合物,该组合物通过将多肽药物与特定的吸收促进剂及其他非活性成分共同制备,能够促进该多肽药物在胃肠道的通透性,改善该多肽药物的口服生物利用度,实现口服给药,从而提高患者的依从性。
本发明提供了一种简单的胃内给药技术,较大程度地简化了工艺过程,同时可大幅提高多肽类化合物A的口服生物利用度。
本发明的一个目的是提供化合物A的口服药物组合物:
本发明显著改善了化合物A的口服生物利用度,更有利于将化合物A开发为药物。
本发明的另一个目的是提供制备所述口服药物组合物的方法。
本发明的另一个目的是提供所述口服药物组合物的用途。
在一个方面,本发明提供了一种口服药物组合物,包括:
a)化合物A:
b)吸收促进剂。
本发明的一些实施方案中,吸收促进剂选自N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐、4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐、月桂酰-L-肉碱或其盐酸盐、辛酸钠、癸酸钠、癸酸、辛酸癸酸聚乙二醇甘油酯中的一种或多种;优选地,所述可药用盐选自钠盐、钾盐或钙盐。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的吸收促进剂。
本发明的一些实施方案中,化合物A与N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的重量比为:1:20-1:80,优选1:40-1:60,进一步优选1:40。
本发明的一些实施方案中,化合物A与N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的重量比为1:20。
本发明的一些实施方案中,化合物A与N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的重量比为1:30。
本发明的一些实施方案中,化合物A与N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的重量比为1:40。
本发明的一些实施方案中,化合物A与N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的重量比为1:80。
本发明的一些实施方案中,吸收促进剂为N-[8-(2-羟基苯甲酰基)氨基]辛酸钠。
本发明的一些实施方案中,吸收促进剂为N-[8-(2-羟基苯甲酰基)氨基]辛酸钾。
本发明的一些实施方案中,吸收促进剂为N-[8-(2-羟基苯甲酰基)氨基]辛酸钙。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的吸收促进剂;
c)一种或多种选自以下的非活性成分:
(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;
(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;
(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;
(4)pH调节剂,优选地所述pH调节剂选自枸橼酸、无水枸橼酸、酒石酸、富马酸、枸橼酸钠、磷酸氢钙、碳酸钙中的一种或多种;
(5)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;
(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的吸收促进剂。
本发明的一些实施方案中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为:1:20-1:200,优选1:40-1:80,进一步优选1:40。
本发明的一些实施方案中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为1:20。
本发明的一些实施方案中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为1:40。
本发明的一些实施方案中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为1:80。
本发明的一些实施方案中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为1:100。
本发明的一些实施方案中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为1:200。
本发明的一些实施方案中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为3:200。
本发明的一些实施方案中,吸收促进剂为4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸钠。
本发明的一些实施方案中,吸收促进剂为4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸钾。
本发明的一些实施方案中,吸收促进剂为4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸钙。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的吸收促进剂;
c)一种或多种选自以下的非活性成分:
(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;
(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;
(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;
(4)pH调节剂,优选地所述pH调节剂选自枸橼酸、无水枸橼酸、酒石酸、富马酸、枸橼酸钠、磷酸氢钙、碳酸钙中的一种或多种;
(5)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;
(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
本发明的一些实施方案中,所述润滑剂为硬脂酸镁。
本发明的一些实施方案中,所述填充剂为微晶纤维素和/或无水磷酸氢钙。
本发明的一些实施方案中,所述粘合剂为聚维酮。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)润滑剂。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:润滑剂的重量比为1:(20-200):(0.2-2)。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:润滑剂的重量比为1:200:2。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)硬脂酸镁。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:硬脂酸镁的重量比为1:(20-200):(0.2-2)。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:硬脂酸镁的重量比为1:200:2。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)填充剂;
d)粘合剂。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂的重量比为1:(20-200):200:5。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂的重量比为1:200:200:5。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)微晶纤维素;
d)聚维酮。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:微晶纤维素:聚维酮的重量比为1:(20-200):200:5。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:微晶纤维素:聚维酮的重量比为1:200:200:5。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)填充剂;
d)粘合剂;
e)润滑剂。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂:润滑剂的重量比为1:(20-200):200:5:(1-5)。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂:润滑剂的重量比为1:200:200:5:(4-5),例如1:200:200:5:4.06。.
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂:润滑剂的重量比为3:200:200:5:1。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂:润滑剂的重量比为3:200:200:5:4。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)微晶纤维素;
d)聚维酮;
e)硬脂酸镁。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:微晶纤维素:聚维酮:硬脂酸镁的重量比为(1-3):(20-200):200:5:(1-5)。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:微晶纤维素:聚维酮:硬脂酸镁的重量比为1:200:200:5:(4-5),例如1:200:200:5:4.06。.
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:微晶纤维素:聚维酮:硬脂酸镁的重量比为3:200:200:5:4。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)聚维酮;
d)无水磷酸氢钙;
e)硬脂酸镁。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:聚维酮:无水磷酸氢钙:硬脂酸镁的重量比为(1-3):(20-200):5:200:(1-5)。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:聚维酮:无水磷酸氢钙:硬脂酸镁的重量比为3:200:5:200:4。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)表面活性剂;
d)填充剂;
e)润滑剂。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:表面活性剂:填充剂:润滑剂的重量比为(1-3):(20-200):(3-9):200:(1-5),例如3:200:6:200:1。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)丙二醇单月桂酸酯和/或聚乙二醇(例如聚乙二醇300);
d)无水磷酸氢钙;
e)硬脂酸镁。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐;
c)丙二醇单月桂酸酯;
d)聚乙二醇300;
e)无水磷酸氢钙;
f)硬脂酸镁。
本发明的一些实施方案中,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:丙二醇单月桂酸酯:聚乙二醇300:无水磷酸氢钙:硬脂酸镁的重量比为(1-3):(20-200):(3-9):(3-9):200:(1-5),例如3:200:3:3:200:1。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自月桂酰-L-肉碱或其盐酸盐的吸收促进剂。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱或其盐酸盐的重量比为1:10-1:150,例如1:10、1:15、1:20、1:30、1:50、1:75、1:100或1:150。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自月桂酰-L-肉碱的吸收促进剂。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱的重量比为1:10-1:50,优选1:10-1:20,进一步优选1:10。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱的重量比为1:10。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱的重量比为1:20。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱的重量比为1:50。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自月桂酰-L-肉碱盐酸盐的吸收促进剂。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱盐酸盐的重量比为1:15-1:150,优选月桂酰-L-肉碱盐酸盐用量为75-150mg,进一步优选月桂酰-L-肉碱盐酸盐用量为75mg。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱盐酸盐的重量比为1:15。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱盐酸盐的重量比为1:20。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱盐酸盐的重量比为1:30。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱盐酸盐的重量比为1:75。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱盐酸盐的重量比为1:100。
本发明的一些实施方案中,化合物A与月桂酰-L-肉碱盐酸盐的重量比为1:150。
本发明的一些实施方案中,口服药物组合物中的吸收促进剂选自月桂酰-L-肉碱或其盐酸盐时,该药物组合物中不含有肠溶辅料。
本发明的一些实施方案中,口服药物组合物中的吸收促进剂选自月桂酰-L-肉碱或其盐酸盐时,该药物组合物的剂型不为肠溶片剂或肠溶胶囊剂。
本发明的一些实施方案中,口服药物组合物中的吸收促进剂选自月桂酰-L-肉碱或其盐酸盐时,该药物组合物的剂型为胃溶胶囊剂、胃溶片剂或胃溶颗粒剂。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自月桂酰-L-肉碱或其盐酸盐的吸收促进剂;
c)一种或多种选自以下的非活性成分:
(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;
(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素的一种或多种;
(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;
(4)pH调节剂,优选地所述pH调节剂选自枸橼酸、无水枸橼酸、酒石酸、富马酸、枸橼酸钠、磷酸氢钙、碳酸钙中的一种或多种;
(5)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;
(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)月桂酰-L-肉碱;
c)pH调节剂。
本发明的一些实施方案中,化合物A:月桂酰-L-肉碱:pH调节剂的重量比为:1:(10-50):24。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)月桂酰-L-肉碱;
c)枸橼酸。
本发明的一些实施方案中,化合物A:月桂酰-L-肉碱:枸橼酸的重量比为:1:(10-50):24。
本发明的一些实施方案中,化合物A:月桂酰-L-肉碱:枸橼酸的重量比为:1:50:24。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自癸酸钠的吸收促进剂。
本发明的一些实施方案中,化合物A与癸酸钠重量比为1:50-1:200,优选1:100-1:200最优选1:100。
本发明的一些实施方案中,化合物A与癸酸钠的重量比为1:50。
本发明的一些实施方案中,化合物A与癸酸钠的重量比为1:100。
本发明的一些实施方案中,化合物A与癸酸钠的重量比为1:200。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自癸酸钠的吸收促进剂;
c)一种或多种选自以下的非活性成分:
(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;
(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;
(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;
(4)甘油酯,优选地所述甘油酯选自单辛酸甘油酯、三辛酸甘油酯中的一种或多种。
(5)表面活性剂,优选地所述表面活性剂选自辛酸癸酸聚乙二醇甘油酯、聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;
(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
本发明的一些实施方案中,粘合剂为聚维酮。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)癸酸钠;
c)聚维酮。
本发明的一些实施方案中,化合物A:癸酸钠:聚维酮的重量比为1:(50-200):50,例如1:50:50,1:100:50或1:200:50。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自癸酸的吸收促进剂;
c)一种或多种选自以下的非活性成分:
(1)填充剂,优选地所述填充剂选在微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;
(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;
(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;
(4)甘油酯,优选地所述甘油酯选自单辛酸甘油酯、三辛酸甘油酯中的一种或多种。
(5)表面活性剂,优选地所述表面活性剂选自辛酸癸酸聚乙二醇甘油酯、聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;
(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自辛酸癸酸聚乙二醇甘油酯的吸收促进剂。
本发明的一些实施方案中,化合物A与辛酸癸酸聚乙二醇甘油酯重量比为:1:600-1:3600,优选1:2400-1:3600,最优选1:2400。
本发明的一些实施方案中,化合物A与辛酸癸酸聚乙二醇甘油酯的重量比为1:600。
本发明的一些实施方案中,化合物A与辛酸癸酸聚乙二醇甘油酯的重量比为1:1200。
本发明的一些实施方案中,化合物A与辛酸癸酸聚乙二醇甘油酯的重量比为1:1800。
本发明的一些实施方案中,化合物A与辛酸癸酸聚乙二醇甘油酯的重量比为1:2400。
本发明的一些实施方案中,化合物A与辛酸癸酸聚乙二醇甘油酯的重量比为1:3600。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自辛酸癸酸聚乙二醇甘油酯的吸收促进剂;
c)一种或多种选自以下的非活性成分:
(1)疏水介质,优选地所述疏水介质选自椰子油、蓖麻油、橄榄油中的一种或多种;
(2)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;
(3)甘油酯,优选地所述甘油酯选自单辛酸甘油酯、三辛酸甘油酯中的一种或多种。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)选自辛酸癸酸聚乙二醇甘油酯的吸收促进剂;
c)一种或多种选自以下的非活性成分:
(1)疏水介质,优选地所述疏水介质选自椰子油、蓖麻油、橄榄油中的一种或多种;
(2)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;
(3)除辛酸癸酸聚乙二醇甘油酯以外的甘油酯,优选地所述甘油酯选自单辛酸甘油酯、三辛酸甘油酯中的一种或多种。
本发明的一些实施方案中,口服药物组合物包括:
a)化合物A:
b)辛酸癸酸聚乙二醇甘油酯;
c)癸酸。
本发明的一些实施方案中,化合物A:辛酸癸酸聚乙二醇甘油酯:癸酸的重量比为1:(3000-6000):(50-200),例如1:3000:(50-100)或1:(4000-6000):200,例如1:3000:50,1:3000:75,1:3000:100,1:4000:200或1:6000:200。
本发明的一些实施方案中,所述口服药物组合物为溶液剂、混悬剂、颗粒剂、粉末剂、胶囊剂、片剂或其他口服剂型。
本发明的一些实施方案中,所述口服药物组合物为胃溶胶囊剂、胃溶片剂或胃溶颗粒剂。
在发明的一些实施方案中,化合物(A)以治疗有效量或单位剂量存在于所述口服药物组合物中。在发明的一些实施方案中,化合物(A)以小于1mg、1-3mg、3-5mg、5-10mg、10-25mg、25-32mg、32-100mg或大于100mg的剂量存在于所述口服药物组合物中。
本发明的一些实施方案中,上述口服药物组合物是这样制备得到的:将化合物A、吸收促进剂和其他非活性成分直接混合后填充胶囊或压片。
本发明的一些实施方案中,上述口服药物组合物是这样制备得到的:将化合物A、吸收促进剂和其他非活性成分湿法制粒后填充胶囊或压片。
本发明的一些实施方案中,上述口服药物组合物是这样制备得到的:将化合物A、吸收促进剂和亲水性非活性成分湿法制粒后分散于疏水介质,填充胶囊。
本发明中,所述口服药物组合物还可以使用常规制备工艺制备为溶液剂、混悬剂、颗粒剂、粉末剂或其他口服剂型。
本发明中,胶囊剂可以是硬胶囊剂或软胶囊剂。
本发明还提供了所述口服药物组合物在制备治疗与κ阿片样物质受体相关的疾病或病况的药物中的用途。
本发明还提供了一种治疗受试者中与κ阿片样物质受体相关的疾病或病况的方法,包括给受试者施用上述任一项的口服药物组合物。
本发明的一些实施方案中,与κ阿片样物质受体相关的疾病或病况选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼。
本发明的一些实施方案中,所述疼痛选自神经性疼痛、躯体痛、内脏痛和皮肤痛。
本发明的一些实施方案中,所述的疾病或病况选自关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、消化不良、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、爆发性癌症疼痛和GI紊乱(胃肠道紊乱)相关的疼痛。
在本发明的一个实施方案中,所述口服药物组合物可用于治疗急慢性疼痛和瘙痒。
在某些实施方案中,所述口服药物组合物按照每天给药1、2或3次的方式被施用于受试者。
在某些实施方案中,所述受试者为哺乳动物,例如牛科动物、马科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物;其中,特别优选的受试者为人。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
(1)SNAC:N-[8-(2-羟基苯甲酰基)氨基]辛酸单钠盐。
(2)4-CNAB:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸单钠盐。
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
实施例中使用的原料/试剂为商购或自制,实施例中处方均为单制剂用量。
如无特殊说明,以下实施例中“0#胶囊”指的是可用于制备胃溶硬胶囊剂的壳,其规格为0#。
化合物A参照WO2019/015644公布的方法制备得到。
实施例1
将3mg化合物A溶于生理盐水中,配制得到0.06mg/mL生理盐水溶液。
实施例2
将5mg化合物A和150mg SNAC混合均匀后填充于0#胶囊中。
实施例3
将5mg化合物A和100mg SNAC混合均匀后填充于0#胶囊中。
实施例4
将5mg化合物A和200mg SNAC混合均匀后填充于0#胶囊中。
实施例5
将5mg化合物A和400mg SNAC混合均匀后填充于0#胶囊中。
实施例6
将5mg化合物A、50mg月桂酰-L-肉碱和120mg枸橼酸混合均匀后填充于0#胶囊中。
实施例7
将5mg化合物A和100mg 4-CNAB混合均匀后填充于0#胶囊中。
实施例8
将5mg化合物A和200mg 4-CNAB混合均匀后填充于0#胶囊中。
实施例9
将5mg化合物A和400mg 4-CNAB混合均匀后填充于0#胶囊中。
实施例10
将1mg化合物A和200mg 4-CNAB混合均匀后填充于0#胶囊中。
实施例11
将1mg化合物A、200mg 4-CNAB、2mg硬脂酸镁混合均匀后压片。
实施例12
将1mg化合物A、200mg 4-CNAB、200mg微晶纤维素、5mg聚维酮混合均匀后填充于0#胶囊中。
实施例13
将1mg化合物A、200mg 4-CNAB、200mg微晶纤维素、5mg聚维酮、4.06mg硬脂酸镁混合均匀后压片。
实施例14
取1mg化合物A、200mg 4-CNAB、200mg微晶纤维素、5mg聚维酮,将化合物A与4-CNAB溶解在水中旋转蒸发干燥后研磨粉碎,与其他非活性成分混合均匀后填充于0#胶囊中。
实施例15
取1mg化合物A、200mg 4-CNAB、200mg微晶纤维素、5mg聚维酮、4.06mg硬脂酸镁,化合物A与4-CNAB溶解在水中旋转蒸发干燥后研磨粉碎,与其他非活性成分混合均匀后压片。
实施例16
将2mg化合物A和200mg 4-CNAB混合均匀后填充于0#胶囊内。
实施例17
将3mg化合物A和200mg 4-CNAB混合均匀后填充于0#胶囊内。
实施例18
将10mg化合物A和200mg 4-CNAB混合均匀后填充于0#胶囊内。
实施例19
将3mg化合物A、200mg 4-CNAB、5mg聚维酮、200mg微晶纤维素、4mg硬脂酸镁混合均匀后填充于0#胶囊内。
实施例20
将3mg化合物A、200mg 4-CNAB、5mg聚维酮、200mg无水磷酸氢钙、4mg硬脂酸镁混合均匀后填充于0#胶囊内。
实施例21
①将3mg化合物A、200mg 4-CNAB混合均匀。
②将3mg丙二醇单月桂酸酯和3mg聚乙二醇300采用200mg无水磷酸氢钙吸收分散。
③将上两步样品混合均匀。
④加入1mg硬脂酸镁,混合均匀后填充于0#胶囊内。
实施例22
将100mg化合物A、5g聚维酮K12和5g癸酸钠在100g纯化水中溶解完全后冷冻干燥,干燥样品过120目筛,填充于0#胶囊内。
实施例23
将100mg化合物A、5g聚维酮K12和10g癸酸钠在100g纯化水中溶解完全后冷冻干燥,干燥样品过120目筛,填充于0#胶囊内。
实施例24
将25mg化合物A、1.25g聚维酮K12和5g癸酸钠在100g纯化水中溶解完全后冷冻干燥,干燥样品过120目筛,填充于00#胶囊内。
实施例25
将1mg化合物A和0.6g辛酸癸酸聚乙二醇甘油酯加纯化水溶解完全得10ml溶液。
实施例26
将1mg化合物A和1.2g辛酸癸酸聚乙二醇甘油酯加纯化水溶解完全得10ml溶液。
实施例27
将1mg化合物A和1.8g辛酸癸酸聚乙二醇甘油酯加纯化水溶解完全得10ml溶液。
实施例28
将1mg化合物A和2.4g辛酸癸酸聚乙二醇甘油酯加纯化水溶解完全得10ml溶液。
实施例29
将1mg化合物A和3.6g辛酸癸酸聚乙二醇甘油酯加纯化水溶解完全得10ml溶液。
实施例30
将1mg化合物A和0.6g辛酸癸酸聚乙二醇甘油酯超声分散混悬均匀后填充于0#胶囊内。
实施例31
将1mg化合物A和1.8g辛酸癸酸聚乙二醇甘油酯超声分散混悬均匀后填充于0#胶囊内。
实施例32
将5mg化合物A和3.0g辛酸癸酸聚乙二醇甘油酯超声分散混悬均匀后填充于0#胶囊内。
实施例33
将1mg化合物A、3g辛酸癸酸聚乙二醇甘油酯和50mg癸酸钠加纯化水溶解完全得10ml溶液。
实施例34
将1mg化合物A、3g辛酸癸酸聚乙二醇甘油酯和75mg癸酸钠加纯化水溶解完全得10ml溶液。
实施例35
将1mg化合物A、3g辛酸癸酸聚乙二醇甘油酯和100mg癸酸钠加纯化水溶解完全得10ml溶液。
实施例36
将1mg化合物A、4g辛酸癸酸聚乙二醇甘油酯和200mg癸酸加纯化水溶解完全得10ml溶液。
实施例37
将1mg化合物A、6g辛酸癸酸聚乙二醇甘油酯和200mg癸酸加纯化水溶解完全得10ml溶液。
实施例38
将5mg化合物A、50mg月桂酰-L-肉碱填充于0#胶囊中。
实施例39
将5mg化合物A、100mg月桂酰-L-肉碱填充于0#胶囊中。
实施例40
将5mg化合物A、250mg月桂酰-L-肉碱填充于0#胶囊中。
实施例41
将5mg化合物A、100mg月桂酰-L-肉碱填充于0#肠溶胶囊中。
实施例42
将5mg化合物A、75mg月桂酰-L-肉碱盐酸盐填充于0#胶囊中。
实施例43
将5mg化合物A、100mg月桂酰-L-肉碱盐酸盐填充于0#胶囊中。
实施例44
将5mg化合物A、150mg月桂酰-L-肉碱盐酸盐填充于0#胶囊中。
实施例45
将1mg化合物A、75mg月桂酰-L-肉碱盐酸盐填充于0#胶囊中。
实施例46
将1mg化合物A、100mg月桂酰-L-肉碱盐酸盐填充于0#胶囊中。
实施例47
将1mg化合物A、150mg月桂酰-L-肉碱盐酸盐填充于0#胶囊中。
实施例48
将1mg化合物A、200mg己酸钠填充于0#胶囊中。
实施例49
将1mg化合物A、100mg辛酸钠填充于0#胶囊中。
实施例50
将1mg化合物A、200mg月桂酸钠填充于0#胶囊中。
实施例51
将1mg化合物A、200mg肉豆蔻酸钠填充于0#胶囊中。
实施例52
将1mg化合物A、200mg棕榈酸钠填充于0#胶囊中。
测试例1
将实施例1得到的化合物A生理盐水溶液单次口服给与雄性Beagle犬(每个制剂3只),于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆 浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
将实施例2得到的胶囊单次口服给与雄性Beagle犬(每个制剂3只)每只5粒样品后,于0、0.083、0.25、0.5、1、2、4、6、8和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表1 SNAC对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例2 | 125±47 | 3.46±1.62 |
结果和讨论:
处方中加入150mg SNAC后生物利用度明显提高,绝对生物利用度可达3.46%。
测试例2
将实施例3-5得到的胶囊单次口服给与雄性Beagle犬(每个制剂3只)每只1粒样品后,于0、0.083、0.25、0.5、0.75、1、2、4、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表2 SNAC用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例3 | 6.88±5.8 | 2.18±1.3 |
实施例4 | 109±56 | 9.82±3.8 |
实施例5 | 41.2±22 | 5.60±3.3 |
结果和讨论:
化合物A与SNAC重量比在1:20-1:80范围内均能显著改善化合物A的生物利用度,化合物A与SNAC重量比为1:40时绝对生物利用度更佳。
测试例3
将实施例6得到的胶囊单次口服给与雄性Beagle犬(每个制剂3只)每只5粒样品后,于0、0.25、0.5、1、2、4、6、8、12、24、28、48和72h时取静脉血,以化合物
A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)
(相对于化合物A静脉注射剂量)。
表3配方对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例6 | 451±384 | 6.62±5.3 |
结果和讨论:
处方中加入50mg月桂酰-L-肉碱和120mg枸橼酸时具有良好促进吸收作用,化合A绝对生物利用度达6.62%。
测试例4
将实施例7-9得到的胶囊单次口服给与雄性Beagle犬(每个制剂3只)每只1粒样品后,于0、0.083、0.25、0.5、0.75、1、2、4、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表4 4-CNAB用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例7 | 61.7±48 | 4.83±2.7 |
实施例8 | 166±54 | 10.5±1.6 |
实施例9 | 80.7±70 | 6.63±4.5 |
结果和讨论:
化合物A与4-CNAB重量比在1:20-1:80范围内均能显著改善化合物A的生物利用度,化合物A与4-CNAB重量比为1:40时绝对生物利用度更佳。
测试例5
将实施例10-15采用不同工艺制备得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只1粒/片样品后,于0、0.083、0.25、0.5、1、2、4、6、8、12、24、28和48h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表5不同制剂工艺对化合物A吸收的影响
结果和讨论:
处方中加入4-CNAB后不同剂型及制备工艺制备样品绝对生物利用度均显著增加。
测试例6
将实施例22-24得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只1粒样品后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表6癸酸钠用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例22 | 1.53±0.19 | 1.36±0.15 |
实施例23 | 9.10±3.7 | 5.59±2.0 |
实施例24 | 15.9±14 | 5.73±3.3 |
结果和讨论:
处方中癸酸钠以剂量响应的方式改善了化合物A的生物利用度,当化合物A与癸酸钠重量比为1:50时生物利用度无明显改变,当化合物A与癸酸钠重量比为1:100和1:200时生物利用度显著增加。
测试例7
将实施例25-29得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只10ml样品后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表7辛酸癸酸聚乙二醇甘油酯用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例25 | 20.0±3.4 | 6.97±2.7 |
实施例26 | 16.3±4.0 | 6.53±1.4 |
实施例27 | 17.4±7.5 | 6.75±2.6 |
实施例28 | 20.6±4.9 | 9.38±1.6 |
实施例29 | 21.9±18 | 7.73±4.6 |
结果和讨论:
处方中化合物A与辛酸癸酸聚乙二醇甘油酯重量比为1:600-1:3600时生物利用度显著提升,且重量比为1:2400时绝对生物利用度更佳。
测试例8
将实施例25、27、30-32得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表8剂型及规格对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例25 | 20.0±3.4 | 6.97±2.7 |
实施例30 | 28.0±11 | 8.63±2.5 |
实施例27 | 17.4±7.5 | 6.75±2.6 |
实施例31 | 17.8±4.7 | 6.47±1.8 |
实施例32 | 65.1±40 | 6.97±4.7 |
结果和讨论:
处方中加入辛酸癸酸聚乙二醇甘油酯的溶液剂与胶囊剂均能将化合物A生物利用度显著提升,且化合物A规格1mg和5mg时生物利用度提升程度相近。
测试例9
将实施例33-35得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只10ml样品后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表9辛酸癸酸聚乙二醇甘油酯和癸酸钠用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例33 | 17.9±12 | 7.52±5.1 |
实施例34 | 16.1±7.3 | 6.95±2.6 |
实施例35 | 23.2±4.5 | 12.2±2.9 |
结果和讨论:
处方中化合物A:辛酸癸酸聚乙二醇甘油酯:癸酸钠重量比为1:3000:50-100时化合物A生物利用度显著提升,重量比为1:3000:100时生物利用度更佳。
测试例10
将实施例36-37得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只10ml样品后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物 A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表10辛酸癸酸聚乙二醇甘油酯和癸酸用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例36 | 15.0±5.8 | 6.02±1.7 |
实施例37 | 15.1±1.7 | 7.86±1.6 |
处方化合物A:辛酸癸酸聚乙二醇甘油酯:癸酸重量比为1:(4000-6000):200时化合物A生物利用度显著提升,当重量比为1:6000:200时生物利用度更佳。
测试例11
将实施例43-45得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只1粒样品后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表11月桂酰-L-肉碱用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例38 | 56.6±82 | 5.33±5.9 |
实施例39 | 232±124 | 16.7±5.2 |
实施例40 | 105±103 | 8.92±8.0 |
实施例41 | 62.8±13 | 4.05±0.48 |
结果和讨论:
处方中化合物A与月桂酰-L-肉碱重量比为1:10-1:50时化合物A生物利用度显著提升,重量比为1:20时生物利用度更佳。
化合物A与月桂酰-L-肉碱重量比为1:20时,胃溶胶囊是肠溶胶囊制剂生物利用度的4倍。
测试例12
将实施例42-47得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只1粒样品后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表12月桂酰-L-肉碱盐酸盐用量对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例42 | 117±49 | 11.8±6.1 |
实施例43 | 90.1±107 | 8.32±9.3 |
实施例44 | 125±33 | 8.30±1.3 |
实施例45 | 25.4±25 | 12.4±8.9 |
实施例46 | 16.5±8.3 | 9.17±5.3 |
实施例47 | 24.1±20 | 6.04±4.1 |
结果和讨论:
化合物A与月桂酰-L-肉碱盐酸盐重量比为1:15-1:150时化合物A生物利用度显著提高,其中重量比为1:15和1:75时生物利用度更佳。
测试例13
将实施例24、48-52得到的制剂样品单次口服给与雄性Beagle犬(每个制剂3只)每只1粒样品后,于0、0.25、0.5、1、2、4、6、8、10、12和24h时取静脉血,以化合物A血浆浓度作为时间的函数所做的点得到的曲线下面积计算出绝对生物利用度(F%)(相对于化合物A静脉注射剂量)。
表13脂肪酸盐种类对化合物A吸收的影响
配方 | C max(ng/ml) | F% |
实施例1 | 2.60±0.49 | 1.81±0.01 |
实施例24 | 15.9±14 | 5.73±3.3 |
实施例48 | 1.80±1.1 | 0.792±0.31 |
实施例49 | 13.7±4.11 | 1.58±1.11 |
实施例50 | 3.54±1.1 | 1.53±0.31 |
实施例51 | 0.837±0.48 | 1.22±0.38 |
实施例52 | 1.48±1.0 | 1.36±0.22 |
结果和讨论:
不同脂肪链长度脂肪酸盐对生物利用度的影响不同,脂肪链长度为C
6-C
16的脂肪酸盐中,仅脂肪链长度为C
10的脂肪酸盐对化合物A的生物利用度具有明显增强作用。
Claims (34)
- 如权利要求1所述的口服药物组合物,其中,吸收促进剂选自N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐、4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐、月桂酰-L-肉碱或其盐酸盐、辛酸钠、癸酸钠、癸酸、辛酸癸酸聚乙二醇甘油酯中的一种或多种;优选地,所述可药用盐选自钠盐、钾盐或钙盐。
- 如权利要求2所述的口服药物组合物,其中,吸收促进剂选自N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐。
- 如权利要求3所述的口服药物组合物,其中,化合物A与N-[8-(2-羟基苯甲酰基)氨基]辛酸或其可药用盐的重量比为:1:20-1:80,优选1:40-1:60,进一步优选1:40。
- 如权利要求3或4所述的口服药物组合物,还包括一种或多种选自以下的非活性成分:(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;(4)pH调节剂,优选地所述pH调节剂选自枸橼酸、无水枸橼酸、酒石酸、富马酸、枸橼酸钠、磷酸氢钙、碳酸钙中的一种或多种;(5)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
- 如权利要求2所述的口服药物组合物,其中,吸收促进剂选自4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐。
- 如权利要求6所述的口服药物组合物,其中,化合物A与4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐的重量比为:1:20-1:200,进一步优选1:40-1:80,更进一步优选1:40或3:200。
- 如权利要求6或7所述的口服药物组合物,还包括一种或多种选自以下的非活性成分:(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素一种或多种;(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;(4)pH调节剂,优选地所述pH调节剂选自枸橼酸、无水枸橼酸、酒石酸、富马酸、枸橼酸钠、磷酸氢钙、碳酸钙中的一种或多种;(5)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
- 如权利要求8所述的口服药物组合物,所述非活性成分为润滑剂;优选地化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:润滑剂的重量比为1:(20-200):(0.2-2),优选地为1:200:2。
- 如权利要求9所述的口服药物组合物,其中润滑剂为硬脂酸镁。
- 如权利要求8所述的口服药物组合物,所述非活性成分为填充剂和粘合剂;优选地,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂的重量比为1:(20-200):200:5,优选地为1:200:200:5。
- 如权利要求11所述的口服药物组合物,其中填充剂为微晶纤维素,粘合剂为聚维酮。
- 如权利要求8所述的口服药物组合物,所述非活性成分为填充剂、粘合剂和润滑剂;优选地,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:填充剂:粘合剂:润滑剂的重量比为1:(20-200):200:5:(1-5),优选地为3:200:200:5:4,1:200:200:5:4或3:200:200:5:1。
- 如权利要求13所述的口服药物组合物,其中填充剂选自微晶纤维素或无水磷酸氢钙,粘合剂为聚维酮,润滑剂为硬脂酸镁。
- 如权利要求8所述的口服药物组合物,所述非活性成分为表面活性剂、填充剂和润滑剂;优选地,化合物A:4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸或其可药用盐:表面活性剂:填充剂:润滑剂的重量比为3:200:6:200:1。
- 如权利要求15所述的口服药物组合物,其中表面活性剂为丙二醇单月桂酸酯和/或聚乙二醇,填充剂为无水磷酸氢钙,润滑剂为硬脂酸镁。
- 如权利要求2所述的口服药物组合物,其中,吸收促进剂选自月桂酰-L-肉碱或其盐酸盐。
- 如权利要求17所述的口服药物组合物,其中,化合物A与月桂酰-L-肉碱或其盐酸盐的重量比为1:10-1:150,优选1:10-1:100,进一步优选1:10-1:75。
- 如权利要求17或18所述的口服药物组合物,还包括一种或多种选自以下的非活性成分:(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;(4)pH调节剂,优选地所述pH调节剂选自枸橼酸、无水枸橼酸、酒石酸、富马酸、枸橼酸钠、磷酸氢钙、碳酸钙中的一种或多种;(5)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
- 如权利要求19所述的口服药物组合物,所述非活性成分为pH调节剂;优选地,化合物A:月桂酰-L-肉碱或其盐酸盐:pH调节剂的重量比为:1:(10-50):24。
- 如权利要求20所述的口服药物组合物,其中,pH调节剂为枸橼酸。
- 如权利要求2所述的口服药物组合物,其中,吸收促进剂为癸酸钠。
- 如权利要求22所述的口服药物组合物,其中,化合物A与癸酸钠的重量比为1:50-1:200,优选1:100-1:200,进一步优选1:100。
- 如权利要求22或23所述的口服药物组合物,还包括一种或多种选自以下的非活性成分:(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;(3)崩解剂,优选地所述崩解剂选自交联聚维酮、低取代羟丙纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或多种;(4)甘油酯,优选地所述甘油酯选自单辛酸甘油酯、三辛酸甘油酯中的一种或多种。(5)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;(6)润滑剂,优选地所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯中的一种或多种。
- 如权利要求2所述的口服药物组合物,其中,吸收促进剂为癸酸。
- 如权利要求25所述的口服药物组合物,还包括一种或多种选自以下的非活性成分:(1)填充剂,优选地所述填充剂选自微晶纤维素、乳糖、甘露醇、无水磷酸氢钙、预胶化淀粉、磷酸氢钙二水合物中的一种或多种;(2)粘合剂,优选地所述粘合剂选自聚维酮、共聚维酮、纤维素衍生物中的一种或多种;所述纤维素衍生物选自羟丙纤维素、羟丙甲纤维素、甲基纤维素中的一种或多种;(3)疏水介质,优选地所述疏水介质选自椰子油、蓖麻油、橄榄油中的一种或多种;(4)表面活性剂,优选地所述表面活性剂选自辛酸癸酸聚乙二醇甘油酯、聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;(5)甘油酯,优选地所述甘油酯选自单辛酸甘油酯、三辛酸甘油酯中的一种或多种。
- 如权利要求2所述的口服药物组合物,其中,吸收促进剂为辛酸癸酸聚乙二醇甘油酯。
- 如权利要求27所述的口服药物组合物,其中,化合物A与辛酸癸酸聚乙二醇甘油酯的重量比为1:600-1:3600,优选1:2400-1:3600,进一步优选1:2400。
- 如权利要求27或28所述的口服药物组合物,还包括一种或多种选自以下的非活性成分:(1)疏水介质,优选地所述疏水介质选自椰子油、蓖麻油、橄榄油中的一种或多种;(2)表面活性剂,优选地所述表面活性剂选自聚乙二醇、泊洛沙姆、磷脂、吐温80、司盘40、丙二醇单月桂酸酯、十二烷基硫酸钠中的一种或多种;(3)甘油酯,优选地所述甘油酯选自单辛酸甘油酯、三辛酸甘油酯中的一种或多种。
- 权利要求1-29任意一项所述的口服药物组合物的制备方法,包括:将化合物A、吸收促进剂和其他非活性成分直接混合后填充胶囊或压片;或将化合物A、吸收促进剂和其他非活性成分湿法制粒后填充胶囊或压片;或将化合物A、吸收促进剂与亲水性的其他非活性成分湿法制粒后分散于疏水介质,填充胶囊;或将化合物A、吸收促进剂和其他非活性成分溶解于纯化水中制成溶液;或将化合物A、吸收促进剂和其他非活性成分溶解干燥粉碎后填充胶囊或压片。
- 权利要求1-29任意一项所述的口服药物组合物在制备治疗与κ阿片样物质受体相关的疾病或病况的药物中的用途。
- 如权利要求31所述的用途,其中与κ阿片样物质受体相关的疾病或病况选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼。
- 如权利要求32所述的用途,其中所述疼痛选自神经性疼痛、躯体痛、内脏痛和皮肤痛。
- 如权利要求33所述的用途,其中所述的疾病或病况选自关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、消化不良、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、爆发性癌症疼痛和GI紊乱相关的疼痛。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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WO2022218250A1 (zh) * | 2021-04-12 | 2022-10-20 | 四川海思科制药有限公司 | 肽酰胺类化合物制备用于治疗瘙痒的药物中的用途 |
WO2023179659A1 (zh) * | 2022-03-23 | 2023-09-28 | 江苏恩华药业股份有限公司 | 多酰胺类化合物、其制备方法及其医药用途 |
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AU2009283821B2 (en) * | 2008-08-18 | 2014-05-29 | Entera Bio Ltd. | Methods and compositions for oral administration of proteins |
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- 2021-03-17 US US17/906,555 patent/US20230172866A1/en active Pending
- 2021-03-17 CN CN202180017925.5A patent/CN115209910A/zh active Pending
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- 2021-03-17 EP EP21772438.4A patent/EP4122483A4/en active Pending
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WO2023179659A1 (zh) * | 2022-03-23 | 2023-09-28 | 江苏恩华药业股份有限公司 | 多酰胺类化合物、其制备方法及其医药用途 |
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EP4122483A4 (en) | 2024-03-27 |
US20230172866A1 (en) | 2023-06-08 |
CN115209910A (zh) | 2022-10-18 |
EP4122483A1 (en) | 2023-01-25 |
TW202143997A (zh) | 2021-12-01 |
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