WO2011043532A1 - Nanoparticules lipidiques destinées à une administration orale, et procédé de préparation associé - Google Patents

Nanoparticules lipidiques destinées à une administration orale, et procédé de préparation associé Download PDF

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WO2011043532A1
WO2011043532A1 PCT/KR2010/003061 KR2010003061W WO2011043532A1 WO 2011043532 A1 WO2011043532 A1 WO 2011043532A1 KR 2010003061 W KR2010003061 W KR 2010003061W WO 2011043532 A1 WO2011043532 A1 WO 2011043532A1
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lipid
docetaxel
nanoparticles
phosphatidylcholine
nanoparticle
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English (en)
Korean (ko)
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이풍석
전정륜
김현미
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건일제약 주식회사
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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K9/127—Liposomes
    • 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
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids

Definitions

  • the present invention relates to a lipid-nanoparticle containing docetaxel and a pharmaceutical composition comprising the same. More particularly, the present invention relates to a liposome including docetaxel, amphoteric phospholipid, anionic phospholipid, and a dissolution aid, wherein the docetaxel is contained in the liposome. Oral lipid-nanoparticles obtained by drying a dispersion containing encapsulated liposomes; Pharmaceutical compositions comprising the same, preferably pharmaceutical compositions comprising the lipid-nanoparticles and P-glycoprotein inhibitors; And to a method for preparing the lipid-nanoparticles.
  • Docetaxel which is used for the treatment of various cancers such as ovarian cancer, breast cancer and lung cancer, is a low permeability and low solubility drug corresponding to the BCS (Biopharmaceutics Classification System) Class IV, and is sold in the form of an injection (commercial name TAXOTERE TM ).
  • BCS Biopharmaceutics Classification System
  • TAXOTERE TM is an injectable drug obtained by dissolving docetaxel in a high-dose dissolution aid (Tween 80) and alcohol (13%), and various side effects such as acute hypersensitivity reactions, fluid retention, and hypotension have been pointed out (KIMS Volume 22 Number 1) 289).
  • docetaxel is a poorly water-soluble drug with a solubility of ⁇ 14 ⁇ g / ml.
  • the oral absorption rate is very low (less than 3%) due to the effect of P-glycoprotein on the small intestinal epithelial membrane. Absorbed in vivo, it is metabolized by cytochrome P450 3A4, that is, it loses drug activity under the influence of liver first pass effect.
  • Liposomes have been studied as new drug carriers because of their ability to contain both poorly water-soluble and water-soluble substances since they were discovered in the 1960s as endoplasmic reticulum surrounded by lipid bilayers (Yechezkel Barenholz, Current Opinion in Colloid & Interface Science, 6, 66-67, 2001).
  • Doxil lipozomal doxorubicin
  • liposomes themselves are components suitable for living organisms, the toxicity problem is relatively low, and injectable drugs are known to have long-lasting drug properties (Tamer et al. International Journal of Pharmaceutics, 359, 272-279). , 2008).
  • the inventors of the present invention have conducted various studies to develop an oral docetaxel-containing formulation that can solve the poor solubility problem of docetaxel and overcome the low bioavailability.
  • a combination of amphoteric phospholipids and anionic phospholipids when docetaxel is encapsulated in liposomes using a dissolution aid and formulated from lipid-nanoparticles in solid form, docetaxel is solubilized effectively, resulting in difficulty in docetaxel egg. It has been found that solubility problems and low bioavailability can be overcome and are very stable in the gastrointestinal tract.
  • a P-glycoprotein inhibitor such as silymarin
  • an object of the present invention is to provide oral lipid-nanoparticles containing docetaxel.
  • docetaxel obtained by drying a dispersion containing a liposome encapsulated inside the liposome.
  • the liposomes may further include a coating layer comprising a chitosan derivative having a weight average molecular weight of 5,000 to 1,000,000 or a chitosan derivative.
  • the amphoteric phospholipids are phosphatidylcholine, hydrogenated phosphatidylcholine, dioleoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, myristoyl palmitoyl phosphatidylcholine, myristoyl stearoyl phosphatidylcholine, stearoyl Palmitoyl phosphatidylcholine, phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, and distearoyl phosphatidylethanolamine, and may be selected from the group consisting of Preferably hydrogenated soybean phosphatidylcholine.
  • the anionic phospholipid may be phosphatidylglycerol or a salt thereof, dioleoyl phosphatidylglycerol or a salt thereof, dimyristoyl phosphatidylglycerol or a salt thereof, dipalmitoyl phosphatidylglycerol or a salt thereof, distearoyl phosphatidylglycerol or a salt thereof, diol At least one selected from the group consisting of leoyl phosphate or salts thereof, dimyristoyl phosphate or salts thereof, dipalmitoyl phosphate or salts thereof, distearoyl phosphate or salts thereof, and preferably 1 , 2-dipalmitoyl- sn -glycero-3-phospho- (1'- rac -glycerol) or a salt thereof; Or 1,2-dstearoyl-sn-glycero-3-phospho- (1′- rac -glycerol) or salt
  • the dissolution aids are polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil, polyethylene glycols, polyoxyglycerides, ⁇ -tocopherol, and ⁇ -tocopheryl It may be selected from the group consisting of polyethylene glycol succinate, preferably ⁇ -tocopheryl polyethylene glycol succinate.
  • the amphoteric phospholipid content may be 1 to 50 wt% with respect to the total weight of lipid-nanoparticles, and the content of the anionic phospholipid may be 1 to 30 wt% with respect to the total weight of lipid-nanoparticles. have.
  • the molar ratio of the amphoteric phospholipid and the anionic phospholipid to the docetaxel is preferably 1: 9 to 20.
  • the content of the dissolution aid may be 1 to 80% by weight relative to the total weight of lipid-nanoparticles.
  • the content of the chitosan or chitosan derivative containing a thiol group may be 5 to 50 parts by weight based on 100 parts by weight of the lipid-nanoparticles.
  • the liposome may further include cholesterol (cholesterols) as a stabilizer, the content of the cholesterol, may be 1 to 10% by weight relative to the total weight of the lipid-nanoparticles have.
  • cholesterol cholesterol
  • an oral pharmaceutical composition comprising the lipid-nanoparticle and a pharmaceutically acceptable additive.
  • an oral pharmaceutical composition comprising the lipid-nanoparticles and a P-glycoprotein inhibitor as an active ingredient and a pharmaceutically acceptable additive, wherein the P-glycoprotein inhibitor May be silymarin.
  • a pharmaceutical composition comprising (a) docetaxel; Amphoteric phospholipids; Anionic phospholipids; And optionally dissolving cholesterol in a water-immiscible organic solvent, (b) dissolving a dissolving aid in water or a mixed solvent of water and C 1 -C 4 alcohol, (c) obtained in step (a) Mixing the solution and the solution obtained in step (b) and homogenizing to obtain an emulsion having an average particle size of 100 to 2000 nm, (d) removing the organic solvent from the emulsion obtained in step (c) Obtaining a dispersion, and (e) drying the dispersion obtained in step (d) to obtain a lipid-nanoparticles, a method for producing the lipid-nanoparticles is provided.
  • step (e) adds a solution containing a chitosan derivative containing a weight average molecular weight of 5,000 to 1,000,000 or a chitosan derivative in a buffer of pH 4 to 6 to the dispersion obtained in step (d). It may be carried out by drying the dispersion obtained by mixing with, wherein the drying may be preferably carried out by spray drying or lyophilization.
  • Oral lipid-nanoparticles according to the present invention can be applied as oral preparations by greatly improving the solubility and bioavailability of poorly soluble and poor membrane permeability docetaxel belonging to BCS class IV.
  • the lipid-nanoparticles of the present invention not only stably solubilize docetaxel by lipids, but also exhibit markedly increased solubility through combination with a dissolution aid and are very stable in the gastrointestinal tract.
  • the lipid-nanoparticles are formulated with a P-glycoprotein inhibitor such as silymarin, the oral bioavailability of docetaxel may be further improved.
  • the lipid-nanoparticles and the lipid-nanoparticles and P-glycoprotein inhibitors according to the present invention can solve the problems caused by the use of a conventional injectable formulation, that is, the economic burden of low medication compliance and hospitalization of the patient. In addition, side effects caused by injections can be avoided.
  • Example 17 is a photograph of a lipid-nanoparticle according to the present invention (Example 17) dispersed in water and measured by transmission electron microscope (TEM).
  • TEM transmission electron microscope
  • Figure 2 is a photograph of the lipid-nanoparticles according to the present invention (Example 19) was measured by transmission electron microscopy (TEM) by dispersing in water.
  • TEM transmission electron microscopy
  • lipidic nanoparticles refers to a dry matter of phospholipid-based liposomes, which have a mean particle size in the range of 50 to 800 nm when redispersed in water.
  • the lipid-nanoparticles when added to an aqueous medium, including the environment in the gastrointestinal tract, are liposomes encapsulated with a drug (ie docetaxel) inside the liposome.
  • docetaxel is a taxane-based anticancer agent used in the treatment of various cancers such as ovarian cancer, breast cancer and lung cancer, and docetaxel free base, as well as pharmaceutically acceptable salts and anhydrides thereof. , Hydrates, polymorphs, and all forms of prodrugs.
  • the docetaxel may be contained in a therapeutically effective amount in a lipid-nanoparticle or a pharmaceutical composition comprising the same according to the present invention, for example, 5 to 100 mg per unit dosage form. And preferably in an amount of about 20-50 mg.
  • the present invention is a docetaxel; Amphoteric phospholipids; Anionic phospholipids; And a liposome comprising a dissolution aid, wherein the docetaxel is obtained by drying a dispersion containing a liposome encapsulated inside the liposome, oral lipid-nanoparticles.
  • the lipid-nanoparticles can be applied as oral preparations by greatly improving the solubility and bioavailability of poorly water-soluble and poorly permeable docetaxel belonging to BCS class IV.
  • the lipid-nanoparticles of the present invention not only stably solubilize docetaxel by lipids, but also exhibit markedly increased solubility through combination with certain solubilizers and are very stable in the gastrointestinal tract.
  • the amphoteric phospholipid is phosphatidyl choline (PC) (eg, egg phosphatidylcholine (Egg PC, EPC), soybean phosphatidylcholine (Soybean PC, SPC), etc.), hydrogenated phosphatidylcholine hydrogenated phosphatidyl choline (eg, hydrogenated soybean phosphatidyl choline (HSPC), etc.), dioleoyl phosphatidyl choline (eg, 1,2-dioleoyl-sn-glycero) -3-phosphocholine (1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC) and the like], dimyristoyl phosphatidyl choline [eg, 1,2-dimyristoyl- sn-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine (1,2-dimyristoyl-
  • the amphoteric phospholipid may be hydrogenated soybean phosphatidyl choline (HSPC).
  • HSPC hydrogenated soybean phosphatidyl choline
  • the amphoteric phospholipid content may be 1 to 50% by weight, more preferably 10 to 30% by weight, based on the total weight of lipid-nanoparticles.
  • the anionic phospholipid may be phosphatidylglycerol or a salt thereof, dioleoyl phosphatidylglycerol or a salt thereof (eg, 1,2-dioleoyl-sn-glycero-3-phospho- ( 1'- rac -glycerol) sodium salt (1,2-dioleoyl-sn-glycero-3-phospho- (1'- rac -glycerol) sodium salt, DOPG-Na), etc.], dimyristoyl phosphatidylglycerol (dimyristoyl) phosphatidylglycerol) or salts thereof [eg, 1,2-dimyristoyl-sn-glycero-3-phospho- (1'- rac -glycerol) sodium salt (1,2-dimyristoyl-sn-glycero- 3-phospho- (1'- rac -glycerol) sodium salt, DMPG-Na) and the like,
  • the anionic phospholipid is 1,2-palmitoyl - sn - glycero-3-phospho - (1'- rac - glycerol) [1,2-dipalmitoyl- sn -glycero- 3-phospho- (1'- rac- glycerol)] or a salt thereof; Or 1,2-distearoyl- sn -glycero-3-phospho- (1'- rac -glycerol) [1,2-distearoyl- sn -glycero-3-phospho- (1'- rac -glycerol )] Or salts thereof.
  • the content of the anionic phospholipid may be 1 to 30% by weight, more preferably 5 to 15% by weight based on the total weight of lipid-nanoparticles.
  • the total phospholipid i.e., the amphoteric phospholipid and the anionic phospholipid, preferably has a molar ratio of at least 1: 9 relative to the active ingredient (ie docetaxel), more preferably The molar ratio of 1: 9 to 20 is preferable.
  • the dissolution aids include polyoxyethylene-polyoxypropylene copolymers (eg, poloxamer 407, etc.), polyoxyethylene alkyl ethers (eg, Brij, Cremophore). (cremophor) A25, etc.], polyoxyethylene sorbitan fatty acid esters (eg, polysorbate 80, etc.), polyoxyethylene castor oil (eg, cremo) Pore (cremophor EL etc.), polyethylene glycols (eg PEG200, etc.), polyoxyglycerides (eg geludire 44/14, etc.), ⁇ -tocopherol, And ⁇ -tocopheryl polyethylene glycol succinate can be selected from the group consisting of.
  • polyoxyethylene-polyoxypropylene copolymers eg, poloxamer 407, etc.
  • polyoxyethylene alkyl ethers eg, Brij, Cremophore. (cremophor) A25, etc.]
  • the dissolution aid may be ⁇ -tocopheryl polyethylene glycol succinate.
  • the content of the dissolution aid may be 1 to 80% by weight, more preferably 40 to 60% by weight based on the total weight of the lipid-nanoparticles.
  • the liposome may further include a coating layer including a biodegradable polymer, for example, a chitosan derivative containing a weight average molecular weight of 5,000 to 1,000,000 or a chitosan derivative or a thiol group.
  • a biodegradable polymer for example, a chitosan derivative containing a weight average molecular weight of 5,000 to 1,000,000 or a chitosan derivative or a thiol group.
  • the coating layer is formed on the surface of the lipid-nanoparticles.
  • the lipid-nanoparticle having a coating layer has a zeta potential of +20 to 70 mV and the surface of the particle is charged with an anode so that it stays longer by interacting with the gastrointestinal mucosa showing anion during oral administration. do.
  • the weight average molecular weight of the chitosan or chitosan derivative containing a thiol group exceeds the above range, it may be difficult to formulate due to low solubility in an aqueous medium or may impede absorption of docetaxel as an active ingredient.
  • the content of the chitosan or chitosan derivative containing a thiol group may be 5 to 50 parts by weight, preferably 10 to 30 parts by weight based on 100 parts by weight of the lipid-nanoparticles.
  • the liposomes may further include cholesterol (cholesterols) as a component that enhances stability, that is, a stabilizer.
  • the stabilizer content may be 1 to 10% by weight, preferably 1 to 5% by weight based on the total weight of the lipid-nanoparticles.
  • the amount of the stabilizer is preferably used in a molar ratio of about 1: 1 with respect to the active ingredient (ie docetaxel).
  • the dispersion containing liposomes may be further added with a cryoprotectant such as maltose, sucrose, a saccharide derivative, arginine, mannitol or an amino acid derivative, and histidine, and then dried (eg, lyophilized). ), Lipid-nanoparticles according to the invention can be obtained.
  • a cryoprotectant such as maltose, sucrose, a saccharide derivative, arginine, mannitol or an amino acid derivative, and histidine
  • the present invention also provides an oral pharmaceutical composition comprising the lipid-nanoparticle and a pharmaceutically acceptable additive.
  • the oral pharmaceutical composition according to the present invention may be formulated into a conventional oral solid preparation such as tablets, capsules and the like with the pharmaceutically acceptable additives.
  • a mixture of the lipid-nanoparticles and a pharmaceutically acceptable additive may be filled into a capsule and formulated into a capsule.
  • the pharmaceutically acceptable additives include, for example, diluents such as lactose, starch, microcrystalline cellulose; Lubricants such as magnesium stearate, talc, and the like, but are not limited thereto.
  • the pharmaceutically acceptable additive may be in the range of 20 to 70% by weight based on the total weight of the composition, but is not limited thereto.
  • Oral pharmaceutical composition according to the present invention as an active ingredient, by adding a P-glycoprotein inhibitor in addition to the lipid-nanoparticles, it is possible to further enhance the oral bioavailability of docetaxel. That is, the present invention provides an oral pharmaceutical composition comprising the lipid-nanoparticle and the P-glycoprotein inhibitor as an active ingredient and a pharmaceutically acceptable additive.
  • the P-glycoprotein inhibitor may be used in an effective amount capable of exhibiting P-glycoprotein inhibitory activity, and each effective amount may be different depending on the type of P-glycoprotein inhibitor.
  • the P-glycoprotein inhibitor may range from 1 to 400 mg per unit doage form of the pharmaceutical composition of the present invention, but of course it may differ depending on the type of P-glycoprotein inhibitor.
  • the P-glycoprotein inhibitors may be used without limitation known P-glycoprotein inhibitors, for example, verapamil, cyclosporine A, quinidine, cephalatin, cephalanthine, feto Thioxazine, dipyridamol, progesterone, biochanin A, silymarin, and the like.
  • flavono which is known to stabilize liver cell membranes as a natural substance, inhibits cellular influx of harmful substances, activates protein synthesis of hepatocytes and promotes regeneration of hepatocytes, and is widely used as a liver medicine.
  • Silymarin a secondary substance, may be contained as a P-glycoprotein inhibitor.
  • Silymarin is a type of flavonoid compound extracted from thistle belonging to the Asteraceae, and includes sillybin, sillycristin, sillydianin, and isisolybin. Silymarin is known to promote the regeneration of hepatocytes by stabilizing hepatocyte membranes, inhibiting the influx of harmful substances into the cells, and activating the protein synthesis of hepatocytes, resulting in various diseases caused by environmental pollution due to smoking, drinking, overwork and various pollutions. It is widely applied as a therapeutic agent for liver disease ( Zhang et al. , Pharmaceutical research, 20 (8), 1184-1191, 2003; Republic of Korea Patent Publication 10-2008-0085930). If necessary, the silymarin may be administered in the form of a solid dispersion using polyethylene glycol.
  • the present invention is also directed to (a) docetaxel; Amphoteric phospholipids; Anionic phospholipids; And optionally dissolving cholesterol in a water-immiscible organic solvent, (b) dissolving a dissolving aid in water or a mixed solvent of water and C 1 -C 4 alcohol, (c) obtained in step (a) Mixing the solution and the solution obtained in step (b) and homogenizing to obtain an emulsion having an average particle size of 100 to 2000 nm, (d) removing the organic solvent from the emulsion obtained in step (c) It provides a method for producing the lipid-nanoparticles comprising the step of obtaining a dispersion, and (e) drying the dispersion obtained in step (d) to obtain a lipid-nanoparticles.
  • amphoteric phospholipids the types and amounts of the amphoteric phospholipids, anionic phospholipids, dissolution aids, and cholesterol are as described above.
  • the water-immiscible organic solvent is an organic solvent which is not mixed with water, and has a boiling point of water or water and C One -C 4 Lower organic solvents may be used than mixed solvents with alcohols, for example, chloroform, methylene chloride, and the like, and chloroform may be preferably used.
  • the mixed solvent with alcohol may preferably be a mixed solvent of water and ethanol, for example, 10 to 30% aqueous ethanol solution.
  • the weight ratio of the organic layer (that is, the solution of step (a)) and the aqueous layer (ie, the solution of step (b)) is not particularly limited, and may be a weight ratio of 1: 0.5 to 2.
  • the weight ratio is the water-immiscible organic solvent and the water or water and C One -C 4 It can be adjusted by adjusting the amount of the mixed solvent with alcohol.
  • the homogenization can be carried out by high speed homogenization using a conventional homogenizer, and in this case, the homogenization is carried out so that an oil-in-water type emulsion or an oil-in-water emulsion having an average particle size of 100 to 2000 nm can be obtained. do.
  • Removal of the organic solvent (ie, water-immiscibility used in step (a)) from the emulsion can be carried out using a conventional evaporator, such as a rotary vacuum evaporator.
  • a conventional evaporator such as a rotary vacuum evaporator.
  • step (e) adds a solution containing a chitosan derivative containing a weight average molecular weight of 5,000 to 1,000,000 or a chitosan derivative in a buffer of pH 4 to 6 to the dispersion obtained in step (d). It can be carried out by drying the dispersion obtained by mixing with. It has been found that biodegradable polymers such as chitosan or chitosan derivatives containing thiol groups in the pH range are effectively coated on lipid-nanoparticles.
  • the dispersion containing liposomes may be further added with a cryoprotectant such as maltose, sucrose, a saccharide derivative, arginine, mannitol or an amino acid derivative, and histidine, and then dried (eg, lyophilized). ), Lipid-nanoparticles according to the invention can be obtained.
  • the amount of the cryoprotectant used varies depending on the amount of liposomes contained in the dispersion, but may be in the range of 1 to 30% by weight, preferably 1 to 10% by weight, based on the total weight of the dispersion.
  • the drying of step (e) may be preferably carried out by spray drying or lyophilization, more preferably lyophilization.
  • the freeze-drying may be performed by a conventional freeze-drying method, for example, a rapid freezing process at -70 ° C., followed by drying in a freeze-dryer to completely remove moisture.
  • the lipid-nanoparticles obtained by drying through spray drying or lyophilization have a particle size of 50 to 800 nm when redispersed in water.
  • the lipid-nanoparticles according to the present invention may increase the solubility by three or more than 30 times compared to docetaxel alone, which corresponds to about 120 times of the intrinsic solubility of 7.8 ⁇ g / ml.
  • lipid-nanoparticles of the invention and pharmaceutical compositions comprising the same, in particular pharmaceutical compositions comprising the lipid-nanoparticles and P-glycoprotein inhibitors, may not only increase stability in the gastrointestinal tract, but also increase solubility and bioavailability.
  • Docetaxel, amphoteric phospholipid (HSPC, DMPC, DPPC, DSPC, or DSPE), anionic phospholipid (DSPG), and cholesterol were dissolved in 20 ml of chloroform.
  • the resulting solution was dried under reduced pressure at 60 ° C. in a rotary evaporator for 3 minutes to evaporate the organic solvent to form a thin lipid membrane, and then dried at 40 ° C. for 24 hours to completely remove the solvent remaining in the lipid membrane.
  • 30 ml of distilled water warmed to 60 ° C. was added thereto, shaken slowly, and the lipid membrane was peeled off to form liposomes.
  • the obtained liposome dispersion was passed through a cellulose membrane having a pore size of 100 to 200 nm 10 times to make the particle size uniform.
  • the obtained liposome dispersion was filtered through a 0.2 ⁇ m filter, and then docetaxel was quantified using HPLC to determine the encapsulation rate as follows: The difference between the amount of docetaxel initially added and the amount of docetaxel after filtered with a 0.2 ⁇ m filter was calculated. The encapsulation rate was calculated according to.
  • Inclusion rate (%) (concentration of docetaxel in liposome dispersion / concentration of docetaxel in liposome dispersion after 0.2 ⁇ m filter) X 100
  • the stability was evaluated through the degree of precipitation of docetaxel and whether or not to maintain a certain size of the particles in the aqueous phase for a certain time. That is, after 24 hours was evaluated through the change in particle size and the filling rate of the liposome dispersion, it was evaluated according to the following criteria.
  • the encapsulation rate was about 10%, and HSPC was the best in encapsulation rate and stability.
  • Example 7 Docetaxel 807.89 10 10 HSPC 785 60 60 Anionic phospholipids DPPG 744.96 30 - DSPG 801.06 - 30 cholesterol 386.65 10 10 Inclusion Rate (%) 96 99 stability +++ +++
  • Examples 6 and 7 showed high encapsulation rate and excellent stability, and both DPPG and DSPG were judged to be suitable as anionic phospholipids.
  • Example 10 Docetaxel 807.89 10 10 10 HSPC 785 90 120 150 DSPG 801.06 30 40 50 cholesterol 386.65 10 10 10 Inclusion Rate (%) 99 92 91 stability +++ +++ +++
  • the ratio of the total phospholipid to the active ingredient is 1: 9 or more, and the ratio of the cholesterol to the active ingredient is 1: 1 is the most suitable ratio.
  • the phospholipid required to encapsulate one molecule of the active ingredient in the liposome is nine molecules.
  • the taxa-based drug exhibits a very high encapsulation efficiency when compared to 20 to 30 molecules of lipid per molecule of the drug. High encapsulation efficiency not only makes it possible to encapsulate a sufficient amount of the drug required to convert the injection into an oral solution, but can also reduce the production cost, since the amount of expensive phospholipids can be reduced.
  • the degree of solubility change of docetaxel was measured by dissolving docetaxel in an aqueous solution containing various dissolution aids. That is, an excess of docetaxel was added to 10 ml of an aqueous solution containing a dissolution aid according to Table 5 (concentration: 0.5%), the shaken solution was stored for 30 minutes at room temperature, and the supernatant was filtered with a 0.45 ⁇ m filter. Docetaxel was quantified to determine solubility. Solubility evaluation was performed according to the following criteria.
  • Tween 80 and ⁇ -tocopheryl polyethylene glycol succinate (TPGS) are effective for solubilization of docetaxel. Since TPGS, unlike Tween 80, is more suitable for the preparation of oral formulations as solid preparations, TPGS is expected to be most effective in solubilizing the active ingredient, preferably in combination with TPGS.
  • the solubility of docetaxel according to TPGS concentration was evaluated as follows. That is, an excess of docetaxel was added to 10 ml of an aqueous solution containing various concentrations of TPGS, shaken for 30 minutes, stored at room temperature for one week, the supernatant was filtered through a 0.45 ⁇ m filter, and docetaxel was quantified by HPLC. The results are shown in Table 6.
  • liposomes were prepared as follows and the solubility of docetaxel was evaluated.
  • Docetaxel, HSPC, DSPG, and cholesterol were dissolved in 20 ml of chloroform.
  • 30 ml of 20% aqueous ethanol (pH 4.0) solution containing 0.05% TPGS was mixed with the above solution to prepare a milky white oil-in-water emulsion, and an oil-in-water emulsion having a particle size of 2000 nm or less was obtained using a high pressure homogenizer.
  • the resulting solution was slowly dried under reduced pressure to 100 mmHg using a rotary evaporator at 60 ° C. to evaporate the organic solvent to obtain a blue transparent liposome dispersion.
  • lipid-nanoparticles were dispersed in water and measured by transmission electron microscopy (TEM), as shown in FIG. 1.
  • TEM transmission electron microscopy
  • the obtained solution was mixed with the liposome dispersion prepared according to Example 13 in a volume ratio of 1: 1 at room temperature.
  • the resulting coating layer-containing liposome dispersion was measured using a photon counting particle size analyzer ELS Z manufactured by Otsuka Electronics (Japan), and the size of the liposome was measured. Zeta potential was measured using ELS Z. The results are shown in Table 8 below.
  • the particle size increased proportionally with the amount of chitosan at pH 4.0-6.0.
  • the zeta potential was changed from negative to positive value according to chitosan coating, but as the amount of chitosan coating increased, the zeta potential was saturated rather than proportionally increased. From the results of the larger increase in liposome size at pH4.0, it is judged that pH4.0 is suitable for chitosan coating conditions.
  • the instability of the liposomes in the gastric juice rapidly changed when the chitosan coating ratio was less than 0.5%. Therefore, it is judged that coating chitosan 0.5% on pH4.0 conditions from the above result is preferable.
  • Example 18 The liposome dispersion obtained in Example 18 (0.5% chitosan, using pH 4.0) was lyophilized in the same manner as in Example 17 to prepare powdery lipid-nanoparticles.
  • the obtained lipid-nanoparticles were dispersed in water and measured by transmission electron microscopy (TEM), as shown in FIG. 2.
  • TEM transmission electron microscopy
  • Intravenous injection (control)-Docetaxel was dissolved in polysorbate 80 to 80 mg / ml, and then diluted with 13% ethanol immediately before administration to prepare 20 mg / ml.
  • Lipid + TPGS + silymarin preparation-2g of silymarin was dissolved in PEG400 and 30ml of ethanol (2: 1, weight ratio) and diluted with distilled water (20mg / kg).
  • the resulting silymarin-containing solution and the liposomes prepared in Example 18 were each prepared by mixing 2 ml.
  • Intravenous injection was performed by inserting a polyethylene tube into the femoral vein of a 6-week-old male Sprague-Dawley rat.
  • the prepared test substance was injected at a dose of 6.7 mg / kg of docetaxel, and was administered at a dose of 50-100 mg / kg of docetaxel using Zone neddle (Zonde) for oral administration.
  • Zone neddle Zone neddle
  • Polyethylene tubes were inserted into the femoral artery of 6-week-old male rats (approximately 250 g), and then syringes filled with saline containing 100 IU / ml of heparin were connected. Receive 0.25 ml of blood in a heparinized tube at defined times (0.033, 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 18 and 24 hours) after dosing and immediately for 5 minutes at 13000 rpm. Centrifuged. 100 ⁇ l plasma was collected and stored at ⁇ 20 ° C. until analysis.
  • Tert-butylmethyl ether was added to 100 ⁇ l plasma, shaken for 5 minutes, centrifuged at 13000 rpm for 3 minutes, and the supernatant was placed in SpeedVac and dried. The residue was redispersed and the concentration of docetaxel was analyzed using a liquid chromatography double mass spectrometer (LC / MS / MS).

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Abstract

La présente invention concerne des nanoparticules lipidiques produites par séchage de la dispersion liquide contenant un liposome comprenant du docétaxel, un phospholipide amphotère, des phospholipides anioniques, et des adjuvants de dissolution, le docétaxel étant encapsulé dans le liposome. La présente invention concerne également une composition pharmaceutique contenant les nanoparticules lipidiques, et un procédé de préparation des nanoparticules lipidiques. La présente invention concerne en outre une composition pharmaceutique comprenant les nanoparticules lipidiques et des inhibiteurs de la glycoprotéine P.
PCT/KR2010/003061 2009-10-07 2010-05-14 Nanoparticules lipidiques destinées à une administration orale, et procédé de préparation associé WO2011043532A1 (fr)

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CN111195230A (zh) * 2018-11-19 2020-05-26 奥维嘉生物科技（北京）有限公司 一种制备柔性脂质体的方法
CN114711288A (zh) * 2022-03-01 2022-07-08 珠海科技学院 一种稳定性高的肉桂醛固体脂质纳米粒及其制备方法
CN114848594A (zh) * 2022-05-11 2022-08-05 南通大学 一种负载抗癌药物的脂质纳米载体及其制备方法与应用
CN116688137A (zh) * 2023-07-21 2023-09-05 中国医学科学院北京协和医院 一种基于核壳结构的药物组合物及应用

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111195230A (zh) * 2018-11-19 2020-05-26 奥维嘉生物科技（北京）有限公司 一种制备柔性脂质体的方法
CN111195230B (zh) * 2018-11-19 2024-01-12 奥维嘉生物科技（北京）有限公司 一种制备柔性脂质体的方法
CN114711288A (zh) * 2022-03-01 2022-07-08 珠海科技学院 一种稳定性高的肉桂醛固体脂质纳米粒及其制备方法
CN114848594A (zh) * 2022-05-11 2022-08-05 南通大学 一种负载抗癌药物的脂质纳米载体及其制备方法与应用
CN114848594B (zh) * 2022-05-11 2023-04-25 南通大学 一种负载抗癌药物的脂质纳米载体及其制备方法与应用
CN116688137A (zh) * 2023-07-21 2023-09-05 中国医学科学院北京协和医院 一种基于核壳结构的药物组合物及应用
CN116688137B (zh) * 2023-07-21 2024-05-14 中国医学科学院北京协和医院 一种基于核壳结构的药物组合物及应用

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