EP1427393A2 - Liposomes a base de principes actifs - Google Patents

Liposomes a base de principes actifs

Info

Publication number
EP1427393A2
EP1427393A2 EP01933914A EP01933914A EP1427393A2 EP 1427393 A2 EP1427393 A2 EP 1427393A2 EP 01933914 A EP01933914 A EP 01933914A EP 01933914 A EP01933914 A EP 01933914A EP 1427393 A2 EP1427393 A2 EP 1427393A2
Authority
EP
European Patent Office
Prior art keywords
active ingredient
liposomally encapsulated
liposomes
substances
phosphatidylcholine
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01933914A
Other languages
German (de)
English (en)
Inventor
Jürgen Ebert
Gerd Berger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacept GmbH
Original Assignee
Pharmacept GmbH
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 Pharmacept GmbH filed Critical Pharmacept GmbH
Publication of EP1427393A2 publication Critical patent/EP1427393A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/14—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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to liposomes which contain active substances, in particular pharmaceutical active substances, a process for their preparation and the use of these liposomes for the production of pharmaceutical products.
  • active pharmaceutical ingredients in particular of large active ingredient molecules
  • the active ingredient is distributed in different amounts over the individual areas of the body, often only small amounts of the active ingredient reaching the target organ.
  • the active substances can be metabolized due to reactions with substances present in the body and undesirable side effects for the whole organism can occur.
  • Liposomes are used as carrier substances, in particular for relatively large active substance molecules.
  • the active substances are enclosed in the liposomes and cannot be attacked by other substances.
  • the liposomes can be built up in such a way that the drugs enclosed in them direct a specific structure of the liposome envelope into certain target organs.
  • Liposomes are artificially produced spherical lipid vesicles that consist of one or more concentric lipid bilayers with an aqueous interior. They can be produced by mechanical fine distribution (dispersion) of phospholipids in aqueous media. A distinction is made between multilamellar vesicles with a diameter of approximately 0.1 to 5 ⁇ m and unilamellar vesicles with a size of 0.02 to 0.05 ⁇ m or by approximately 1 ⁇ m. The liposomes play an important role particularly in the treatment of tumors as carrier systems.
  • An active ingredient that is administered encapsulated liposomally is e.g. B. Paclitaxel.
  • Paclitaxel shows only a low solubility in water and is therefore often used in combination with solubilizers such as Cremophor (polyethoxylated castor oil).
  • solubilizers such as Cremophor (polyethoxylated castor oil).
  • Cremophor polyethoxylated castor oil
  • the dilution of such solutions with physiological saline for application has the disadvantage that paclitaxel in physiological saline does not have sufficient stability.
  • International patent application WO 93/18751 discloses paclitaxel-liposome combinations, of which in particular vesicles with a positive charge have been produced based on cardiolipin, phosphatidylcholine and cholesterol.
  • the liposomes produced had to be applied in animal experiments on four consecutive days, from which it can be concluded that the desired antitumor effect could not be achieved after a single administration.
  • the present invention was accordingly based on the object of providing a liposomal system in which the activity of active substances in the treatment of diseases or the accumulation of active substances and / or pharmaceutical substances which are to be accumulated in a specific target organ, such as e.g. Contrast agents from imaging processes etc. can be accumulated.
  • a specific target organ such as e.g. Contrast agents from imaging processes etc.
  • the effectiveness of such systems in the treatment of diseases etc. should be increased and, preferably, the number of side effects should also be reduced.
  • liposomally encapsulated active substances such as anti-tumor active substances
  • the effect of liposomally encapsulated active substances can be increased many times over if the active substance is not completely liposomally encapsulated, i.e. if there are still free active substance molecules in the solution / emulsion to be applied outside the liposomes.
  • the present invention accordingly relates to a liposomally encapsulated active substance, which is characterized in that it is encapsulated in a proportion of 1% by weight to 90% by weight, based on the amount of active substance used.
  • the proportion of the encapsulation means that encapsulated active substance molecules are located in the center of the liposomes or in the membrane in the
  • Active substances which can be used in the present invention are pharmaceuticals and pharmacologically active substances, nutrients, cosmetic substances, diagnostic substances and contrast agents for imaging processes.
  • the term active ingredient also includes the pharmacologically acceptable salts of the active ingredients.
  • Suitable compounds are lipophilic and amphiphilic molecules, i.e. Substances which are insoluble in water or only slightly soluble in water and which can be prepared in the form of emulsions or micellar preparations.
  • Suitable drugs are e.g. Anti-cancer agents, anti-tumor agents, antibiotics, antimicotic, antivirual, anthelmintic and anti-parasitic compounds.
  • Anthracyclines such as doxorubicin, daunorubicin, karinomycin, N-acetylatriamycin, rubidacon, 5-imidodaunomycin, N-acetyldaunomycin, pirarubicin and epirubicin, alkaloids such as vincristine, vinbline, vinblastine, vinblastine, vinblastine, vinblastine, vinblastine, vinblastine, vinblastine be used. Further suitable substances are 5-fluorouracil, taxanes such as paclitaxel (Taxol ®), and derivatives of paclitaxel z.
  • Taxotere Docetaxol ®
  • Mitrotan platinum compounds such as cisplatin, carboplatin, lobaplatin and phenestrin).
  • anti-inflammatory agents examples include steroidal and non-steroidal and other anti-inflammatory compounds such as prednisone, methyl-prednisolone, paramethazone, 11-fluorocortisol, triamciniolone, betamethasone and dexamethasone, ibuprophen, piroxicam, beclomethasone Methotrexate, acaridine, etritinate, anthralin, psoraline, salycilate such as aspirin, and immunosuppressants such as cyclosporin.
  • anti-inflammatory corticosteids and the anti-inflammatory and immunosuppressive cyclosporin are lipophilic compounds which can be used particularly advantageously in the present invention.
  • anesthetics such as methoxyflurane, isoflurane, N-flurane, halothane and bezocaine
  • antiulcerative agents such as cimetidine
  • anticonvulsant agents such as barbiturates, azothioprine, an immunosuppressant and anti-rheumatic agent
  • muscle relaxants such as dantrolene and diazepam.
  • contrast agents for ultrasound, X-ray and NMR processes.
  • Radioisotopes or compounds containing such radioisotopes such as e.g. Iodine, octane, halogenated hydrocarbon and renograph.
  • Suitable contrast agents (gadolinium) that can be used in NMR methods are lipid-soluble paramagnetic compounds.
  • Dietary supplements that can be incorporated into the liposomal system according to the present invention are amino acids, sugars, proteins, carbohydrates, fat-soluble vitamins, fats (lipids). Combinations of different nutritional supplements are also suitable.
  • the active ingredients used can be encapsulated in a manner known per se with the addition of liposomes. In order to set the desired degree of encapsulation, it is possible to encapsulate the active ingredient only partially.
  • the partial encapsulation can be carried out using appropriate starting materials or suitable process conditions.
  • a completely or almost completely liposomally encapsulated active substance can be mixed with the corresponding amount of unencapsulated active substance or their solutions / emulsions, so that the desired degree of encapsulation is obtained.
  • the degree of encapsulation can be adjusted by simple process changes.
  • the liposome has a closed structure, which consists of a lipid bilayer that surrounds an aqueous inner core.
  • the liposomes used in accordance with the invention are not limited to certain liposomes; both neutral, negatively or positively charged liposomes can be used which are unilamellar, i.e. from a lipid bilayer, or polylamellar, i.e. be composed of several lipid bilayers and can be produced by methods known to the person skilled in the art.
  • the liposomes are usually produced from phospholipids and, if appropriate, cholesterol and cholesterol derivatives and / or one or more hydrophilic, lipophilic or amphiphilic component (s).
  • suitable phospholipids are phosphatidylcholine (PC), distearoylphsphatidylcholine (DSPC), soy phosphatidylcholine (soybean PC), hydrogenated soy phosphatidylcholine (HSPC), egg phosphatidylcholine (egg PC), hydrogenated egg phosphatidylcholine (HEPCcholine) (HEPCcholine), diphenylpholine (HEPC) DPPC), dimyristoylphosphatidylcholine (DMPC) as well as any mixtures thereof, whereby the substances can be synthetic, semi-synthetic or natural products.
  • PC phosphatidylcholine
  • DSPC distearoylphsphatidylcholine
  • phospholipids are phosphatidylglycerides (PG) and phosphatidic acid, such as dimynstoylphosphatidylglycerid (DMPG), dilaurylphosphatidylglycerid (DLPG), dipalmitoylphosphatidylglycerid (DPPG), distearoylphosphatidylglycerid (DSPGilidic acid, DSistGilid) , Distearoylphosphatidic acid (DSPA), and phosphatidylethanolamines, phosphatidylinositols and phosphatidic acid, which contain residues of lauric acid, myristic acid, stearic acid and / or palmitic acid.
  • DMPG dimynstoylphosphatidylglycerid
  • DLPG dilaurylphosphatidylglycerid
  • DPPG dipalmitoylphosphatidylglycerid
  • Preferred phospholipids are HSPC, DSPC and HEPC.
  • positively charged liposomes can be formed from a solution containing phosphatidylcholine, cholesterol and stearylamine.
  • Negatively charged liposomes can be obtained, for example, from solutions containing phosphatidylcholone, cholesterol and phosphatidylserine or, preferably, cardiolipin. It is known to the person skilled in the art that other additives can also be added in order to modify the properties of the liposomes obtained.
  • liposomes can be changed, for example, by adding -Tocopherol. Good results are also achieved with so-called PEG liposomes, i.e. Liposomes with polyethylene glycol chains (PEG) in the lipid layer, the PEG either being bound in the molecule of the phospholipids or being present as a free substance.
  • PEG polyethylene glycol chains
  • the molecular weight of the PEG chains is preferably between 400 and 20,000, particularly preferably between 600 and 10,000 and in particular between 600 and 5,000.
  • liposomes can also be used as liposomes.
  • Preferred liposomes are e.g. B. from HSPC, DSPC and / or HEPC as phospholipid, cholesterol and / or N- (O-methyl-poly (ethylene glycol) -1, 2-distearoyl-sn-glycero-3-phosphoethanolamine and optionally polyethylene glycol.
  • the ratio of lipid to active ingredient can be adjusted within a wide range and generally depends on the active ingredient used and the lipid used for liposome production and the other components.
  • the final encapsulated product contains lipid and active ingredient in a ratio of 5: 1 to 100: 1, preferably 10: 1 to 40: 1, in particular 15: 1 to 25: 1.
  • the molar ratio of lipid to cholesterol is preferably from 3: 1 to 1: 3, preferably from 2: 1 to 1: 2.
  • Polyethylene glycol is preferably used in an amount of 1 to 50 mol%. , in particular from 5 to 20 mol%, based on the lipid.
  • the size of the active ingredients encapsulated liposomally according to the invention is preferably below 200 nm, particularly preferably below 150 nm.
  • microspheres are preferably produced from polysaccharides or polysaccharide derivatives and are particularly preferably degradable.
  • the polysaccharides are preferably selected from starch and starch derivatives, gelatin, albomine, collagen, dextran, dextane derivatives or similar materials. Lyophilized or degradable starch or gelatin particles are particularly preferred.
  • microspheres preferably have a water-insoluble, but hydrophilic, water-swellable, three-dimensional network of polysaccharide molecules or corresponding derivatives. Suitable microspheres are described in DE-US-25 24 279, WO 88/09163 and WO 89/03207.
  • the diameter of the microspheres is preferably between 0.1 and 200 ⁇ m, in particular between 10 and 100 ⁇ m.
  • the liposomal systems produced according to the invention can be added directly to the bloodstream of the person to be treated, and intraperitoneal, subcutaneous or inhalation administration is also possible.
  • the liposomes used according to the invention can be produced by any method known from the prior art.
  • the liposomes in be dissolved in a suitable solvent, usually in a non-polar or only slightly polar solvent which can be removed without leaving harmful substances, such as ethanol, methanol, chloroform, butanol or acetone.
  • a suitable solvent usually in a non-polar or only slightly polar solvent which can be removed without leaving harmful substances, such as ethanol, methanol, chloroform, butanol or acetone.
  • active ingredient mixtures are used, the individual solutions can also be mixed with one another.
  • the lipophilic material is also dissolved and mixed with the solution containing the active ingredient. After the solvent has been removed, for example by a lyophilization process, the lipid film remains on the active ingredient.
  • the mixture can be stored in this form, optionally under an inert gas atmosphere, with low storage temperatures, such as at -20 ° C., being particularly preferred.
  • the liposomes are usually formed by adding a suitable solution to the lipid film.
  • suitable solutions are polar solutions, preferably aqueous salt solutions, such as isotonic saline. Liposomes are formed, for example, by mixing and vortexing. If small vesicles, such as unilamellar vesicles, are produced, the solution can also be treated with ultrasound.
  • mixtures of multilamellar vesicles and unilamellar vesicles can also be used.
  • the liposomes produced can be administered directly to the patient or stored under suitable conditions.
  • the lipophilic active substances are preferably stored at about -20 ° C. as dry substances to which lipid films have been applied. After hydration, liposome suspensions to which a suitable amount of unencapsulated active ingredient has been added can be stored in buffered or neutral saline solutions for a period of a few hours to months, depending on the temperature and the ingredients.
  • the liposomal drug system according to the present invention can be administered in amounts of about 5 to 150 mg of drug / kg body weight of the patient within a period of 1 minute to 5 hours.
  • This liposome dispersion is shaken at room temperature for 24 h, the resulting multilayer vesicles (MLV) are subjected to sonication (proboscis, 6x4 min with 50% intensity, Branson B225 sonifer; Branson, Carouge-Geheve, Switzerland) and then centrifuged (3000 rpm) 20 min) to remove the titanium abrasion from the liposome dispersion.
  • sonication proboscis, 6x4 min with 50% intensity, Branson B225 sonifer; Branson, Carouge-Geheve, Switzerland
  • 5-fluorouracil (Riboluor ® 1000; 50 mg / ml Infusion solution Ribosepharm GmbH, Kunststoff, Germany) and carboplatin (Ribocarabo ® 50 mg / ml Infusion solution Ribosepharm GmbH, Kunststoff, Germany) was used.
  • the vesicle size was determined with a photon correlation spectrometer (Coulter Counter N4 MD modeil and the AccuComp ® system, Coulter Electronics Inc., Hialeah, US) and moved for both active ingredients in the order of 100 ⁇ 50 nm.
  • NOE Nuclear Overhauser Effect
  • the active substances were administered intravenously and intraarterially as well as in encapsulated form with and without starch microspheres (Spherex ® , Pharmacia Upjohn), generally for the treatment of tumors in liver tumors.
  • Spherex ® starch microspheres
  • the tumor was targeted by liposomally encapsulating the cytostatics and adding starch microspheres.
  • the SUV PEG used Liposomes have a particle size of 113 nm ⁇ 25 nm, the starch microspheres on average 45 ⁇ m.
  • the drug concentrations in the tumor and in the liver were measured in AUC (Area under the Curve). The results are shown in Table 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des principes actifs à encapsulation liposomale, caractérisés en ce que le(s) principe(s) actif(s) sont encapsulés dans une proportion de l'ordre de 1 à 90 % en poids par rapport à la quantité de principes actifs utilisée. Ces principes actifs s'utilisent notamment pour traiter des tumeurs, comme compléments alimentaires, pour produire des agents de contraste pour des procédés d'imagerie et pour produire des agents diagnostiques pour déceler des affections.
EP01933914A 2000-05-02 2001-05-02 Liposomes a base de principes actifs Withdrawn EP1427393A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10021030 2000-05-02
DE10021030 2000-05-02
PCT/EP2001/004900 WO2001082892A2 (fr) 2000-05-02 2001-05-02 Liposomes a base de principes actifs

Publications (1)

Publication Number Publication Date
EP1427393A2 true EP1427393A2 (fr) 2004-06-16

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EP01933914A Withdrawn EP1427393A2 (fr) 2000-05-02 2001-05-02 Liposomes a base de principes actifs

Country Status (4)

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US (1) US20030124180A1 (fr)
EP (1) EP1427393A2 (fr)
AU (1) AU2001260270A1 (fr)
WO (1) WO2001082892A2 (fr)

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WO2004087105A1 (fr) * 2003-04-02 2004-10-14 Celator Pharmaceuticals, Inc. Formulations associant du platine et des fluoropyrimidines
US20050255154A1 (en) * 2004-05-11 2005-11-17 Lena Pereswetoff-Morath Method and composition for treating rhinitis
JP5735724B2 (ja) * 2004-11-08 2015-06-17 インスメッド， インコーポレイテッド 腹腔内投与される脂質ベースの白金化合物製剤を用いた、癌の治療方法
EP1745788A1 (fr) * 2005-07-22 2007-01-24 KTB Tumorforschungsgesellschaft mbH Acylglycerophospholipides pour le traitement du cancer et de la cachexie
US9107824B2 (en) 2005-11-08 2015-08-18 Insmed Incorporated Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
DE102009031274A1 (de) 2009-06-30 2011-01-13 Justus-Liebig-Universität Giessen Liposomen zur pulmonalen Applikation
US20110070291A1 (en) * 2009-09-11 2011-03-24 T*Amine, Llc. Food or beverage composition fortified with thyronamines and/or thyronamine precursors
MX2015002842A (es) 2012-09-04 2015-08-12 Eleison Pharmaceuticals LLC Prevencion de la recurrencia pulmonar del cancer con cisplatino lipido-complejado.
WO2015061449A1 (fr) 2013-10-22 2015-04-30 Lipella Pharmaceuticals, Inc. Administration d'agents à l'aide de liposomes métastables
WO2017097196A1 (fr) * 2015-12-08 2017-06-15 正大天晴药业集团股份有限公司 Procédé de préparation d'un liposome
DE102018006443A1 (de) * 2018-08-14 2020-02-20 Abnoba Gmbh Verfahren zur Verkapselung von Wirkstoffen in Liposomen

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CA1338702C (fr) * 1987-03-05 1996-11-12 Lawrence D. Mayer Formulations d'agents liposomiques-antineoplasiques a faible teneur en medicaments-lipides
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CA2126648C (fr) * 1993-11-09 2000-10-10 Tomas De Paoli Liposomes renfermant du fer (ii) biodisponible; methode de preparation
CN1148812A (zh) * 1994-03-28 1997-04-30 尼科梅德成像有限公司 “脂质体”
US5702722A (en) * 1994-09-30 1997-12-30 Bracco Research S.A. Liposomes with enhanced entrapment capacity, method and use
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DE19724796A1 (de) * 1997-06-06 1998-12-10 Max Delbrueck Centrum Mittel zur Antitumortherapie

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Also Published As

Publication number Publication date
AU2001260270A1 (en) 2001-11-12
WO2001082892A2 (fr) 2001-11-08
US20030124180A1 (en) 2003-07-03
WO2001082892A3 (fr) 2004-04-15

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