WO2012113116A1 - Émulsion contenant une macromolécule biologique hydrophile, sa méthode de préparation et application - Google Patents

Émulsion contenant une macromolécule biologique hydrophile, sa méthode de préparation et application Download PDF

Info

Publication number
WO2012113116A1
WO2012113116A1 PCT/CN2011/000814 CN2011000814W WO2012113116A1 WO 2012113116 A1 WO2012113116 A1 WO 2012113116A1 CN 2011000814 W CN2011000814 W CN 2011000814W WO 2012113116 A1 WO2012113116 A1 WO 2012113116A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
parts
vitamin
emulsion
polyethylene glycol
Prior art date
Application number
PCT/CN2011/000814
Other languages
English (en)
Chinese (zh)
Inventor
马二利
郑昌学
Original Assignee
美迪思生物科技(北京)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 美迪思生物科技(北京)有限公司 filed Critical 美迪思生物科技(北京)有限公司
Publication of WO2012113116A1 publication Critical patent/WO2012113116A1/fr

Links

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • 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
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • 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 (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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • 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 invention belongs to the field of pharmacy and preparation, and relates to an emulsion containing a hydrophilic biomolecule, a preparation method thereof and use thereof. Background technique
  • Hydrophilic biomacromolecules including proteins or peptides, polysaccharides, and nucleic acids, are an increasingly important class of drugs in the pharmaceutical field.
  • oral administration is ineffective and clinically needed. Frequent injection administration. Therefore, it is a common ideal in the medical field to develop a drug delivery system that is highly patient-compliant and suitable for oral administration.
  • Oral insulin microemulsion bioavailability is only 4.44% (Amani Elsayed, et al, European Journal of Pharmaceutics and Biopharmaceutics 73 (2009) 269 - 279 ); oral PTH formulation bioavailability is only 2.1% ( Andrea Leone-Bay, et Al, Pharmaceutical Research, Vol. 18, No. 7, 2001).
  • Vitamin E also known as tocopherol, is a common fat-soluble vitamin E. When used as an antioxidant, the concentration is generally less than 1%. Vitamin E is also often used as a nutritional supplement for a wide range of applications in health care, food, medical, and beauty. Due to its special structure, vitamin E has good solubility for some hydrophobic molecules such as paclitaxel, cyclosporine and body substances. According to this, Constantinides et al., in addition to “water-soluble” and “oil-soluble”, The concept of "vitamin E dissolution” (Constantinides, PP, et al. (2004) Adv Drug Deliv Rev. 56: 175-82).
  • Vitamin E is highly safe as a food-borne substance and a nutritional supplement. However, the current study only uses vitamin E as a carrier for hydrophobic drugs. Vitamin E has not yet been used to achieve oral administration of hydrophilic biomacromolecules. Report of the drug. Summary of the invention
  • the inventors have conducted extensive experiments and creative labor to obtain an emulsion containing a hydrophilic biomacromolecule in which an ester derivative of vitamin E or vitamin E is used as a carrier of a hydrophilic biomacromolecules.
  • Vitamin E or its ester derivatives are not toxic by themselves, and can effectively solve the safety hazards of currently administered hydrophilic biomacromolecules.
  • the present inventors have surprisingly found that the use of an ester derivative of vitamin E or vitamin E as a carrier for the administration of a hydrophilic biomacromolecule can significantly improve the oral bioavailability of these hydrophilic biomacromolecules.
  • An emulsion containing a hydrophilic biomacromolecule comprising a hydrophilic biomacromolecule, an aqueous phase, an oil phase, an emulsifier, characterized in that the emulsion further comprises an ester derivative of vitamin E and/or vitamin E .
  • hydrophilic biomacromolecule is selected from the group consisting of a protein or a polypeptide, a polysaccharide, and a nucleic acid.
  • the hydrophilic biomolecule can be isolated from a living organism, or can be obtained by genetic engineering or organic synthesis.
  • the emulsion according to any one of the present invention wherein the vitamin E is one or more selected from the group consisting of d- ⁇ -vitamin E and d- ⁇ -vitamin E, and the vitamin oxime ester derivative
  • the substance is selected from the group consisting of d-a-vitamin E acetate, dl-a-tocopheryl acetate, da-vitamin E succinate, d-a-vitamin E succinate, da-vitamin E succinic acid polyethylene glycol One or more of an ester, and a polyethylene glycol dl-a-tocopheryl succinate.
  • the ester derivative of vitamin E or vitamin E in the present invention may be natural or artificially synthesized.
  • the emulsion according to any one of the present invention wherein the hydrophilic biomacromolecule is 0.01 to 1 part by weight, and the ester derivative of the vitamin E and/or vitamin E is 50 - 1 Q0G parts by weight, 50 - 5 QQ parts by weight, or 100 - 300 parts by weight.
  • emulsion according to any one of the invention wherein the aqueous phase, the oil phase, and the emulsifier are 20 - 2000 parts by weight, 20 - 1000 parts by weight, or 50 - 500 parts by weight in total.
  • the amount of each of the aqueous phase, the oil phase, and the emulsifier can be readily determined by those skilled in the art.
  • the emulsion according to any one of the present invention wherein the protein or polypeptide is selected from the group consisting of calcitonin, insulin, GLP-1 (glucagon-like peptide-1), parathyroid hormone, and growth hormone
  • the polysaccharide is selected from the group consisting of heparin, low molecular weight heparin (average molecular weight of 4000-6000), chondroitin sulfate, keratan sulfate, and hyaluronic acid
  • the nucleic acid is selected from the group consisting of an antisense nucleic acid, a ribozyme, an interfering RNA, and a DECOY nucleic acid.
  • the calcitonin is salmon calcitonin, salmon calcitonin, or human calcitonin
  • the insulin is porcine insulin, bovine insulin, or human insulin
  • the gland hormone is human parathyroid hormone 1-84, or human parathyroid hormone 1-34, and the growth hormone is porcine growth hormone, bovine growth hormone, or human growth hormone.
  • aqueous phase is one or more selected from the group consisting of water, physiological saline, and an aqueous phase buffer.
  • emulsifier is selected from the group consisting of soy lecithin, egg yolk lecithin, poloxamer 188, poloxamer 407, carbomer, tween 20, spit Warm 80, polyethylene glycol dodecyl stearate, polyoxyethylene ether (35) castor oil, polyoxyethylene ether (40) hydrogenated castor oil, polyglycerol-6-dioleate, polyglycerol-3 - oleate, polyethylene glycol-32-lauric acid glyceride, polyethylene glycol-32-stearic acid One or more of a glyceride, and a polyethylene glycol caprylic/capric glyceride.
  • 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.
  • any of the emulsions of the present invention further comprising a pH adjusting agent, a P H adjusting agent selected from hydrochloric acid, lactic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate 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.
  • hydrophilic biopolymer-containing emulsion An emulsion according to any one of the invention, which is administered orally.
  • the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
  • Oleic acid 0.3 parts by weight
  • the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of 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 hydrophilic biomacromer-containing emulsion are as follows:
  • Polyethylene glycol octanoate / glyceryl citrate eg 2.5-3.5 parts by weight Sofitgen® 767, SAS0L
  • the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for the reduction of 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 contents of the hydrophilic biomacromer-containing emulsion are as follows:
  • Recombinant human insulin 0.04 parts by weight 1 part by weight of sodium hydroxide in deionized water
  • Dl- ⁇ -vitamin E acetate 1 weight * part medium chain fatty acid glyceride (eg Labrafac 0.5 parts by weight
  • Polyethylene glycol caprylic acid / glyceryl citrate (for example, 3 parts by weight)
  • Soy lecithin 0.5 weight The invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for lowering blood glucose.
  • the components and contents of the hydrophilic biomacromer-containing emulsion are as follows:
  • the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of diabetes, or for the reduction of 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 hydrophilic biomacromer-containing emulsion are as follows:
  • 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 contents of the hydrophilic biopolymer-containing emulsion are as follows:
  • Dl- ⁇ -vitamin ⁇ 0.7 parts by weight of d- ⁇ -vitamin succinic acid polyethylene glycol ester 0.5 parts by weight of soybean oil 1.2 parts by weight of soybean lecithin 0.7 parts by weight of polyoxyethylene ether (40) hydrogenated castor oil 3 parts by weight Ethylene glycol 400 2 parts by weight.
  • the invention further relates to the use of the emulsion in the manufacture of a medicament for the treatment or prevention of osteoporosis, in a particular embodiment of the invention, the hydrophilic biological fraction 0 ⁇
  • the invention also relates to the use of the emulsion in the manufacture of a medicament for anticoagulation and or thrombolysis.
  • the invention further relates to a method of treating or preventing a thrombus, or anticoagulation, comprising the step of administering an effective amount of the emulsion.
  • the components and contents of the hydrophilic biopolymer-containing emulsion are as follows:
  • the present invention is a glycerol phthalic acid glyceride.
  • the method for preparing a hydrophilic biomacromer-containing emulsion according to any one of the present invention comprises the steps of:
  • step 3 At 4 - 37. Under the condition of C, the product of step 1) is added dropwise to the product of step 2), and stirring is continued at 200 - 800 rpm until a clear and clear homogeneous preparation is formed, and finally a hydrophilic biomacromolecular emulsion is obtained. Still another aspect of the present invention relates to the use of the hydrophilic biomacromer-containing emulsion of the present invention for the preparation of a medicament for treating or preventing diabetes, or lowering blood glucose, wherein the hydrophilic biomacromolecule is insulin or GLP- 1.
  • Still another aspect of the present invention relates to the use of the hydrophilic biomacromolecular-containing emulsion of the present invention for the preparation of a medicament for treating or preventing osteoporosis, wherein the hydrophilic biomacromolecule is calcitonin or scorpion Parathyroid hormone, parathyroid hormone 1-84, or human parathyroid hormone 1-34.
  • a further aspect of the invention relates to the use of an ester derivative of vitamin E and/or vitamin E for the preparation of a hydrophilic biomolecular-containing emulsion.
  • the hydrophilic biomacromer-containing emulsion is the hydrophilic biomacromolecular emulsion according to any one of the inventions.
  • the vitamin E is one or more selected from the group consisting of d- ⁇ -vitamin E and cU-a-vitamin E
  • the ester derivative of the vitamin E is selected from the group consisting of da-vitamin E acetate.
  • d a-vitamin E acetate, d-a-tocopheryl succinate, d-a-vitamin E succinate, d-a-vitamin E succinate, and d la-vitamin E amber One or more of acid polyethylene glycol esters.
  • the hydrophilic biomacromolecule and the aqueous phase, the oil phase, the emulsifier, the pH adjuster, and the like, and the amounts thereof are as described above.
  • oral administration of a hydrophilic biomacromolecular drug is achieved by means of an ester derivative of vitamin E and/or vitamin E, and is safe, effective, and has high oral bioavailability, and bioavailability. Degree can reach 5%, 10%, 12%, 15% or even 30%;
  • the prepared vitamin E microemulsion containing a hydrophilic bio-low molecular drug can spontaneously emulsify into a droplet of 300 nm or less after being in contact with water, and is better absorbed and utilized by the gastrointestinal tract to exert better biological activity.
  • Fig. 1 Diagram of blood glucose changes in rats under different modes of administration.
  • Fig. 2 Phase diagram of plasma concentration of rat PTH1-34 under different modes of administration. detailed description
  • Example 1 Preparation of an emulsion containing salmon calcitonin (microemulsion)
  • D- ⁇ -vitamin E 0.7 g oleic acid Q.3 g polyethylene glycol dodecyl stearate (Solutol 1.5 g
  • step 3 30. Under C, add the A solution dropwise to the product of step 2), stir the mixture to a clear and clear at 800 r/min, and finally obtain an emulsion (microemulsion) containing salmon calcitonin (called sample 1). ).
  • Example 2 Preparation of emulsion containing recombinant human insulin (microemulsion)
  • Poloxamer 188 (Lutrol F68, BASF) 0.2 g
  • Soy lecithin (Epikuron 170, Degussa) 0.5 g.
  • Example 3 Preparation of an emulsion containing GLP-1 (microemulsion)
  • TPGS d- ⁇ -Vitamin E succinic acid polyethylene glycol ester
  • Example 4 Preparation of an emulsion containing PTH 1-34 (microemulsion)
  • TPGS D- ⁇ -vitamin succinic acid polyethylene glycol ester
  • Soy lecithin (Epikuron 170, Degussa) 0 ⁇ 7 g
  • step 3 Add the A solution dropwise to the product of step 2) at 30 ° C, and continue stirring at 500 r / min to clear and clear, and finally obtain a PTH 1-34 containing emulsion (microemulsion) ( Called sample 4).
  • Example 5 Preparation of emulsion containing low molecular weight heparin (microemulsion)
  • Polyethylene glycol 400 0.5 g.
  • step 3 Add the A solution dropwise to the product of step 2) at 30 ° C, and continue stirring at 500 r / min to clear and clear, and finally obtain an emulsion (microemulsion) containing low molecular weight heparin. For sample 5).
  • Example 6 Preparation of an emulsion containing small interfering RNA (microemulsion) The composition is as follows:
  • Dg- ⁇ -vitamin E 0. 2 g Polyglycerol-3-oleate 0. 3 g Polyethylene glycol octanoic acid / glyceryl citrate 2. 7 g Glycerol 0. 5 g.
  • sample 6 an emulsion (microemulsion) containing small molecule interference RNA (referred to as sample 6) was obtained.
  • Example 6 Particle size measurement test
  • Example 8 Efficacy test of emulsion containing recombinant human insulin (microemulsion) Oral test group: 6 male SD rats in the range of 180 - 220 g, drug (test drug) was sample 2 prepared in Example 2.
  • Oral control group 6 male Sprague-Dawley rats in the range of 180-220 g, the drug (control drug) was prepared according to the composition and procedure of Example 2, except that no d- ⁇ -vitamin oxime acetate was added.
  • Intravenous control group 6 male Sprague-Dawley rats in the range of 180-220 g, the drug was an aqueous insulin solution.
  • Rats in the experimental group were anesthetized with sodium pentobarbital at a dose of 50 rag before the test, then bundled in the supine position, and cut into a small mouth in the abdomen, and administered to the ileum by the applicator. After that, suture the incision.
  • the control group was administered subcutaneously as a control drug, and the dose was 0.04 mg/kg based on the insulin.
  • the three groups were all taken from the tail vein at the time of 0.5, 1, 2, 3, and 4 h after administration.
  • the blood glucose was measured using a Roche blood glucose meter and the average blood glucose level of 6 rats in each group was calculated.
  • Figure 1 As can be seen from Fig. 1, the bioavailability of the test group administered orally was 12.5% relative to the control group administered by injection.
  • Example 9 Emulsion containing PTH1-34 (microemulsion) Bioavailability test Test group: 10 male SD rats in the range of 180 - 220 g, and the drug (test drug) was the sample prepared in Example 4.
  • Control group 10 male SD rats in the range of 180-220 g, the drug was PTH1-34 aqueous solution, and administered by injection.
  • mice Male SD rats weighing 180-220 g were fasted for 12 h before starting the test.
  • the test group was orally administered, and the dose was 10 ( ⁇ g/kg) according to PTH1-34.
  • the animals in the oral group were anesthetized with sodium pentobarbital at a dose of 50 mg before the experiment, and then tied in an upright manner. A small opening was made in the abdomen, and the ileum was administered by the applicator. After the administration, the incision was sutured.
  • the control group was subcutaneously injected with PTH1-34, and the dose was 10 g/kg as PTH1-34.
  • the blood was taken from the tail vein at the time points of 15, 30, 45, 60, 75, 90, and 105 minutes after administration, and the serum was separated for testing.
  • Serum PTH 1-34 concentrations were measured using the PTH 1-34 high sensitivity EIA kit. The results are shown in Figure 2, where the area under the PTH1-3 blood concentration curve is calculated. 2% ⁇ The bioavailability of the test group administered orally was 23.13%.

Abstract

Une émulsion contenant une macromolécule biologique hydrophile, sa méthode de préparation et son application sont divulguées. L'émulsion contient une macromolécule biologique hydrophile, une phase aqueuse, une phase huileuse, un agent émulsifiant, de la vitamine E et/ou des dérivés esters de vitamine E.
PCT/CN2011/000814 2011-02-24 2011-05-10 Émulsion contenant une macromolécule biologique hydrophile, sa méthode de préparation et application WO2012113116A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110044426.3 2011-02-24
CN2011100444263A CN102125520A (zh) 2011-02-24 2011-02-24 含亲水性生物大分子的乳剂、其制备方法及用途

Publications (1)

Publication Number Publication Date
WO2012113116A1 true WO2012113116A1 (fr) 2012-08-30

Family

ID=44263957

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2011/000814 WO2012113116A1 (fr) 2011-02-24 2011-05-10 Émulsion contenant une macromolécule biologique hydrophile, sa méthode de préparation et application

Country Status (2)

Country Link
CN (1) CN102125520A (fr)
WO (1) WO2012113116A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013134267A1 (fr) * 2012-03-05 2013-09-12 Archer Daniels Midland Company Microémulsions et utilisations de celles-ci comme systèmes d'administration
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
CN104840415B (zh) * 2014-02-19 2019-03-15 香港浸会大学 含有降血糖活性成分的长效控释脂质体凝胶组合物及其制备方法
CN110114061A (zh) * 2016-12-28 2019-08-09 小林制药株式会社 外用组合物
CN108013475B (zh) * 2017-12-26 2021-06-08 华中农业大学 一种多肽-多糖复合乳液及其制备方法
KR102216578B1 (ko) * 2019-09-05 2021-02-17 주식회사 아이큐어비앤피 테리파라타이드를 포함하는 경구용 약학 조성물 및 이의 제조방법
CN112220752A (zh) * 2020-10-21 2021-01-15 四川大学 一种胶束及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1839876A (zh) * 2006-01-18 2006-10-04 复旦大学 肝素口服纳米乳组合物及其制备方法
CN101076354A (zh) * 2004-08-03 2007-11-21 生命健康科学有限公司 用于肠道给药的载体
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
US20090202596A1 (en) * 2006-06-13 2009-08-13 Farmatron Limited Pharmaceutical compositions with biological barriers permeation enhancing properties

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1160122C (zh) * 2001-04-20 2004-08-04 清华大学 一种制备口服胰岛素油相制剂的方法
US6951655B2 (en) * 2001-10-11 2005-10-04 Imi Biomed, Inc. Pro-micelle pharmaceutical compositions
CN1596889A (zh) * 2004-07-23 2005-03-23 沈阳药科大学 维生素e乳剂及其冻干乳剂的组方及制备方法
CN1743000A (zh) * 2004-08-30 2006-03-08 上海医药工业研究院 一种甲状旁腺素经鼻给药制剂及制备方法
CN101428009B (zh) * 2008-04-09 2013-01-09 上海医药工业研究院 胰岛素经鼻吸入粉雾剂
CN102113996B (zh) * 2011-02-24 2013-06-12 美迪思生物科技(北京)有限公司 一种含有蛋白质或多肽的口服制剂、其制备方法及用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101076354A (zh) * 2004-08-03 2007-11-21 生命健康科学有限公司 用于肠道给药的载体
CN1839876A (zh) * 2006-01-18 2006-10-04 复旦大学 肝素口服纳米乳组合物及其制备方法
US20090202596A1 (en) * 2006-06-13 2009-08-13 Farmatron Limited Pharmaceutical compositions with biological barriers permeation enhancing properties
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

Also Published As

Publication number Publication date
CN102125520A (zh) 2011-07-20

Similar Documents

Publication Publication Date Title
KR100508695B1 (ko) 인슐린의 경구투여용 제형과 그의 제조방법
AU2004305395B2 (en) Nanoparticle compositions of water-soluble drugs for oral administration and preparation methods thereof
JP3903061B2 (ja) 薬物を含有するナノ粒子およびその製造方法、ならびに当該ナノ粒子からなる非経口投与用製剤
WO2012113116A1 (fr) Émulsion contenant une macromolécule biologique hydrophile, sa méthode de préparation et application
CA2058835C (fr) Composition pharmaceutique stable et methode pour la preparer
KR20020066778A (ko) 체내 난흡수 물질의 흡수촉진용 조성물과 제형 및 그의제조방법
Wei et al. A novel sustained-release formulation of recombinant human growth hormone and its pharmacokinetic, pharmacodynamic and safety profiles
US20100278922A1 (en) Methods and compositions for oral administration of insulin
CN109069651A (zh) 稳定的尼莫地平肠胃外制剂
EP1731139A1 (fr) Preparation pharmaceutique de type s/o et procede de production associe
CN101366697A (zh) 一种新的包含紫杉醇类物质的注射用纳米脂质载体及其制备方法
US20040147578A1 (en) Use of lipoaminoacids as absorption promoters in a pharmaceutical composition
KR20140125353A (ko) 부분불소화 알칸에 기초한 안정화된 단백질 조성물
Le Dévédec et al. PEGylated bile acids for use in drug delivery systems: enhanced solubility and bioavailability of itraconazole
CN1857222A (zh) 多西紫杉醇静脉注射亚微乳剂及其制备方法
US20230372436A1 (en) Somatostatin receptor agonist formulations
JP6305555B2 (ja) 血糖降下作用の有効成分を有する持続徐放性リポソームゲル組成物及びその製造方法
US20230398072A1 (en) Concentrate containing poorly soluble drug and emulsion prepared therefrom
US7087246B2 (en) Controlled release preparation of insulin and its method
CN108434118A (zh) 胰高血糖素样肽-1类似物缓释微球及其制备方法
WO2012113117A1 (fr) Préparation orale comprenant une protéine ou un polypeptide, son procédé de préparation et son utilisation
EP3906019A1 (fr) Compositions pharmaceutiques de furosémide et leurs utilisations
US20110033527A1 (en) Opthalmic compositions of cyclosporin
TWI728959B (zh) 不穩定或難溶藥物的口服投予
TWI472340B (zh) Taxanes containing solution and a preparation method of the co-solvent

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11859379

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11859379

Country of ref document: EP

Kind code of ref document: A1