WO2008140203A1 - Nanosphères phospholipidiques pour la solubilisation d'un alcaloïde diterpénique et leur préparation - Google Patents

Nanosphères phospholipidiques pour la solubilisation d'un alcaloïde diterpénique et leur préparation Download PDF

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Publication number
WO2008140203A1
WO2008140203A1 PCT/KR2008/002533 KR2008002533W WO2008140203A1 WO 2008140203 A1 WO2008140203 A1 WO 2008140203A1 KR 2008002533 W KR2008002533 W KR 2008002533W WO 2008140203 A1 WO2008140203 A1 WO 2008140203A1
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Prior art keywords
lipid
based drug
diterpenoid alkaloid
drug solution
mixture
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PCT/KR2008/002533
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English (en)
Inventor
Byung Cheol Shin
Sun Hang Cho
Hasoo Seong
Jung Eun Lee
Soon Hwa Jung
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Korea Research Institute Of Chemical Technology
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Publication of WO2008140203A1 publication Critical patent/WO2008140203A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—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
    • A61K9/127—Liposomes
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B1/00—Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a diterpenoid alkaloid drug solution comprising lipid nanospheres and a preparation method thereof.
  • a poorly water soluble drug is characterized by low bioavailability because it is hardly soluble in an aqueous medium for medication such as sterile water, water for injection, deionized water and buffer solution. Even a solubilized pharmaceutical composition is limited in the development of stable pharmaceutical formulations as, for example, the drug is precipitatedin the body fluid or tissues upon administration.
  • a diterpenoid alkaloid-based drug is often prepared into salt or prodrug form in order to improve solubility in water and enhance absorption by the gastrointestinal tract.
  • a drug in salt or prodrug form is associated with the problem that the pharmacophore of the drug may be changed or decreased.
  • paclitaxel has an excellent anticancer activity against various cancers, especially breast and ovarian cancers in the later stage (The Chemistry and Pharmacology of Taxol and its Derivatives, p 103, Edited by Vittorio Farina, Elsevier Press).
  • Paclitaxel has a complicated diterpenoid structure with large rings and long side chain. The poor solubility of paclitaxel is due to the taxane backbone and the hydrophobic moiety of the side chain.
  • Paclitaxel has a low solubility in water of about 0.7 to 10 ⁇ g/mL, which results in several problems when administered into the human body.
  • paclitaxel is sold under the trademark Taxol by Bristol-Meyers Squibb.
  • Cremophor and anhydrous ethanol are used to solubilize paclitaxel.
  • solubilizer particularly Cremophor
  • Cremophor effectively solubilizes paclitaxel, it may cause serious allergic reactions.
  • an adrenocortical hormone drug or an antihistamine agent has to be administered in advance.
  • US Patent Nos. 5,439,686, 5,498,421 and 5,560,933 disclose the preparation of formulations in which paclitaxel is stably dispersed in microparticles of albumin.
  • Korean Patent Publication No. 2001-0105248 discloses a method of treatment using microparticles of albumin stabilized paclitaxel.
  • Japanese Patent No. 206,815/94 discloses a block copolymer comprising polyethylene oxide as hydrophilic block and polyamino acid having hydrophobic groups as hydrophobic block to contain a hydrophobic drug such as adriamycin or in- domethacin in the hydrophobic cavity of micelles formed in aqueous solution by the amphiphilic copolymer.
  • Korean Patent Publication No. 1999-0069033 discloses an amphiphilic block copolymer comprising polylactide, polyglycolide, etc., as biodegradable hydrophobic polymer and polyethylene glycol as hydrophilic polymer to solubilize a diterpenoid alkaloid-based drug.
  • the aforementionedtechniques are effective in solu- bilizing the diterpenoid alkaloid-based drug and reducing toxicity thereof, the core- shell structure of the unstable micelle is easily damaged upon administration, thereby resulting in the precipitation of the drug encapsulated therein.
  • lipid nanospheres with a dimension of dozens of nanometers prepared by dispersing a bio- compatible lipid constituent comprising phospholipid, sterol, cationic or anionic lipid and polyethylene glycol with a predetermined proportion in organic solvent, can solubilize a diterpenoid alkaloid-based drug in aqueous solution with high concentration, and have completedthe present invention.
  • an object of the present invention is to provide an diterpenoid alkaloid- based drug solution comprising lipid nanospheres that can solubilize a diterpenoid alkaloid-based drug such as paclitaxel in aqueous solution with high concentration, without using a harmful surfactant, and can be prepared into pharmaceutically stable forms, and a preparation method thereof.
  • FIG. 1 compares the solubility of aqueous solutions and lipid nanospheres of paclitaxel and docetaxel as examples of diterpenoid alkaloiddrugs in water. Best Mode for Carrying Out the Invention
  • the present invention provides a diterpenoid alkaloid-based drug solution comprising lipid nanospheres prepared by dispersing lipid nanospheres, which are formed by dispersing a diterpenoid alkaloid-based drug in solid solution state and a lipid mixture comprising phospholipid, sterol, cationic or anionic lipid and polyethylene glycol with a molar ratio of 3-8 : 2-6 : 1-5 : 0-3 dispersed in an organic solvent, in an aqueous medium.
  • the present invention provides a preparation method of a diterpenoid alkaloid-based drug solution comprising the steps of:
  • the present invention provides a diterpenoid alkaloid-based drug solution capable of solubilizing the hardly soluble drug in an aqueous medium with high concentration and enabling preparation of pharmaceutically stable formulations by dispersing bio- compatible lipids comprising phospholipid, sterol, cationic or anionic lipid and polyethylene glycol with a predetermined proportion to particularize them and maintaining the diterpenoid alkaloid-based drug such as paclitaxel, docetaxel, etc. in solid solution state, and a preparation method thereof.
  • the lipid nanospheres used in the diterpenoid alkaloid-based drug solution of the present invention are prepared by dispersing a lipid mixture comprising phospholipid, sterol, cationic or anionic lipid and polyethylene glycol as biocompatible lipids in an organic solvent.
  • the lipid mixture is dispersed in an organic solvent with a concentration of 3.0 to 7.5 mm.
  • the lipid nanospheres dispersed in the organic solvent have a particle size in the range from 50 to 200 nm, more preferably from 80 to 120 nm.
  • the organic solvent in which the lipid mixture is dispersed may be selected from chloroform, methanol, ethanol, acetone, acetonitrile, isopropyl alcohol and a mixture thereof.
  • the lipid mixture dispersed in the organic solvent and the diterpenoid alkaloid-based drug are preferably comprised with a volume proportion of 1 : 1 to 1 : 9.
  • the diterpenoid alkaloid-based drug may be a drug with a low solubility in general, and may be, specifically, selected from paclitaxel, docetaxel and taxane.
  • the phospholipid may be selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phos- phatidylglycerol, phosphatidylinositol, lecithin, lysophosphatidylcholine, phosphatidic acid, sphingomyelin, saturated fatty acid containing phospholipid and a mixture thereof.
  • the phosphatidylcholine may be selected from soybean phosphatidylcholine, egg yolk phosphatidylcholine, bovine phosphatidylcholine, dilau- roylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphos- phatidylcholine, distearoylphosphatidylcholine and a mixture thereof.
  • the phosphatidylethanolamine may be selected from dilauroylphos- phatidylethanolamine, dilauroylphosphatidylethanolamine, dipalmitoylphos- phatidylethanolamine, distearoylphosphatidylethanolamine, dioleoylphos- phatidylethanolamine and a mixture thereof.
  • the phosphatidylserine may be selected from dilauroylphosphatidylserine, dilau- roylphosphatidylserine, dipalmitoylphosphatidylserine, distearoylphosphatidylserine and a mixture thereof.
  • the phosphatidylglycerol may be selected from dilauroylphosphatidylglycerol, dilau- roylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidyl- glycerol and a mixture thereof.
  • the phosphatidylinositol may be selected from dilauroylphosphatidylinositol, dilau- roylphosphatidylinositol, dipalmitoylphosphatidylinositol, distearoylphos- phatidylinositol and a mixture thereof.
  • the lecithin may be selected from egg yolk lecithin, soybean lecithin and a mixture thereof.
  • the sterol may be selected from cholesterol, cholesterol hexasuccinate, 3 ⁇ - [/V- (/V ,./V '- dimethylaminoethane)carbamoyl] cholesterol, ergosterol, stigmasterol, lanosterol and a mixture thereof.
  • the anionic lipid may be selected from dipalmitoylglycerophosphate, disteroyl glyc- erphosphoglycerol, dipalmitoyl lypostatic acid and a mixture thereof.
  • the cationic lipid may be selected from dioleyltrimethylammoniumpropane, dimethyloctadecylammonium, dioleylphosphatidylethanolamine , dialkyldimethylam- moniumpropane, dialkyltrimethylammoniumpropane and a mixture thereof.
  • the polyethylene glycol may be selected from l,2-disteroyl-sn-glycero-3-phosphoethanolamine-./V-[methoxy-(polyethylene glycol)-2000] (DSPE-mPEG-2000), l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine- ⁇ f-[methoxy(polyethylene glycol)-350] , 1 ,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N -
  • the lipid nanospheres used in the diterpenoid alkaloid-based drug solution of the present invention are structures with a dimension of dozens of nanometers, can solubilize the diterpenoid alkaloid-based drug with high concentration in aqueous solution, without using a harmful surfactant, and can be made into pharmaceutically stable formulations.
  • the diterpenoid alkaloid-based drug solution of the present invention can be prepared into various forms including injection drug, oral drug, transdermal drug, and so forth. [45] Hereunder is given a detailed description of the method of preparing the diterpenoid alkaloid-based drug solution of the present invention.
  • step 1) a mixture of phospholipid, sterol, cationic or anionic lipid and polyethylene glycol with a molar ratio of 3-8 : 2-6 : 1-5 : 0-3 is mixed with an organic solvent to obtain a lipid solution having a total lipid concentration in the range from 3.0 to 7.5 mm.
  • the lipids are contained in the organic solvent with a concentration of 3.0 to 7.5 mm, preferably 4.0 to 7.0 mm, in total. When the total lipid concentration is below the aforementioned range, particles may not be formed. In contrast, when the total lipid concentration exceeds the aforementioned range, particles may crystallize and/or coagulate.
  • the organic solvent may be selected from chloroform, methanol, ethanol, acetonitrile, ispropyl alcohol and a mixture thereof.
  • step 2) a drug solution is prepared.
  • a diterpenoid alkaloid-based drug is dissolved in an organic solvent with a concentration of 0.5 to 10.0 mg/mL, preferably 2.0 to 8.0 mg/mL.
  • concentration 0.5 to 10.0 mg/mL, preferably 2.0 to 8.0 mg/mL.
  • the organic solvent may be selected from chloroform, methanol, ethanol, acetonitrile, ispropyl alcohol and a mixture thereof.
  • step 3 the lipid solution of step 1) is mixed with the drug solution of step 2) to obtain a drug-lipid solution.
  • the lipid solution and the drug solution are mixed with a volume proportion of 1 : 1 to 1 : 9, preferably 2 to 3 : 7 to 8.
  • step 4) the drug-lipid solution of step 3) is mixed with water to obtain a mixed solution dispersed in water.
  • the drug-lipid solution is dispersed (emulsified) by slowly adding to an aqueous liquid (deionized water) at a rate of 10 mL/min using an ultrasonicator (Model 500, Fisher Scientific, Hampton, Kentucky, USA).
  • the volume proportion of the drug-lipid solution to the aqueous liquid is maintained at 1 : 2 to 3.
  • the proportion is lower, the dispersed nanoparticles may coagulate, resulting in increased particle size of the final lipid nanospheres.
  • a concentration process may be required.
  • step 5 the organic solvent is removed from the mixed solution of step 4)under reduced pressure, and unreacted lipid and drug are filtered.
  • the removal of the organic solvent under reduced pressure is preferably performed at 45 0 C.
  • prepared diterpenoid alkaloid-based drug solution may be stored after adding monosaccharide or disaccharide thereto.
  • Phospholipid Sterol Cationic or anionic lipid Phospholipid Sterol Cationic or anionic lipid
  • Examples 1 to 4 Preparation of paclitaxel solution [68] A drug solution was prepared by dissolving paclitaxel in methanol to a concentration of 10.0 mg/mL. A lipid solution was prepared in the same manner as in Preparation Example 1.
  • 10 mL of a drug-lipid solution was prepared by mixing the lipid solution and the drug solution with a volume proportion of 1 : 4.
  • 10 mL of the drug-lipid solution was mounted on an ultrasonicator (Model 500, Fisher Scientific, Hampton, Kentucky, USA), and 20 mL of triply distilled water was added to the drug-lipid solution at a rate of 10 mL/min using a 23-gauge syringe. While adding triply distilled waterto the drug-lipid solution, ultra- sonication was carried out for 1 minute under 50 watt output condition, followed by allowing the solution to stand for 30 minutes.
  • paclitaxel concentration of thus prepared paclitaxel drug solution comprising the lipid nanospheres was measured at the maximum absorption wavelength of 222 nm.
  • paclitaxel solubility is given in the following Table 3.
  • the drug solution of the present invention exhibits remarkably improved solubility of the diterpenoid alkaloid-based drug, considering that the solubility of paclitaxel in methanol is 0.03 mg/mL.
  • paclitaxel concentration of thus prepared paclitaxel drug solution comprising the lipid nanospheres was measured at the maximum absorption wavelength of 222 nm.
  • paclitaxel solubility is given in the following Table 4.
  • Example 5 Lipid sample 5 7.5 i n ⁇
  • Example 6 Lipid sample 6 6.5
  • Examples 7 to 10 Preparation of docetaxel solution
  • Diterpenoid alkaloid-based drug solutions were prepared in the same manner as in Examples 1 and 2, except for using docetaxel as diterpenoid alkaloid-based drug. The result is given in the following Table 5.
  • the docetaxel solution of the present invention exhibits remarkably improved solubility, considering that the solubility of docetaxel in methanol is 0.03 mg/mL.
  • Example 11 Preparation of diterpenoid alkaloid-based drug solution
  • DPPA dipalmi- toylglycerophosphate
  • a drug solution was prepared by dissolving paclitaxel in methanol to a concentration of 10 mg/mL.
  • 10 mL of adrug-lipid mixed solution was prepared by mixing 2 mL of the lipid solution with 8 mL of the paclitaxel solution.
  • the organic solvent was removed from the mixed solution at 40 0 C using a rotary evaporator.
  • 10 niL of thus obtained clear solution was passed through a syringe filter (Cellulose, Japan) with a pore size of 0.2 ⁇ m in order to obtain uniform particle size, and concentrated by centrifuging at 15,000 rpm for 15 minutes (Centrifuge 5415D, Eppendorf, Hamburg, Germany) using a centrifuge tube (Amicon Ultra- 15, MWCO 100,000 Millipore, USA).
  • paclitaxel solubility differed depending on the phospholipids.
  • the drug solution of the present invention exhibited remarkably improved solubility, considering that the solubility of paclitaxel in methanol is 0.03 mg/mL.
  • the lipid nanospheres presented by the present invention can solubilize diterpenoid alkaloid-based drugs in aqueous solutionwith high concentration. Inside the lipid structure, they can contain diterpenoid alkaloid-based drugs such as paclitaxel, docetaxel, etc.
  • the present invention provides lipid nanospheres that can easily solubilize diterpenoid alkaloid-based drugs as compared with conventional diterpenoid alkaloid- based drugs and solubilization techniques thereof and can be applied for injection drugs, oral drugs and transdermal drugs with uniform particle size distribution and desirable safety.
  • the present invention enables the solubilization of diterpenoid alkaloid-based drugs in aqueous solution with high concentration, without including a harmful surfactant.

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Abstract

L'invention se rapporte à une solution médicamenteuse à base d'alcaloïde diterpénique comprenant des nanosphères lipidiques et sa méthode de préparation. La présente invention se rapporte plus spécifiquement à une solution médicamenteuse à base d'alcaloïde diterpénique comprenant des nanosphères lipidiques préparées en dispersant des nanosphères lipidiques qui sont formées en dispersant un médicament à base d'alcaloïde diterpénique comme le paclitaxel, le docétaxel, etc. dans un état de solution solide et des lipides biocompatibles comprenant un phospholipide, du stérol, un lipide cationique ou anionique et du polyéthylène glycol avec une proportion prédéterminée dans un solvant organique, dans un milieu aqueux et sa méthode de préparation.
PCT/KR2008/002533 2007-05-15 2008-05-06 Nanosphères phospholipidiques pour la solubilisation d'un alcaloïde diterpénique et leur préparation WO2008140203A1 (fr)

Applications Claiming Priority (2)

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KR1020070047259A KR20080101056A (ko) 2007-05-15 2007-05-15 지질나노입자를 포함하는 디테르페노이드 알칼로이드계약물 용액 및 이의 제조방법
KR10-2007-0047259 2007-05-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102813682A (zh) * 2012-07-19 2012-12-12 李振刚 薄膜超声法炙制富含紫杉醇脂质体的红豆杉粉的技术
CN104083382A (zh) * 2014-07-02 2014-10-08 内蒙古大学 麦角甾醇过氧化物与紫杉醇在杀伤Hela癌细胞方面的协同作用及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5415869A (en) * 1993-11-12 1995-05-16 The Research Foundation Of State University Of New York Taxol formulation
WO2003039437A2 (fr) * 2001-11-08 2003-05-15 Max-Delbrück-Centrum für Molekulare Medizin Preparation pharmaceutique d'administration orale contenant du paclitaxel encapsule dans des liposomes
US20040126886A1 (en) * 2000-09-25 2004-07-01 Industrial Technology Research Institute Liposome for incorporating large amounts of hydrophobic substances
WO2004071466A2 (fr) * 2003-02-11 2004-08-26 Neopharm, Inc. Procede de production de preparations liposomales

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5415869A (en) * 1993-11-12 1995-05-16 The Research Foundation Of State University Of New York Taxol formulation
US20040126886A1 (en) * 2000-09-25 2004-07-01 Industrial Technology Research Institute Liposome for incorporating large amounts of hydrophobic substances
WO2003039437A2 (fr) * 2001-11-08 2003-05-15 Max-Delbrück-Centrum für Molekulare Medizin Preparation pharmaceutique d'administration orale contenant du paclitaxel encapsule dans des liposomes
WO2004071466A2 (fr) * 2003-02-11 2004-08-26 Neopharm, Inc. Procede de production de preparations liposomales

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102813682A (zh) * 2012-07-19 2012-12-12 李振刚 薄膜超声法炙制富含紫杉醇脂质体的红豆杉粉的技术
CN102813682B (zh) * 2012-07-19 2014-03-19 李振刚 薄膜超声法炙制富含紫杉醇脂质体的红豆杉粉的技术
CN104083382A (zh) * 2014-07-02 2014-10-08 内蒙古大学 麦角甾醇过氧化物与紫杉醇在杀伤Hela癌细胞方面的协同作用及其应用

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