Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Processes of preparing a desired or intentional composition...
Reexamination Certificate
1999-03-01
2001-03-20
Sanders, Kriellion (Department: 1714)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Processes of preparing a desired or intentional composition...
C523S122000, C424S078370
Reexamination Certificate
active
06204308
ABSTRACT:
FIELD OF THE INVENTION
This invention is concerned with a process of microencapsulating an active agent to form a microencapsulated product, in particular a microencapsulated product containing polymers of poly(ethylenecarbonate).
BACKGROUND OF THE INVENTION
The term “microencapsulated product” as used in this specification is understood to mean a product, e.g. a microparticle or microcapsule, wherein a pharmaceutically active agent is dispersed within a polymeric matrix or is encapsulated by a polymer coating, wall or membrane. Microencapsulated products are known in the art and methods for forming said microencapsulated products may be based on emulsion technology.
Prior art processes employing emulsion-based technology may proceed by producing a water-in-oil emulsion (so-called primary emulsion) by dispersing a solution of active agent in a solution of matrix- or wall-forming polymer (Polymer) (the solvent for active agent and the solvent for the polymer (the polymer solvent) being immiscible). The primary emulsion is then dispersed in, e.g. an aqueous phase (so-called external phase) to form droplets (containing active agent-in polymer) dispersed in the external phase. The droplets so formed are then hardened by removing the polymer solvent from the droplets to form a microencapsulated product. Several methods for polymer solvent removal are known including distillation, evaporation under reduced pressure and/or heat or extracting the polymer solvent by partitioning the droplets in an extraction medium immiscible with the polymer solvent. A problem with all of these hardening steps is that they are slow and during polymer solvent removal the active agent may leach out of the droplets, resulting in poor encapsulation efficiency. By “encapsulation efficiency” is meant the measure of the amount of active substance incorporated into the microencapsulated product as a percentage of the total amount of active agent employed in a process.
In an attempt to accelerate the hardening step, it has been suggested to transfer the mixture containing the droplets to an extraction medium immediately after the mixture is formed thereby removing sufficient polymer solvent sufficiently quickly to enable the droplets to harden before a significant quantity of active agent can leach out of the droplets. Nevertheless, the need to transfer the mixture to the extraction medium immediately after the mixture is formed imposes a constraint on the process which may render it impractical and unreliable particularly when active agents are used which are highly soluble in an extraction medium.
There remains a need to provide a process of microencapsulation of an active agent to form a microencapsulated product which reliably incorporates an active agent in a polymer with high encapsulation efficiency.
Surprisingly the applicant has found that the mixture formed by mixing primary emulsion and an external phase may be dispersed to form a microencapsulated product, the microencapsulated product being formed without the need for a subsequent hardening step, i.e. a polymer solvent removal step.
SUMMARY OF THE INVENTION
Accordingly, the invention provides in one of its aspects an emulsion-based method of microencapsulating an active agent to form a microencapsulated product wherein the microencapsulated product is formed as a result of dispersing a primary emulsion, comprising or consisting of a dispersion of active agent in a solution of polymer, with an external phase.
DETAILED DESCRIPTION OF THE INVENTION
The polymer solvent used in forming the primary emulsion should be immiscible or substantially immiscible in the external phase. Preferably the polymer solvent is an organic solvent which is suitable for dissolving the polymer and which is unreactive and otherwise inert with or to the active agent, for example methylene chloride.
The external phase may be water and is preferably water when the polymer solvent is an organic solvent. However, where the polymer solvent is aqueous-based the external phase may be an organic solvent. The external phase may contain surfactants, for example suitable cationic, anionic and non-ionic compounds known in the art. Examples of suitable surfactants are gelatine or PVA, in particular PVA, preferably PVA having a molecular weight of from 5000 to 60000 Mw, in particular 15000 Mw. Other excipients may be present in the external phase, for example buffers, in particular phosphate buffers, e.g. potassium or sodium phosphates.
Surfactant, e.g. PVA may be present in the external phase in a concentration of 0.1 to 20% depending on the nature of the external phase, surfactant and polymer solvent employed. In the case of PVA the concentration preferably is, 0.5 to 5%, e.g. 2.0%. Likewise the buffer concentration is dependent upon the nature of external phase, polymer solvent and nature of the buffer. Preferably, in the case of sodium or potassium phosphate may be present in the external phase in a concentration of 20 to 100 millimolar, e.g. 60 to 70, more particularly 66 millimolar.
The polymer may be chosen from any of those polymer materials disclosed in U.S. Pat. No. 5,407,609, the contents of which is incorporated herein by reference as if set forth in its entirety. Preferred polymers are those polymers disclosed in published application WO 95/06077 which is incorporated herein by reference and in particular the poly(ethylenecarbonate) polymers disclosed therein. Preferred poly(ethylenecarbonate) polymers are those disclosed in WO 95/06077 having, e.g. a Mw of 100 000 to 800 000; and/or an ethylene carbonate content of 70 to 100% and/or an intrinsic viscosity of 0.4 to 4.0 dl/g in chloroform; and/ or a glass transition temperature of 15 to 50° C.
The concentration of polymer dissolved in the polymer solvent may be 2 to 20% w/w. Preferably the polymer may be present in amounts of 10% w/w. The viscosity of the polymer solution may be 50 to 250 mPas, e.g. 240 mPas. Preferably higher viscosity polymer solutions are employed as they may contribute to producing microencapsulated product having higher encapsulation efficiency.
The active agent may be chosen from any of those active agents disclosed in U.S. Pat. No. 5,407,609. Preferably the process is used to encapsulate water soluble active agents, in particular peptides, proteins, cytokines, nucleic acids, or antibodies or viruses or parts thereof. Particularly preferred active agents are TGF-beta, Interleukins, e.g. IL-2, 3, 4, 6, 10 or 12 or, most preferably, hematopoetic growth factors, e.g. GM-CSF.
The primary emulsion may be formed by dissolving the polymer in the polymer solvent and dispersing active agent, optionally a solution of active agent, therein. Optionally the solution of polymer and the solution of the active agent may each be filtered, for example through a 0.2 micron filter before carrying out the dispersing step.
The dispersing step may be carried out using, e.g. conventional techniques and apparatus, for example turbines, static mixers, high pressure homogenisers, gear pumps or other homogenising systems using the rotor/stator principle. When, the microencapsulation process is to be carried out under aseptic conditions one may use any static mixer known in the art, however most preferred are gear pumps, e.g. an Ismatec MCP-Z gear pump.
The external phase may be formed by dissolving the surfactant and optionally any other excipients, e.g. buffers in an appropriate solvent having regard to the nature of polymer solvent. The solution thus formed may be filtered, e.g. through a 0.2 micron filter.
External phase and primary emulsion may be stored in separate tanks before mixing. Said tanks may each be equipped with pumps and flow regulating and metering equipment known in the art. Each tank may be equipped with connecting pipe work for accepting and carrying the flow of primary emulsion and external phase from their respective tanks and directing their respective flows into admixture before directing the mixture so formed onto means for dispersing the primary emulsion in the external phase (hereinafter referred to as
Ausborn Michael
Bodmer David
Marchal Laurent
Nagele Oskar
Novartis AG
Pfeiffer Hesna J.
Sanders Kriellion
Wissing William Kent
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