WO1994028876A1 - Poudres de liposomes - Google Patents

Poudres de liposomes Download PDF

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Publication number
WO1994028876A1
WO1994028876A1 PCT/US1994/006137 US9406137W WO9428876A1 WO 1994028876 A1 WO1994028876 A1 WO 1994028876A1 US 9406137 W US9406137 W US 9406137W WO 9428876 A1 WO9428876 A1 WO 9428876A1
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WO
WIPO (PCT)
Prior art keywords
liposome
powder
liposomes
particles
micronized
Prior art date
Application number
PCT/US1994/006137
Other languages
English (en)
Inventor
Hans Schreier
Original Assignee
Advanced Therapies, Inc.
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 Advanced Therapies, Inc. filed Critical Advanced Therapies, Inc.
Publication of WO1994028876A1 publication Critical patent/WO1994028876A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes

Definitions

  • a liposome can be defined as any structure composed of lipid bilayers that enclose a volume.
  • the lipid is not necessarily phospholipid but this is a commonly- used component.
  • Liposomes can generally be formed by sonicating a lipid in an aqueous medium, by resuspension of dried lipid layers in a buffer, or by dialysis of lipids dissolved in a detergent solvent against a buffer of choice (New, R.R.C., Ed.
  • Phospholipids form closed, fluid-filled spheres when they are mixed with water, in part because the molecules are amphipathic: they have a hydrophobic (water-insoluble) tail and a hydrophilic (water-soluble) or "polar" head. Two fatty acid chains, each containing from 10 to 24 carbon atoms, make up the hydrophobic tail of most naturally occurring phospholipid molecules. Phosphoric acid esters of choline, serine, glycerol, inositol, or other molecules compose the hydrophilic head. When a high enough concentration of phospholipids is mixed with water, the hydrophobic tails spontaneously align together to exclude water, whereas the hydrophilic heads bind to water.
  • the result is a bilayer in which the fatty acid tails point into the membrane's interior and the polar head groups point outward.
  • the polar groups at one surface of the membrane point toward the liposome's interior and those at the other surface point toward the external environment.
  • any water soluble molecules that have been added to the water are incorporated into the aqueous spaces in the interior of the spheres, whereas any lipid soluble molecules added to the solvent during vesicle formation are incorporated into the lipid bilayer.
  • MLVs multilamellar vesicles
  • SUNs small unilamellar vesicles
  • LUVs large unilamellar vesicles
  • liposomes have been studied extensively as a method for delivering drugs or other materials or compounds.
  • the desired drug can be encapsulated within the liposome by dissolving the drug in the water solution in which the liposomes are made.
  • Liposomes employed for drug delivery typically range in diameter from 25 nm to several microns (for comparison, the diameter of an erythrocyte is about 10 microns) and are usually suspended in a solution. Because of the nature of the lipid bilayer which forms the shell of the spherical liposome, liposomes present some difficulties in storage and formulation.
  • Liposomes have been lyophilized (freeze-dried) in order to improve their physical stability, retention of encapsulated material, and overall shelf-life (Nanlerberghe L'Oreal BE 873865, 8/1/79; Schneider/Batelle GB 200,2319; 2/24/82; Janoff/Liposome Comp. IL 76010, 12/31/85; Crowe/Regents Univ. Cal., WO 86/03938, 7/16/86; Moro/Farmitalia,
  • Crommelin [1991] Pharm. Res. 8:102-106; Talsma, H., M.J. van Steenbergen, D.J.A. Crommelin [1992] Cryobiology 29:80-86; Talsma, H., M.H. van Steenbergen, D.J.A. Crommelin [1991] Int. J. Pharmaceut. 77:119-126; see also Ozer, Y., H. Talsma, D.J.A. Crommelin, A. Hincal [1988] Acta Pharm. Technol.
  • Lyophilization results in the formation of a porous cake which has a large surface area and which can be rapidly and readily reconstituted prior to use to yield an aqueous dosage form.
  • This aqueous dosage form can then be used for intravenous injection or other such routes of administration.
  • lyophilization is the method of choice to preserve liposomes for future reconstitution to an aqueous form
  • lyophilized cakes cannot directly be incorporated in other pharmaceutical dosage forms.
  • Such dry or semi-solid states include powders filled in gelatine capsules or compressed powder mixtures in the form of tablets which can be administered orally.
  • compositions which would be desirable for liposomes include powders to be sprinkled on healthy or diseased skin for cosmetic or therapeutic purposes; powders suspended in cremes, ointments, pastes, or lotions for use on healthy or diseased skin or mucosal membranes (e.g., buccal or vaginal membranes) for cosmetic or therapeutic purposes; and powders suspended in waxy bases, e.g., carbopols, to form suppositories for rectal or vaginal application.
  • powders to be sprinkled on healthy or diseased skin for cosmetic or therapeutic purposes powders suspended in cremes, ointments, pastes, or lotions for use on healthy or diseased skin or mucosal membranes (e.g., buccal or vaginal membranes) for cosmetic or therapeutic purposes
  • powders suspended in waxy bases e.g., carbopols, to form suppositories for rectal or vaginal application.
  • liposome aerosols for inhalation therapy has been studied experimentally in mice
  • the liposome composition and procedures which have been used to date for liposome inhalation studies involve the use of nebulizers to produce the liposome particles, and these procedures have drawbacks which limit the utility of these compositions and methods.
  • Brief Summary of the Invention The subject invention provides, for the first time, liposomes in a free-flowing dry powder form. This powder form is highly advantageous because it enables the use of liposomes as a method of delivering drugs and other compounds in formulations such as pills, cremes, gels, and powders which have not previously been possible.
  • the subject invention concerns the unexpected finding that lyophilized liposome cakes survive further processing to form advantageous free-flowing liposome powders.
  • This further processing can be done with an appropriate milling device to produce particles in a size range which produces a free-flowing dry powder.
  • lyophilized liposome cakes are processed with a jet mill. Jet mills and their use are generally well known to those skilled in the art. However, jet mills and the like have not previously been used with lyophilized liposome cakes.
  • milling results in the formation of micronized liposome particles in a size range of about 1 to about 100 ⁇ m diameter.
  • aggregation of such micronized powders is inhibited by the use of electrically charged lipid mixtures. This can be accomplished by, for example, incorporation of the negatively charged phosphatidylglycerol into the lipid mixture used to form the liposome.
  • the procedures of the subject invention create floes of weakly bound particles which are separated upon delivery of the dosage form.
  • the flow properties of the liposome powders of the subject invention can further be improved by mixing the liposome powder with carrier powders such as spray-dried lactose and other carbohydrates.
  • carrier powders such as spray-dried lactose and other carbohydrates.
  • the liposome powders may also be mixed with carbohydrate alcohols such as mannitol or sorbitol, with cellulose (e.g., Avicell), or with silica derivatives with a size range of, for example, 40-100 ⁇ m diameter.
  • the subject invention pertains to a method for making a dry, free-flowing liposome powder.
  • this liposome powder comprises phospholipids and can be in combination with other lipidic material, or with a variety of other compounds.
  • the liposome powders of the subject invention form a free- flowing dry powder and advantageously retain the original vesicular structure of the liposomes.
  • Reference herein to "dry" powders refers to powders which are essentially free of water.
  • the liposome components of these powders are in particles which range in size from about 1 ⁇ m to about 100 ⁇ m. These liposome particles are weakly bound floes obtained by micronizing lyophilized liposome cakes.
  • the particle floes can comprise individual liposomes which are typically around 0.2 ⁇ m in diameter.
  • the particle floes typically comprise additional material which has been added as a cryoprotectant or bulking agent before or during the lyophilization process. Such additional material may be lactose, for example.
  • additional material may be lactose, for example.
  • the micronized liposome floe particles can then be dispersed in a carrier powder which typically consists of particles of similar or somewhat greater size compared to the liposome particles.
  • the subject invention concerns a process to micronize lyophilized liposome cakes with a jet mill, ball mill, or other manual or mechanical milling device to generate dry powder particles with a diameter of about 1 to about 100 ⁇ m. Preferably, these particles are from about 1 to about 10 ⁇ m.
  • the process of the subject invention advantageously forms a stable flocculated micronized liposome powder formulated to form weakly bound floes which are dispersed upon delivery of the dosage form.
  • liposomes can be formed utilizing any one of a number of procedures well known to those skilled in the art. Typically, this will involve introducing a lipid into an aqueous solution. A variety of other components can be added to create liposomes with particular desired characteristics. This is also the point at which compounds to be encapsulated can be dissolved into the aqueous solution. These water-soluble compounds would be enclosed in the inner core of the liposome which contains the aqueous solution. With lipid-soluble compounds, the compounds can be incorporated into the lipid bilayer of the liposome.
  • Lipids which can be used in making the liposomes include, but are not limited to, phospholipids including phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, cardiolipin, sphingomyelin, ceramides, cholesterol, dicetylphosphate, fatty acids, stearylamine, synthetic single-chain or double chain cationic, neutral, or anionic lipid constructs.
  • phospholipids including phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, cardiolipin, sphingomyelin, ceramides, cholesterol, dicetylphosphate, fatty acids, stearylamine, synthetic single-chain or double chain cationic,
  • cryoprotectants can be added to the liposome solution.
  • Such cryoprotectants and their use are well known to those skilled in the art.
  • the cryoprotectants help to reduce the possibility of the liposome being damaged by the freezing process.
  • a carbohydrate can be added as the cryoprotectant during the liposome formation step of the process.
  • a lipid to carbohydrate ratio of about 1:1 to about 3:1 can be used.
  • Lyophilization processes are well known to those skilled in the art and can be readily used to create dry, porous cake compositions comprising liposomes which encapsulate desired materials.
  • micronizing refers to the process whereby particles of about 1 to about 100 ⁇ m are produced from a large clump or cake preparation.
  • a jet mill or equivalent device produces micronized particles from the lyophilized liposome cake in a size range from about 1 ⁇ m to about 100 ⁇ m and, preferably, from about 1 ⁇ m to about 10 ⁇ m.
  • These particles are essentially stable floes which contain the intact liposomes which are typically embedded or otherwise associated with lactose or other cryopreservative or bulking agent. These weakly -bound floes are dispersed upon delivery of the dosage forms.
  • the liposome composition obtained after micronization will be dispersed in the a carbohydrate preparation.
  • the micronized liposomes can then be further dispersed in carrier powder which can be used to modulate the free-flowing properties of the liposome powder.
  • carrier powder can be used to modulate the free-flowing properties of the liposome powder.
  • free-flowing refers to a powder which consists of particles that move past each other freely without substantial chemical or physical interaction which could produce clumps or a sticky consistency.
  • carrier powders can be used which will give the desired flow characteristics to the liposome powder.
  • the carrier powder can also be used essentially as a diluent to decrease the concentration of the liposomes dispersed in the powder.
  • Carrier powders useful according to the subject invention include, but are not limited to, carbohydrates including lactose, maltose, saccharose, and trehalose. Also, carbohydrate alcohols can be used, and these would include mannitol, sorbitol, and xylitol. Other carriers which can be used include cellulose derivatives and silica derivatives. Spray-dried lactose is particularly advantageous as a carrier powder because its spherical particulate characteristics enhance the free-flowing nature of the liposome powder.
  • one composition of the subject invention comprises micronized liposome powders comprising liposomes and spray-dried lactose.
  • micronized liposome powder of the subject invention can be formulated into a variety of useful products.
  • a micronized liposome powder can be formulated as an oral powder capsule.
  • the oral powder capsule may be coated with polymeric coats to impart pH-sensitivity for selective release in the gastrointestinal tract.
  • the liposome powder of the subject invention can be mixed with commonly used tablet powder components and compressed to give an oral tablet.
  • these tablets may be coated with polymeric coats to impart pH-sensitivity for selective release in the gastrointestinal tract.
  • the tablets may be formulated with effervescent materials for rapid dissolution in water prior to oral administration.
  • a micronized liposome powder can be formulated with waxy materials and fats to form suppositories for rectal and vaginal application.
  • the liposome powder can be formulated as a suspension in cremes, ointments, pastes, or lotions for dermal and mucosal application.
  • the liposome powder can be formulated as a powder for inhalation to be used with a dry powder inhaler for delivering drugs to the nose, mouth, trachea, and lungs.
  • a dry powder inhaler for delivering drugs to the nose, mouth, trachea, and lungs.
  • spray- dried lactose is a particularly attractive carrier powder because of its free-flow characteristics.
  • L- ⁇ -phosphatidylcholine [plant] SPC; in ethanol
  • 1-palmitoyl- 2-oleyl phosphatidylglycerol [sodium salt] POPG; in chloroform
  • Each lipid formulation was dried via rotary evaporation in a round-bottom flask followed by hydration in the appropriate CF- or buffer-lactose solution.
  • Each preparation was extruded by passing at least 21 times through a 100 nm polycarbonate filter using a central filter housing connected to dual syringes (LiposoFast, Avestin Inc., Ottawa, Canada) as described by MacDonald et al. (MacDonald, R.C., R.I. MacDonald, B.P.M. Menco, K. Takeshita, N.K. Subbarao, L. Hu [1991] Biochim.
  • Unencapsulated CF was removed via column chromatography (Sephadex G-75, swollen in lactose solution [125 mg/ml in phosphate buffered saline]).
  • Liposome lyophilization The liposomes were lyophilized in an Edwards Model 12K Supermodulyo freeze-dryer (Edwards High Vacuum, West Wales,
  • Micronized powders were generated by the principle of opposing jets and cyclone separation. Samples were filled and the mill operated under dry nitrogen so as to minimize potential oxidation and absorption of trace amounts of water. Samples were milled for 3 minutes at an inlet pressure of 40 psig and 2 minutes at 50 psig with an opposing pressure of 50 psig in both cases. The majority of the sample was collected in the cyclone (5-10 ⁇ m particle size) rather the collection vessel ( ⁇ 5 ⁇ m), with a total recovery after milling of «30-40%. During the milling process, there was no evidence of smearing.
  • Liposome powder was introduced into gelatine capsules (Elanco HC #2) with the help of a manual capsule filling machine. Capsules were closed with gelatine tops and weighed to determine accuracy of filling. Capsules were dipped into Eudragit solution to impart a polymer coat for enteric coating.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Procédé unique en son genre destiné à produire des poudres de liposomes sèches qui peuvent entrer la composition de produits pharmaceutiques. Ledit procédé comporte la micronisation de pains de liposomes lyophilisés.
PCT/US1994/006137 1993-06-07 1994-05-31 Poudres de liposomes WO1994028876A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7323493A 1993-06-07 1993-06-07
US08/073,234 1993-06-07

Publications (1)

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WO1994028876A1 true WO1994028876A1 (fr) 1994-12-22

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0664116A1 (fr) * 1994-01-20 1995-07-26 F. Hoffmann-La Roche Ag Procédé pour la préparation de liposomes et/ou préliposomes
WO1997038677A2 (fr) * 1996-04-18 1997-10-23 Mehl Thomas L Sr Systeme d'administration de liposomes lyophilises destine a l'application d'agents de traitement de la peau
WO1999061003A1 (fr) * 1998-05-27 1999-12-02 Euroceltique S.A. Systeme de presentation de medicament comprenant de la matiere medicamenteuse solide fortement compactee
WO2001082897A2 (fr) * 2000-05-02 2001-11-08 Enzrel, Inc. Administration de medicaments a l'aide de liposomes
WO2004054555A1 (fr) 2001-06-15 2004-07-01 Otsuka Pharmaceutical Co., Ltd. Nouveau systeme d'inhalation a poudre seche pour administration transpulmonaire
US6824790B2 (en) 2002-01-09 2004-11-30 Enzrel Inc. Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds
JP2005526119A (ja) * 2002-05-07 2005-09-02 カパック，エルエルシー 疎水性薬剤の吸収および胃腸の生物学的利用能を向上させるための方法および調剤
US7297344B1 (en) 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
US7300667B1 (en) 1999-05-27 2007-11-27 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
US8658202B2 (en) 2001-04-25 2014-02-25 Western University Of Health Sciences Coated drug delivery formulations
EP2475352B1 (fr) 2009-09-07 2015-06-17 Epitech Group S.r.l. Composition contenant du palmitoyl-éthanolamide ultramicronisé
US9107825B2 (en) 2002-05-07 2015-08-18 Zomanex, Llc Methods and formulations for enhancing the absorption and gastro-intestinal bioavailability of hydrophobic drugs

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2085729A (en) * 1980-10-17 1982-05-06 Dainippon Pharmaceutical Co Pharmaceutical composition for oral administration containing coagulation factor VIII
EP0152379A2 (fr) * 1984-02-15 1985-08-21 Ciba-Geigy Ag Procédé pour la préparation de compositions pharmaceutiques contenant des liposomes unilamellaires
EP0170642A2 (fr) * 1984-07-30 1986-02-05 Aktiebolaget Draco Liposomes contenant des esters de stéroides
WO1987007502A1 (fr) * 1986-06-06 1987-12-17 Phares Pharmaceutical Research N.V. Composition et methode
EP0260241A1 (fr) * 1986-09-12 1988-03-16 Aktiebolaget Draco Système pour l'administration de liposomes aux mammifères

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2085729A (en) * 1980-10-17 1982-05-06 Dainippon Pharmaceutical Co Pharmaceutical composition for oral administration containing coagulation factor VIII
EP0152379A2 (fr) * 1984-02-15 1985-08-21 Ciba-Geigy Ag Procédé pour la préparation de compositions pharmaceutiques contenant des liposomes unilamellaires
EP0170642A2 (fr) * 1984-07-30 1986-02-05 Aktiebolaget Draco Liposomes contenant des esters de stéroides
WO1987007502A1 (fr) * 1986-06-06 1987-12-17 Phares Pharmaceutical Research N.V. Composition et methode
EP0260241A1 (fr) * 1986-09-12 1988-03-16 Aktiebolaget Draco Système pour l'administration de liposomes aux mammifères

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6183451B1 (en) 1991-05-30 2001-02-06 Thomas L. Mehl, Sr. Method of delivery of skin treatment agents using freeze-dried liposomes
EP0664116A1 (fr) * 1994-01-20 1995-07-26 F. Hoffmann-La Roche Ag Procédé pour la préparation de liposomes et/ou préliposomes
US5635206A (en) * 1994-01-20 1997-06-03 Hoffmann-La Roche Inc. Process for liposomes or proliposomes
WO1997038677A2 (fr) * 1996-04-18 1997-10-23 Mehl Thomas L Sr Systeme d'administration de liposomes lyophilises destine a l'application d'agents de traitement de la peau
WO1997038677A3 (fr) * 1996-04-18 1997-12-11 Thomas L Mehl Sr Systeme d'administration de liposomes lyophilises destine a l'application d'agents de traitement de la peau
WO1999061003A1 (fr) * 1998-05-27 1999-12-02 Euroceltique S.A. Systeme de presentation de medicament comprenant de la matiere medicamenteuse solide fortement compactee
AU747877B2 (en) * 1998-05-27 2002-05-30 Euro-Celtique S.A. Drug delivery system comprising a tightly compacted solid medicament stock
US7300667B1 (en) 1999-05-27 2007-11-27 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
US7297344B1 (en) 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
WO2001082897A2 (fr) * 2000-05-02 2001-11-08 Enzrel, Inc. Administration de medicaments a l'aide de liposomes
US6761901B1 (en) 2000-05-02 2004-07-13 Enzrel Inc. Liposome drug delivery
US7387791B2 (en) 2000-05-02 2008-06-17 Oradel Medical Ltd. Liposome drug delivery
WO2001082897A3 (fr) * 2000-05-02 2002-11-28 Enzrel Inc Administration de medicaments a l'aide de liposomes
US8658202B2 (en) 2001-04-25 2014-02-25 Western University Of Health Sciences Coated drug delivery formulations
US8889180B2 (en) 2001-04-25 2014-11-18 Western University Of Health Sciences Coated drug delivery formulations
EP1579855A4 (fr) * 2001-06-15 2009-11-04 Otsuka Pharma Co Ltd Nouveau systeme d'inhalation a poudre seche pour administration transpulmonaire
EP1579855A1 (fr) * 2001-06-15 2005-09-28 Otsuka Pharmaceutical Co., Ltd. Nouveau systeme d'inhalation a poudre seche pour administration transpulmonaire
US7735485B2 (en) 2001-06-15 2010-06-15 Otsuka Pharmaceutical Co., Ltd. Dry powder inhalation system for transpulmonary administration
WO2004054555A1 (fr) 2001-06-15 2004-07-01 Otsuka Pharmaceutical Co., Ltd. Nouveau systeme d'inhalation a poudre seche pour administration transpulmonaire
US7316818B2 (en) 2002-01-09 2008-01-08 Oradel Medical Ltd. Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds
US6824790B2 (en) 2002-01-09 2004-11-30 Enzrel Inc. Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds
JP2005526119A (ja) * 2002-05-07 2005-09-02 カパック，エルエルシー 疎水性薬剤の吸収および胃腸の生物学的利用能を向上させるための方法および調剤
EP1501480B1 (fr) * 2002-05-07 2010-05-26 Zomanex, LLC Methodes et formulations destinees a favoriser l'absorption et la biodisponibilite gastro-intestinale de medicaments hydrophobes
US9107825B2 (en) 2002-05-07 2015-08-18 Zomanex, Llc Methods and formulations for enhancing the absorption and gastro-intestinal bioavailability of hydrophobic drugs
EP2475352B1 (fr) 2009-09-07 2015-06-17 Epitech Group S.r.l. Composition contenant du palmitoyl-éthanolamide ultramicronisé
EP2796129B1 (fr) 2009-09-07 2015-06-17 Epitech Group S.r.l. Composition contenant de - l'éthanolamide - du palmitoyle ultra - micronisés

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