Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-10-15
2004-08-17
Kishore, Collamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S491000
Reexamination Certificate
active
06777002
ABSTRACT:
The present invention relates to a process for the preparation of microparticles comprising a water-soluble substance in a biodegradable polymer.
Many different methods of preparation of microspheres are described in the literature (Herrmann et al., European Journal of Pharmaceutics and Biopharmaceutics 45 (1998) 75-82). The methods presently used for the preparation of microspheres from hydrophobic polymers are organic phase separation and solvent removal techniques.
The solvent removal techniques can be divided into solvent evaporation, solvent extraction, spray drying and supercritical fluid technology. In solvent evaporation or solvent extraction techniques, a drug containing organic polymer solution is emulsified into an aqueous or another organic solution. The drug is dissolved, dispersed or emulsified in the inner organic polymer solution.
These solvent removal techniques for production of microspheres by evaporation or extraction necessitate the step of preparing a stable emulsion of organic droplets before solvent removal. The size and characteristics of the final microspheres depend on this step during which a stable emulsion in the presence of the solvent is a prerequisite. The proportions of organic solvent and aqueous phase in the solvent removal methods are carefully maintained so as to control the solvent migration in the aqueous phase. Below a certain ratio organic solvent/aqueous phase, the formation of droplets is not possible any more (see H. Sah, “Microencapsulation techniques using ethyl acetate as a dispersed solvent: effects of its extraction rate on the characteristics of PLGA microspheres,” Journal of controlled release, 47 (3) 1997, 233-245). In some methods, solvent is even added to the aqueous phase in order to saturate it and to prevent the solvent migration during the formation of the primary emulsion.
Several related patents and published applications describe various aspects of these processes.
EP 0 052 105 B2 (Syntex) describes a microcapsule prepared by the phase separation technique using a coacervation agent such as mineral oils and vegetable oils.
EP 0 145 240 B1 (Takeda) discloses a method for encapsulating a water soluble compound by thickening the inner phase of a W/O emulsion, building a W/O/W and subjecting the emulsion to an “in water drying” process. This method brings different drawbacks such as: the necessity of using a thickening agent to retain the drug, and the multi-step procedure including two emulsification steps and the “in water drying” step.
EP 0 190 833 B1 (Takeda) describes a method for encapsulating a water soluble drug in microcapsules by increasing the viscosity of a primary W/O emulsion to 150-5,000 cp (by the procedure of increasing the polymer concentration in the organic phase or by adjusting the temperatures) prior to formation of a second W/O/W emulsion which is then subjected to “in water drying”. The drawbacks of this procedure are the complexity of the necessary steps, including formation of two emulsions (W/O and W/O/W) one after the other, and the step of “in-water drying”.
U.S. Pat. No. 5,407,609 (Tice/SRI) describes a microencapsulation process for highly water soluble agents. This process involves the distinct steps of forming a primary O/W emulsion, the external aqueous phase being preferably saturated with polymer solvent. This O/W emulsion is then poured to a large volume of extraction medium in order to extract immediately the solvent. The drawback of this method is that the O/W emulsion is formed in the presence of the organic solvent in a small volume. The solvent is subsequently removed by extraction in a large aqueous volume. The polymeric droplets are prevented to harden in the primary emulsion, allowing the migration of the drug into the external phase.
WO 95/11008 (Genentech) describes a method for the encapsulation of adjuvants into microspheres. The process comprises the three distinct steps of preparing a primary W/O emulsion, followed by the production of a W/O/W and finally the hardening of the microspheres by extraction of the solvent. As already mentioned above, the drawback of such a method is the complication due to a multi-step procedure separating droplet production from solvent elimination.
EP 0 779 072 A1 (Takeda) describes an “in-water drying” method used for the removal of solvent after production of a W/O/W or a O/W emulsion. It is mentioned that the O/W method is preferable for active substances insoluble or sparingly soluble in water.
It is an object of the present invention to provide with a new process for the preparation of microparticles comprising water soluble biologically active substances.
It is still further an object of the present invention to provide with a new process for the preparation of microparticles of high encapsulating efficiency comprising water soluble biologically active substances.
It is further an object of the present invention to provide with a process which allows for a reduction of time of exposure of water soluble active substances to external water phase in the production of microparticles.
It is further an object of the present invention to avoid the formation of specific emulsions, and the problems they have caused as described in the prior art in the production of microparticles comprising water soluble active substances.
To these effects, the present invention relates to a process for the preparation of microparticles with an extremely high encapsulation rate thanks to the optimal reduction of diffusion for the substance to be encapsulated.
More precisely, the present invention relates to a process for the preparation of microparticles comprising at least one water-soluble substance in at least one biodegradable polymer, said water-soluble substance and said biodegradable polymer being first incorporated in an organic liquid phase comprising at least one organic non-water miscible solvent, said organic phase being then poured into an aqueous liquid phase having a volume which is sufficient to dissolve said organic solvent, said aqueous phase containing a surfactant, the resulting organic-aqueous phase being homogenised in order to perform in one single step the microparticle formation and the organic solvent removal.
The methods available up to now for encapsulating certain compounds and agents, and particularly, water soluble compounds and agents, were not efficient enough for encapsulating water soluble biologically active substances due to the high affinity that water soluble biologically active substances have with the aqueous phase.
The present invention has found a solution to this problem by reducing the time required for encapsulating water soluble biologically actives substances, and therefore avoiding the problem of formation of the primary emulsion and solvent removal steps which were far too long and allowed the migration of the water soluble biologically active substances into the external aqueous phase.
The microparticle formation and their hardening is performed in one single step. After homogenisation, the dispersion is directly filtered. The particles are then harvested and optionally lyophilised.
Using the process of the present invention offers the advantage of providing an encapsulation efficiency greater than 50% or 80%.
Furthermore, in the process of the present invention, it has been surprisingly found that it is possible to obtain microparticles with an extremely high encapsulation efficiency of water soluble active substances using a new one step O/W or W/O/W homogenisation process.
One of the specific features in the process of the present invention is characterised by the fact that no stable primary emulsion comprising organic solvent droplets occurs. Avoiding such a step results in a better retention of the water-soluble substance.
Furthermore, because of the almost instantaneous lack of organic solvent when the polymer precipitates and captures the water-soluble substance, no further emulsion stage is observed. The microparticles can thus be directly harvested after their formation.
Because the microparticle fo
Orsolini Piero
Vuaridel Evelyne
Debio Recherche Pharmaceutique S.A.
Ghali Isis
Kishore Collamudi S.
Nixon & Vanderhye P.C.
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