WO1996009037A1 - Procede de fabrication d'un liposome lyophilise - Google Patents

Procede de fabrication d'un liposome lyophilise Download PDF

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Publication number
WO1996009037A1
WO1996009037A1 PCT/US1994/010812 US9410812W WO9609037A1 WO 1996009037 A1 WO1996009037 A1 WO 1996009037A1 US 9410812 W US9410812 W US 9410812W WO 9609037 A1 WO9609037 A1 WO 9609037A1
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WO
WIPO (PCT)
Prior art keywords
liposomes
mixture
product
lyophilized
bioactive agent
Prior art date
Application number
PCT/US1994/010812
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English (en)
Inventor
Laura M. Edgerly-Pflug
Royden M. Coe
Original Assignee
The Liposome Company, 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 The Liposome Company, Inc. filed Critical The Liposome Company, Inc.
Priority to PCT/US1994/010812 priority Critical patent/WO1996009037A1/fr
Priority to JP8510843A priority patent/JPH10508578A/ja
Priority to EP94929326A priority patent/EP0783295A1/fr
Publication of WO1996009037A1 publication Critical patent/WO1996009037A1/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
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes

Definitions

  • the present invention is generally directed to a method of producing lyophilized liposomes and particularly to a method in which an organic solvent, typically used for dissolving the lipid and other components of the process, is eliminated. This enables the liposomes to be lyophilized in a more efficient and less costly manner.
  • association shall mean bioactive agent which is encapsulated within the liposome and bioactive agent which, while not encapsulated, remains with the liposome and is not readily separated therefrom.
  • Some methods of forming liposomes employ an organic solvent to dissolve a lipid alone or the lipid and a bioactive agent such as a drug.
  • a bioactive agent such as a drug
  • lipids are dissolved in an organic solvent and combined with an aqueous medium to form liposomes.
  • a bioactive agent such as a drug is loaded into the preformed liposomes using a transmembrane concentration gradient.
  • Lenk et al. U.S. Patent No. 5,082,664
  • a lipid and a bioactive agent are dissolved together in an organic solvent, and combined with an aqueous medium to form liposomes associated with the bioactive agent.
  • the lipid and the bioactive agent are co-dissolved in an aqueous-miscible organic solvent such as ethanol, then added slowly to an aqueous solution, which may additionally contain a drying protectant and/or a buffer, as discussed in the Lenk et al. patent. Both of these patents are hereby incorporated by reference into the present disclosure.
  • an aqueous-miscible organic solvent such as ethanol
  • Another method for forming liposomes employs ethanol injection and is discussed in Batzri et al. , Biochem. Biophys. Acta. 298:1015 (1973) .
  • the ethanol injection method has been used to form liposomes having associated therewith a lipophilic or hydrophilic bioactive agent.
  • liposomes containing a lipophilic bioactive agent e.g. prostaglandin
  • an optional preservative and the bioactive agent are added to the ethanol containing lipid.
  • the resulting mixture is then slowly added to an aqueous medium.
  • This process forms liposomes entrapping the aqueous medium.
  • Ethanol injection processes, as well as other liposome formation processes, using a desalted charged lipid are disclosed in Vietnamese et al. , U.S. Patent No. 5,154,930, incorporated by reference into the present specification.
  • a method of controlling size distribution of resultant liposomes in an ethanol infusion process is discussed in Aitcheson et al. , U.S. Patent No. 4,994,213.
  • the bioactive agent is added to the aqueous phase.
  • the lipid and ethanol are combined to form a solution which is added to the aqueous phase and the resulting mixture is processed to form liposomes.
  • the aqueous phase may be a solution of one or more drying protectants with or without a preservative.
  • the liposome preparations prepared by such methods typically contain liposomes having a wide variety of particle sizes. It is often desirable to reduce the size of the larger liposomes to obtain a single-modal size distribution encompassing a desired mean particle size.
  • the term "single-modal size distribution” as used herein shall mean that most of the liposomes have a particle size within a continuous range of particle sizes encompassing the mean particle size.
  • the term "mean particle size” shall mean the sum of the diameters of each liposome of the population divided by the total number of liposomes.
  • Size reduction to obtain a single-modal size distribution can be achieved by a number of methods such as by extrusion through a filter, as described in Pieter Cullis et al. , U.S. Patent No. 5,008,050, incorporated herein by reference.
  • a method of sizing liposomes by filtration through a 200 nm Unipore TM polycarbonate filter is discussed in Szoka,
  • U.S. Patent No. 4,737,323 describes a method for sizing liposomes by extrusion through an asymmetric ceramic filter. Such filters are designed for operation at relatively high pressure, and can be backflushed to prevent clogging.
  • U.S. Patent No. 4,927,637 describes a method of sizing liposomes by passing them through a polymer filter having a web-like "tortuous-path" construction.
  • FIG. 1 An alternative type of filter medium is described in Furneaux et al., U.S. Patent No. 4,687,551.
  • This patent discloses a filter sheet comprising an anodic aluminum oxide film having branched pores extending from one surface of the film to the other.
  • the film is unique in that it includes a system of larger pores extending in from one face and a system of smaller pores extending in from the other face.
  • the system of larger pores interconnects with the system of smaller pores such that the inner ends of one or more smaller pores are joined to the inner end of a larger pore and there are substantially no larger pores that terminate within the film.
  • the application of an aluminum oxide porous film to the size reduction of liposomes is disclosed in Royden M. Coe et al., U.S. Serial No. 771,267 filed on October 4, 1991.
  • Homogenization is another method for size reducing liposomes.
  • a suspension of liposomes is repeatedly pumped under high pressure through a small orifice or reaction chamber until a desired size distribution is achieved.
  • the resulting liposomes may be dehydrated or lyophilized by any method known in the art, so that the size and contents are maintained during the drying procedure and through rehydration. It has been found that one group of drying protectants, the saccharides, when included in the liposome formulations, are especially useful at maintaining the liposome particle size after rehydration.
  • an aqueous solution such as distilled water with or without buffer may be added.
  • the pH gradient may be established by adding a relatively acidic aqueous solution to the formulation. Reconstitution may proceed at a temperature of about 20° to 70°C and the solutions diluted as needed and administered.
  • the present invention is directed to a process employing no added organic solvent for the production of a lyophilized liposome product.
  • the process comprises combining at least one lipid with an aqueous solution containing a drying protectant in the absence of added organic solvent and lyophilizing the resulting mixture to form the liposome product.
  • the liposome product may contain a bioactive agent.
  • the temperature needed to lyophilize the final product may not be as low as previously required in systems using an organic solvent. As a result, the time and cost of the lyophilization procedure may be significantly reduced over processes which employ an organic solvent.
  • a method of forming a lyophilized liposome product comprising: (a) without adding organic solvent, combining at least one lipid with an aqueous solution containing a drying protectant to form a mixture;
  • a bioactive agent is associated with the liposomes.
  • the invention is also directed to the lyophilized liposome product produced by the above method, and to compositions of liposomes produced by reconstituting the lyophilized product.
  • the invention further provides a lyophilized liposome product comprising a lipid- encapsulated bioactive agent having a reduced level of organic solvent, and preferably substantially absent organic solvent.
  • the present invention is premised, inter alia , on the discovery that a lyophilized liposome product can be made without adding organic solvent. Processing of liposomes in accordance with the present invention eliminates the time and cost of adding the solvent, as well as removing the solvent during lyophilization.
  • the liposomes of the present invention are prepared by adding a lipid to an aqueous solution containing a drying protectant.
  • a particular type of lipid material for use in this invention is one which is amphipathic in character. Hydrophilic character can be imparted to the molecule through the presence of phosphato, carboxylic, sulphato, amino, sulfhydryl, nitro, and other like groups. Hydrophobicity can be conferred by the inclusion of groups that include, but are not limited to, long chain saturated and unsaturated aliphatic hydrocarbon groups and such groups substituted by one or more aromatic, cycloaliphatic or heterocyclic group.
  • the preferred amphipathic compounds are phosphoglycerides, representative examples of which include phosphatidylcholine, phosphatidylethanola ine, lysophosphatidyl- choline, lysophosphatidylethanolamine, phosphatidylserine, phos- phatidylinositol, phosphatidic acid, dimyristoylphosphatidyl- glycerol and diphosphatidylglycerol alone or in combination with other lipids.
  • Synthetic saturated compounds such as dimyristoyl- phosphatidylcholine, dipalmitoylphosphatidylcholine, or distearoylphosphatidylcholine or unsaturated species such as dioleoylphosphatidylcholine or dilinoleoylphosphatidylcholine might also be usable.
  • Other compounds lacking phosphorus, such as members of the sphingolipid and glycosphingolipid families, are also within the group designated as lipid.
  • a variety of cholesterols and other sterols and their water soluble derivatives have also been used to form liposomes; see specifically Janoff et al. , U.S. Patent No. 4,721,612 and references referred to therein, all of which are incorporated herein by reference.
  • Various tocopherols and their water soluble derivatives have also been used to form liposomes, as disclosed in Janoff et al. U.S. Patent No. 4,861,580, incorporated herein by reference.
  • Preferred of this group are cholesterol hemisuccinate and tocopherol hemisuccinate.
  • drying protectants which are employed for lyophilization in accordance with the present invention are selected from saccharides such as sucrose, dextrose, maltose, mannose, galactose, raffinose, trehalose, lactose, as well as polyhydric alcohols such as mannitol, and mixtures thereof.
  • Other drying protectants which can be employed in the present process include albumin, dextrans, or polyvinyl alcohol. Maltose is particularly preferred.
  • the concentration of the drying protectants is generally in the range of from about 1 to 20% by weight, preferably about 5 to 10% by weight, based on the weight of the aqueous phase.
  • the polyhydric alcohol when present and used in addition to the saccharides, is preferably provided at a concentration of up to 2% by weight, more preferably about 1% by weight, based on the weight of the aqueous phase.
  • the preferred polyhydric alcohol is mannitol.
  • the bioactive agents which may be encapsulated within the lipid bilayer include nucleic acids, polynucleotides, antibacterial compounds, antiviral compounds, tumoricidal compounds, proteins, toxins, enzymes, hormones, neurotrans- mitters, glycoproteins, immunoglobulins, immunomodulators, dyes, radio labels, radio-opaque compounds, fluorescent compounds, polysaccharides, cell receptor binding molecules, anti- inflammatories, antiglaucomic agents, mydriatic compounds, local anesthetics, and the like.
  • Specific examples of such active agents and their incorporation into liposomes can be found in Lenk et al. , U.S. Patent No. 4,522,803; Fountain et al. , U.S.
  • Patent No. 4,588,578 Janoff et al. , U.S. Patent No. 4,861,580 and 4,897,394; and Lenk et al. , U.S. Patent No. 5,082,664; each of which is incorporated herein by reference.
  • the bioactive agents which find particularly effective application to the present invention are lipophilic bioactive agents, particularly arachidonic acid metabolites including their structural analogs and synthetic enzyme inhibitors.
  • arachidonic acid metabolites is the group of bioactive agents known as prostaglandins including, but not limited to prostaglandin Ei.
  • Hydrophilic bioactive agents such as the aminoglycoside antibiotics and their structural analogs, are examples of hydrophilic bioactive agents.
  • Gentamicin is the preferred aminoglycoside antibiotic.
  • the process of forming liposomes, in accordance with the present invention is essentially the same for lipophilic and hydrophilic bioactive agents.
  • an optional preservative such as disodium EDTA and the bioactive agent (e.g. prostaglandin Ei or gentamicin) are added to an aqueous medium, preferably a solution of a drying protectant, most preferably a maltose solution at a preferred concentration of about 5 to 10% by weight based on the total weight of the aqueous phase.
  • the liposomes are prepared at a temperature above the phase transition temperature of the lipid membrane.
  • the resulting bulk liposomes may if desirable, undergo size reduction. Size reduction may be accomplished by utilizing any one of the methods described hereinbefore to obtain a single-modal size distribution of liposomes encompassing a desired mean particle size.
  • the size reduction of the liposomes is preferably conducted by extruding the liposomes through filters having straight through or tortuous paths, according to the procedure disclosed in U.S. Serial No. 07/771,267 filed October 4, 1991, using an Anopore TM filter or by homogenization such as by the use of a Microfluidizer to form a single-modal size distribution, preferably having a mean particle size in the range of no more than 200 nm, most preferably 150 to 190 nm.
  • the bulk liposomes produced by the process of the present invention may be separated from unassociated bioactive agent, if necessary, as well as from free lipid, salts and water by the common technique of ultrafiltration such as disclosed in Munir Cheryan, Ultrafiltration Handbook, pp. 205-213 and 377, Technomic Publishing Company (1986) .
  • Diafiltration is one such ultrafiltration system in which permeable solutes are removed by the addition of fresh solvent or other solution to the feed liquid. The remaining liquid (the retentate) containing non-permeated substances including the desired liposome product is recovered.
  • a preferred method of diafiltration is disclosed in Lenk, et al. , PCT Published Application No. WO89/00846, the disclosure of which is incorporated herein by reference.
  • Diafiltration systems typically employ a filter device having one or more primary pathways formed by a porous filter composition.
  • the filter device has a rated pore size such that generally materials having a size equal to or less than the rated pore size will be able to pass through the filter device via narrower secondary pathways. Generally, the larger components will remain in the primary pathways and pass through the filter device as part of the liquid retentate.
  • liposomes are prepared using a diafiltration system, the liposomes pass out of the filter device through the primary pathways while the permeable solutes pass through the narrower secondary pathways.
  • the dehydration or lyophilization of the liposomes of the present invention may be performed by any methods known in the art for dehydrating or lyophilizing liposomes.
  • the liposomes may be dried according to the procedures of Janoff et al. , U.S. Patent No. 4,880,635, incorporated herein by reference.
  • the liposomes of the invention are preferably lyophilized by first pre-cooling the liposomes in a vessel at a temperature of from about 0 to 8°C and then freezing the pre- cooled liposomes to a temperature of from about -50 to -38°C, preferably about -40°C. Thereafter, the pressure of the vessel is reduced while raising the shelf temperature to a temperature of from about -18 to -22°C, preferably about -20°C until the product and shelf temperature equilibrate. Once the primary drying stage is completed, secondary drying is commenced by raising the shelf temperature to about 36 to 40°C, preferably about 38°C, and maintaining that temperature until the water content is reduced to below about 2% by weight, preferably to below about 1% by weight.
  • the lyophilized liposome formulation prepared in this manner in the absence of an organic solvent may be stable for at least one year when stored at temperatures of up to 25°C.
  • rehydration can be accomplished by adding an aqueous solution, e.g., distilled water, water for injection (WFI) , or buffer or aqueous solution of appropriate pH, as described above, to the liposomes, and gently agitating them to rehydrate and suspend them.
  • the rehydration may be performed at about room temperature, that is 25°C. If the bioactive agent was incorporated into the liposomes prior to dehydration, and no further composition changes are desired, the rehydrated liposomes can be used directly in the therapy following known procedures for administering liposome associated drugs.
  • organic solvents are not used to suspend the lipids and/or the active agent, such as prostaglandin or gentamicin. It being understood, however, that minor amounts of residual solvent may be present in components used to make the liposomes including the lipids and perhaps the bioactive agent. Accordingly, the final liposome product contains no residual organic solvent other than very small amounts which may be present in the raw materials used to make the liposomes.
  • the resulting liposome product may be freeze dried at higher temperatures than liposomes containing an organic solvent such as ethanol.
  • a bioactive agent such as prostaglandin can be added to an aqueous solution containing a drying protectant, such as maltose and mixed in a reactor equipped with an impeller.
  • the lipid such as egg phosphatidylcholine, can then be added to the reaction vessel without mixing.
  • mixing can be commenced again to produce a liquid medium containing a heterogeneous (non- uniform) size distribution of liposomes associated with the bioactive agent.
  • much of the bioactive agent is encapsulated as part of the aqueous phase within the liposomes.
  • the resulting bulk liposome medium can be extruded through a filter, such as a branched-pore aluminum oxide filter, and then sterilized by filtration to form a single-modal size distribution of liposomes.
  • the resulting liposomes can then be lyophilized, for example, as follows.
  • the liposomes can be placed in a freeze dryer that is preferably pre-cooled to about 5°C and then frozen by lowering the shelf temperature to preferably about -42°C. Once the liposomes reached -40°C, primary drying can be initiated by lowering the pressure of the vessel, preferably to about 0.150 mm Hg and raising the shelf temperature, preferably to about 20 °C, which is preferably maintained until the product and shelf temperature equilibrate.
  • secondary drying can be commenced by raising the shelf temperature, preferably to about 38°C and preferably maintaining that temperature for about 7-8 hours. According to the following example, this process can result in 99.6% liposomes having a size between 50 nm and 450 nm, and the lyophilized liposome product having a water content of 0.9%.
  • the liposomes resulting from the processes of the present invention can be used therapeutically in mammals, including man, in the treatment of infections or conditions which require the sustained delivery of the drug in its bioactive form.
  • infections or conditions which require the sustained delivery of the drug in its bioactive form.
  • Such conditions include, but are not limited to, disease states such as those that can be treated with prostaglandins or aminoglycosides.
  • the process of the present invention is capable of producing a single-modal size distribution of liposomes under less severe and time consuming conditions than are possible when the liposomes are prepared using an organic solvent.
  • prostaglandin Ei PGEi
  • aqueous solution containing 880 mg/mL of maltose was mixed for 10 minutes in a 3 liter ApplikonTM reactor equipped with 3 baffles and a LightninTM R-100 impeller.
  • the resulting bulk liposome medium was then extruded through a 100 nm backed AnoporeTM branched-pore aluminum oxide filter (manufactured by Whatman Corp. of Banbury Oxon, United Kingdom) and then sterilized by filtration using a 220 nm MillipakTM 100 filter to form a single-modal size distribution of liposomes.
  • the resulting liposomes were then lyophilized in the following manner:

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Abstract

Procédé destiné à fabriquer un liposome lyophilisé par association d'un lipide avec une solution aqueuse contenant un protecteur contre le sèchement, sans adjonction de solvant organique, par agitation du mélange pour former une population de liposomes, et par lyophilisation dudit mélange pour créer un liposome lyophilisé. L'invention porte également sur les produits lyophilisés obtenus par ce procédé et sur les liposomes que l'on prépare en reconstituant le produit lyophilisé. L'étape de lyophilisation peut s'effectuer à des températures de séchage plus élevées, ce qui permet d'aboutir, entre autres, à un procédé plus rentable.
PCT/US1994/010812 1994-09-23 1994-09-23 Procede de fabrication d'un liposome lyophilise WO1996009037A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/US1994/010812 WO1996009037A1 (fr) 1994-09-23 1994-09-23 Procede de fabrication d'un liposome lyophilise
JP8510843A JPH10508578A (ja) 1994-09-23 1994-09-23 凍結乾燥リポソーム生成物の製造方法
EP94929326A EP0783295A1 (fr) 1994-09-23 1994-09-23 Procede de fabrication d'un liposome lyophilise

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Application Number Priority Date Filing Date Title
PCT/US1994/010812 WO1996009037A1 (fr) 1994-09-23 1994-09-23 Procede de fabrication d'un liposome lyophilise

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1074278C (zh) * 1996-11-12 2001-11-07 蔡海德 前列腺素e1无菌冻干粉针剂生产工艺
WO2004069284A3 (fr) * 2003-02-04 2004-11-25 Bracco Research Sa Agents de contraste pour ultrasons et procede pour leur elaboration
ES2275443A1 (es) * 2005-11-30 2007-06-01 Italfarmaco, S.A. Procedimiento de preparacion de liposomas.
US9248204B2 (en) 2004-08-18 2016-02-02 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
US9750821B2 (en) 2003-12-22 2017-09-05 Bracco Suisse S.A. Gas-filled microvesicle assembly for contrast imaging
WO2020027466A1 (fr) * 2018-07-28 2020-02-06 주식회사 엑소코바이오 Procédé pour lyophilisation d'exosomes
CN114886785A (zh) * 2022-06-07 2022-08-12 美尚(广州)化妆品股份有限公司 一种三元冻干组合物及其在冻干制剂中的应用
US11529306B2 (en) 2018-07-30 2022-12-20 Exocobio Inc. Lyophilized formulation of stem cell-derived exosomes and anti-inflammatory composition including the same as active ingredient
US11730695B2 (en) 2018-05-31 2023-08-22 Exocobio Inc. Composition for alleviating facial redness, comprising stem cell-derived exosomes as active ingredient

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006508126A (ja) * 2002-11-06 2006-03-09 アザヤ セラピューティクス インコーポレイティッド 薬学的製剤のタンパク質安定化されたリポソーム製剤
JP6084371B2 (ja) * 2012-05-23 2017-02-22 富士製薬工業株式会社 薬剤安定化医薬組成物

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1074278C (zh) * 1996-11-12 2001-11-07 蔡海德 前列腺素e1无菌冻干粉针剂生产工艺
US9364569B2 (en) 2003-02-04 2016-06-14 Bracco Suisse S.A. Ultrasound contrast agents and process for the preparation thereof
WO2004069284A3 (fr) * 2003-02-04 2004-11-25 Bracco Research Sa Agents de contraste pour ultrasons et procede pour leur elaboration
CN100374165C (zh) * 2003-02-04 2008-03-12 伯拉考国际股份公司 超声造影剂及其制备方法
US9750821B2 (en) 2003-12-22 2017-09-05 Bracco Suisse S.A. Gas-filled microvesicle assembly for contrast imaging
US10076580B2 (en) 2004-08-18 2018-09-18 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
US9248204B2 (en) 2004-08-18 2016-02-02 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
WO2007063156A1 (fr) * 2005-11-30 2007-06-07 Italfarmaco, S.A. Procede de preparation de liposomes
ES2275443A1 (es) * 2005-11-30 2007-06-01 Italfarmaco, S.A. Procedimiento de preparacion de liposomas.
US11730695B2 (en) 2018-05-31 2023-08-22 Exocobio Inc. Composition for alleviating facial redness, comprising stem cell-derived exosomes as active ingredient
WO2020027466A1 (fr) * 2018-07-28 2020-02-06 주식회사 엑소코바이오 Procédé pour lyophilisation d'exosomes
US11337419B2 (en) 2018-07-28 2022-05-24 Exocobio Inc. Method for lyophilizing exosome
US11529306B2 (en) 2018-07-30 2022-12-20 Exocobio Inc. Lyophilized formulation of stem cell-derived exosomes and anti-inflammatory composition including the same as active ingredient
CN114886785A (zh) * 2022-06-07 2022-08-12 美尚(广州)化妆品股份有限公司 一种三元冻干组合物及其在冻干制剂中的应用
CN114886785B (zh) * 2022-06-07 2023-02-03 美尚(广州)化妆品股份有限公司 一种三元冻干组合物及其在冻干制剂中的应用
WO2023237004A1 (fr) * 2022-06-07 2023-12-14 吴冬 Composition de lyophilisation ternaire et son utilisation dans une formulation lyophilisée

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JPH10508578A (ja) 1998-08-25

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