Preparation of sterile stabilized nanodispersions

Details Preparation of sterile stabilized nanodispersions Preparation of sterile stabilized nanodispersions

2002-03-18

2004-08-24

Drodge, Joseph (Department: 1723)

Liquid purification or separation

Processes

Liquid/liquid solvent or colloidal extraction or diffusing...

C210S649000, C264S005000, C424S489000

Reexamination Certificate

active

06780324

ABSTRACT:

FIELD OF THE INVENTION
This application relates to sterile, stabilized nanodispersions or micelles comprising a polymer and a biologically active composition; particularly to nanodispersions or micelles produced by rehydration of a freeze-dried cake produced via the direct lyophilization of a solution comprising a dispersing agent such as an amphiphilic block copolymer, or a small molecular weight surfactant, a biologically active composition, a suitable solvent, and optionally, an additive.
BACKGROUND OF THE INVENTION
Many important biologically active agents, such as drugs, are hydrophobic and have limited solubilities in water. In order to attain the expected therapeutic effect of such agents, it is usually required that a solubilized form or nanodispersed form of the agent be administered to a patient.
Thus, a number of methods have been developed which are based on the use of auxiliary solvents; surfactants; soluble forms of the drug, e.g., salts and solvates; chemically modified forms of the drug, e.g., prodrugs; soluble polymer-drug complexes; special drug carriers such as liposomes; and others. Indeed, the use of amphiphilic block copolymer micelles has attracted a great deal of interest as a potentially effective drug carrier which is capable of solubilizing a hydrophobic drug in an aqueous environment.
Each of the above methods is hampered by one or more particular problems, e.g., the method based on the use of surfactant micelles to solubilize hydrophobic drugs has problems in that some of the surfactants are relatively toxic and that precipitation of hydrophobic drugs occurs when subjected to dilution.
A variety of methods and procedures have been described in the prior art for preparing nanodispersions of hydrophobic compounds, particularly pharmaceutical preparations. It is known to incorporate hydrophobic biologically active agents having limited solubility in an aqueous or hydrophilic environment into block copolymers which form micelles capable of acting as carriers for the biologically active agents.
A variety of methods have been utilized, either alone or in combination, in order to incorporate or solubilize one or more biologically active agents, within polymer carriers. Included among these prior art methods are:
(1) Stirring
This method consists in adding the drug to a polymeric micelle solution and permitting the drug to dissolve in the micellar core. Such a procedure yields generally poor entrapment efficiency mainly because of the poor affinity of the drug for the aqueous medium. The water solution can then be freeze dried;
(2) Heating
A drug and a block copolymer are dissolved in an organic solvent and the solvent is evaporated off at an elevated temperature (from about 40° C. to about 80° C. under a nitrogen atmosphere or by rotary evaporator under vacuum). The resulting mixture is kept at a temperature of 20° C. to about 80° C., preferably at about 40-70° C., for 2 hours. Then, warm water (about 40° C. to about 70° C.) is added thereto, and the mixture is stirred until a polymeric micelle containing drug is formed.
(3) Ultrasonic Treatment
A mixture of a drug and an aqueous solution of a block copolymer is subjected to ultrasonic treatment for a period ranging from about 1 second to 1 hour and then stirred at room temperature to obtain micelles containing the drug.
(4) Solvent Evaporation
A drug is dissolved in a water-immiscible organic solvent, for example, dichloromethane, chloroform and the like, and then added to an aqueous solution of a block copolymer. Subsequently, the organic solvent is slowly evaporated off, e.g. at 25-40° C. while stirring, optionally under vacuum, and then filtered to remove undissolved drug.
(5) Dialysis
A drug and a block copolymer are dissolved in a water-miscible organic solvent. The solution is dialyzed against a buffer solution and then against water.
In the dialysis method, suitable water-miscible organic solvents for dissolving drugs may include members selected from the group comprising acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, dimethylacetamide (DMAC) and the like.
The unloaded drug can diffuse with the organic solvent and/or precipitate in the dialysis bag. The precipitated drug can be removed by filtration. The colloidal dispersion is then generally freeze-dried.
(6) Emulsification-Evaporation/Salting Out Procedure
The drug and polymer are dissolved in a water-immiscible organic solvent which is emulsified in water. The aqueous phase may or may not contain stabilizers. The organic solvent is then removed by evaporation or other methods. If needed, the nanodispersion can be further purified to remove the stabilizers. Then, the colloidal dispersion can be freeze-dried.
(7) Spray-Drying
The drug is dissolved in an organic solvent which is then nebulized so as to obtain drug loaded nanoparticles. Such a process may not be adapted for temperature-sensitive drugs and is not optimal to produce particles of less than 1 &mgr;m.
(8) Micronization/Controlled Precipitation/High Pressure Homogenization
These methods are aimed at producing nanoscaled drug dispersions. Such techniques can be applied to almost any kinds of hydrophobic drugs. All require specific specialized equipment and/or are difficult to control.
Each of the above procedures are associated with certain drawbacks. For example, with some of the procedures the stabilizers need to be removed. Others yield poor entrapment efficiencies (e.g. equilibration), relatively large particle sizes (e.g. spray drying) or are time-consuming (e.g. dialysis).
DESCRIPTION OF THE PRIOR ART
Many studies, literature articles and patents have been directed toward the use of amphiphilic block copolymers having surfactant-like properties, particularly regarding their use as carriers for hydrophobic drugs.
For example, EP No.0397307A2 discloses polymeric micelles of an AB type amphiphilic diblock copolymer which contains poly(ethylene oxide) as the hydrophilic component and poly(amino acid derivatives) as the hydrophobic component, wherein therapeutically active agents are chemically bonded to the hydrophobic component of the polymer.
EP No. 0583955A2, on the other hand, discloses a method for physically incorporating hydrophobic drugs into amphiphilic diblock copolymer micelles described in EP No. 0397307A2. This method, thus, solves the above disadvantage of the chemical bond type polymeric micelle drug
U.S. Pat. No. 4,745,160 discloses a pharmaceutically or veterinary acceptable amphiphilic, non-cross linked linear, branched or graft block copolymer having polyethylene glycol as the hydrophilic component and poly(D-, L- and DL-lactic acids) as the hydrophobic components. In the preparation process, a water-miscible and lyophilizable organic solvent is used. When a mixture of the polymer, drug and organic solvent is mixed with water, precipitates are formed and then the mixture is directly lyophilized to form particles. Thereafter, when this particle is dispersed in water, it forms a colloidal suspension containing fine particles wherein hydrophilic components and hydrophobic components are mixed.
In contrast to that which is disclosed in the prior art, the present invention forms a clear solution that can be sterilized by filtration (220 nm pore size filter) prior to freeze-drying, and yields a storable powder which is readily reconstituted. What is particularly unique, is that the micelle or nanodispersion is produced directly and spontaneously upon addition of an aqueous medium. This is in direct contrast to prior art processes which must first produce a nanodispersion which is subsequently lyophilized and then reconstituted. Furthermore, the instant process suffers no loss of drug during the loading procedure.
U.S. Pat. No. 6,322,805 discloses a biodegradable polymeric drug carrier micelle composition capable of solubilizing a hydrophobic drug in a hydrophilic environment. The patent discloses a biodegradable polymeric drug carrier micelle and a hydrophobic drug wherein the drug is physically trapped within and not covalently bonded to the pol

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