Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-10-25
2004-04-06
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S489000, C424S493000, C424S495000, C424S497000
Reexamination Certificate
active
06716456
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of microcapsule production by coaceravation phase separation.
PRIOR ART
Coacervation is phenomenon consisting of the salting out of macromolecules into liquid-like colloidal droplets rather than solid or gel aggregates. The separation of a polymer-rich liquid phase occurs via the action of one or more inducers, such as the variation of the temperature, or the addition of salts, non-solvents or incompatible compounds.
Liquid droplets or solid particles are suspended in the microencapsulation medium (water or organic solvent) where they are insoluble. The coacervates are able to surround and preferably uniformly engulf the particles with a fluid film of polymer.
The fluid polymeric film may be solidified (solid or gel phase) and hardened by an appropriate method, such as temperature or pH variation, or chemical reaction. The microcapsules may be separated by settling or filtration, and then washed, filtered and dried.
Microencapsulation by coacervation is an effective coating technology for taste masking, sustained/controlled release and avoiding gastric irritation of drugs as well as for the technological and stability improvement of the product, e.g. separation of incompatible substances, improved stability, increased flowability and conversion of liquid substances into a free-flowing powder (M. Calanchi and S. Ghanta; Taste-masking of oral formulations, Pharmaceutical Manufacturing International, 139-141 (1996)).
The microcapsules may be formulated into a variety of final dosage forms including tablets (eg chewable, dispersible, fast dissolving, effervescent), hard gelatin capsules and permanent or temporary suspensions (eg granulates, dry mono-dose sachets; M. Calanchi, S. Ghanta, supra).
Microencapsulation uses either organic solvents or aqueous media for drugs insoluble in organic solvents or water, respectively. In general, the process can generate microcapsules in sizes from less than one micron to over one millimeter. Various processes have attempted in the prior art to produce microcapsules in an aqueous system. For example, EPO 0212751A, discloses microencapsulation by dissolving a coating agent in water by salification, dispersing the medicament particles first in water, then in the solution of salified coating agent to form a suspension, and adding an acidifying agent thereof to precipitate the coating agent onto the particles of medicament and recovering the microcapsules thus formed.
U.S. Pat. No. 4,460,563 (Calanchi), relates to a process for preparing microcapsules in a liquid vehicle, preferably an aqueous medium, where the formation of a coacervate is obtained by adding a substance to cause phase separation. The present invention relates to the preparation of microcapsules of water insoluble, or sparingly water soluble, compounds in a buffered aqueous solution at high buffer ionic strength (high buffer concentration or capacity), by coacervation phase separation of a ionic polymer (polyelectrolyte) previously dissolved in the water solution as its salified form. The coacervate formation is induced by the addition of a substance which can bind the water forming an aqueous complex and cause the phase separation. The Hofmeister (lyotropic) salts are a particular class of substances which form water complexes and cause phase separation. The Hofmeister effect and the behaviour of water at interfaces is described in Quarterly Review of Biophysics 18 (4), 323-422, 1985.
In EP 02120751/A3 and WO 85/00105, the phase separation or precipitation of an engulfing polymer is induced by the pH change of the system. Moreover, the presence of only an acid organic compound is described in WO 85/00105.
Using the process described in U.S. Pat. No. 4,460,563, it has been found that the pH of the water solution (deionized water or sodium bicarbonate solution) changes when the solution is in contact with the air or when a weakly acid or alkaline compound is suspended in the solution. In the first case, the rate and extent of the pH change increased when the solution was stirred.
In fact, carbon dioxide is normally formed in suitable conditions of pH from a sodium bicarbonate solution. Carbon dioxide can easily evaporate resulting in a pH change of the solution. Moreover, the addition of an acid or alkaline compound, sparingly soluble in water, shifts easily the initial pH of the bicarbonate solution, since the buffering characteristics and capacity of sodium bicarbonate are scarce. From these considerations, sodium bicarbonate can be classified as an “unstable” buffer.
Difficulties have been experienced in controlling pH during the dissolution of a coating polymer into a bicarbonate solution, and a drastic change of pH (more than 2 units) has been observed after the addition of a weakly acid or alkaline compound, sparingly soluble in an aqueous solution.
SUMMARY
The present invention relates to a process for preparing microcapsules in an aqueous vehicle. The microcapsules consist of a core of water insoluble or sparingly soluble drugs and a membrane of a chargeable polymer (polyelectrolyte), soluble in the aqueous vehicle, enclosing the core. The microcapsules may vary in size from a few microns to hundreds or thousands microns. The aqueous vehicle comprises a stable buffer solution having high buffering capacity and ionic strength.
DETAILED DESCRIPTION OF THE INVENTION
The present invention uses “stable buffers” (such as phosphate, citrate, tartrate or acetate buffers) which do not generate gaseous substances, and at the same time increases the buffer capacity, so as to increase the buffer ionic strength which is defined as:
I
=½*&Sgr;(
c
i
*z
i
2
)
where I is the ionic strength, c
i
and z
i
are the molar concentration and charge of each ion species, respectively.
It has now surprisingly been found that by increasing the ionic strength of the buffer solution the amount of the phase separation inducing agent (lyotropic salt or water-complexing compound) required to effect coacervation phase separation can be reduced.
Using a stable buffer with a high ionic strength allows to:
1. reduce the amount of coacervation inducing agent necessary to effect the polymeric phase separation (coacervation).
2. Reduce the time (“stability window”) necessary for the liquid-like colloidal polymeric phase to engulf the solid particles.
The combined effects 1. and 2. allow to increase substantially the efficiency microencapsulation process, i.e. the microencapsulation yield.
Phase separation may be divided into different stages, each of them characterized by a typical appearance, Theological behaviour and phase volume. Only when a stable dispersion of well defined coacervate droplets with a suitable viscosity is formed is the drug surrounded and engulfed by the polymeric film. The behaviour and the stability of coacervate droplets in this stage are the most critical point for the successive transfer of the drug-coacervate dispersion into the hardening phase and the isolation of discrete microcapsules therefrom (C. Thomasin, H. P. Merkle, B. Gender. Drug microencapsulation by PLA/PLGA coacervation in the light of thermodynamics. 2. Parameters determining microsphere formation. J. Pharm. Sci. 87(3), 269-275 (1998)). This may be called the “stability window” for microencapsulation.
Outside the stability window, particle enwrapping does not occur because either the viscosity condition of the coacervate emulsion does not permit the drug enwrapping (lower induction limit) or aggregation and precipitation of polymer droplets occur (higher induction limit).
The kinetics of phase separation influences the engulfing of the solid particle in the “stability window”. In fact, the distribution of polymeric fluid film around the insoluble particles is more uniform at a slower phase separation rate. This results in the formation of single microcapsules having homogeneous physico-chemical characteristics (particle size distribution, film thickness and porosity): N. Nihant, C. Grandfils, R. Jerome, P. TeyssiË. Microencapsulation by coacer
Dobetti Luca
Mapelli Luigi Giovanni
Eurand International S.p.A.
Oh Simon J.
Spear James M.
Thompson Hine LLP
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