Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-06-22
2001-02-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S401000, C424S059000
Reexamination Certificate
active
06183783
ABSTRACT:
The invention relates to the field of the microencapsulation of active substances. It relates to a process for preparing microcapsules of the type comprising an active substance coated with a layer of polymer by the so-called supercritical fluid technique.
It also relates to novel microcapsules comprising in particular pharmaceutical or cosmetic substances or processed foodstuffs.
A great many documents describe the principles and the methods for preparing such microcapsules, for example J. A. Bakan, Microencapsulation via Coacervation—Phase Separation, National Industrial Research Conference, Land O'lakes, Wis., June 1966. Other publications are cited in the article by J. P. Benoit et al., Microencapsulation Methods and Industrial Applications, Marcel Dekker, Inc. 1996, pages 35-72.
The size of the microcapsules obtained is of the order of 0.5 to 200 &mgr;m (sometimes more). They are composed of a nucleus of active material covered with a coating agent.
The coating agent is chosen from a range of various compounds (hydrocolloids, hydrophobic polymers, waxes, fats or enteric agents, and the like) according to various factors:
the goals targeted by the microencapsulation: for example, to mask the taste or the smell of the active principle per os, to decrease the volatility of certain liquids, to increase the physicochemical stability of the active principle, to prevent the coalescence of the droplets within an emulsion, to modify and improve the compression of the active principle, to delay or prolong the action of a medicament, to have an enteric-coated pharmaceutical dosage form, and the like,
the desired method of release of the active principle (dissolution, diffusion, and the like),
the physicochemical nature of the nucleus (size, compatibility, and the like),
the microencapsulation methods (fluidization, turbine, desiccation by nebulization, interfacial polymerization, coacervation, and the like).
The preparation of microcapsules is commonly carried out by the so-called coacervation method, which will be briefly restated below:
Chemical or physicochemical modification of a medium comprising an active substance in suspension in a solution of polymer in a solvent causes the coacervation (or aggregation) of the polymer.
The coacervate droplets thus formed are adsorbed at the surface of the particles of active material and form a continuous coating.
The medium is subsequently subjected to complete desolvation and optionally to crosslinking of the polymeric chains, which results in the production of microcapsules.
All these abovementioned methods very often require toxic and polluting organic solvents with a relatively high industrial cost.
For this reason, the Applicant Company has for several years attempted to search for alternative methods which make it possible to prepare microcapsules without the aid of organic solvents or at least without chlorinated solvents (dichloromethane, chloroform, and the like).
Thus it is that the Applicant Company has recently provided, by Patent Application EP-A-706,821, the use of the properties of CO
2
in the supercritical (SC) state as solvent.
CO
2
is said to be in the supercritical state (SC CO
2
) if the temperature is greater than 31° C. and its pressure is greater than 73.8×10
5
Pa.
This is because the latter simultaneously retains the properties of a gas, such as its high diffusion, and acquires those of a liquid, such as its relative density, which is 0.7 kg/cm
3
at the supercritical point. CO
2
in this state has a significant solvating power. It is said to be similar to heptane.
The advantages of SC CO
2
are therefore:
a high solvating power for fairly low temperature conditions (30° C.), which is not without advantage in the case of the use of thermolabile active principles;
a high variation in this solvating power for low variations in pressure,
its non-toxic nature,
the ready separation of the solvent-solute mixture by simple decompression;
its low cost in comparison with the current organic solvents.
The method according to the abovementioned patent application involves suspending, in an autoclave, an active substance which is insoluble in supercritical CO
2
and then introducing the coating agent into the autoclave, which coating agent is found in the solute state in supercritical CO
2
. The pressure and/or the temperature are subsequently modified, so that the solubility of the coating agent in CO
02
decreases. The affinity of the coating agent for the surface of the active substance increases, for this reason causing the adsorption of the coating agent around the particles of active substance. Once deposition is accomplished, the autoclave is depressurized and the microcapsules are recovered. This method gives excellent results for coating agents which exhibit a good solubility in CO
2
, that is to say for coating agents which have a marked lipophilic nature and low molar masses, such as fatty substances (waxes, fatty alcohol triglycerides, fatty acids) and many other compounds.
However, in the case of polymers which exhibit a substantially more polar nature than fatty substances and a higher molar mass (acrylic polymers, vinyl polymers, polysaccharides), this method is not very satisfactory.
This is because these polymers are not soluble in supercritical CO
2
. Now this is an essential condition in order to be a coating agent according to the method disclosed in Patent Application EP-A-706,821. The use was indeed envisaged, in this patent application, of a low level (<5%) of an entraining agent, such as ketones, alcohols, esters and chlorinated solvents, as a mixture with CO
2
with the aim of increasing the solubility of the polymer in the supercritical phase. However, such an alternative form would nevertheless result, in many cases, in a low degree of solubilization of the polymer with a substantially polar nature and in a significant modification of the supercritical conditions, or in a disappearance of the supercritical phase, replaced by a two-phase system.
Furthermore, mention is made of the document U.S. Pat. No. 5,424,076, which discloses a method based on an atomization or spray-drying technique in the presence of supercritical fluid.
Firstly, although the document mentions the fact that the active substance is in dispersed form, all the examples relate to solutions of these active materials. Furthermore, this method results in the production of microspheres and not of microcapsules. The fundamental difference between microspheres and microparticles should be remembered. Microspheres are matrix systems in which the active material is homogeneously dispersed. Microcapsules are composed of a nucleus of active material coated with a layer of polymer.
Document EP-A-542,314 relates to a method for preparing particles of active material without coating with polymer by precipitation by virtue of an anti-solvent fluid in the supercritical state.
The object of the present invention is therefore firstly to provide a novel method involving a supercritical fluid which makes it possible to obtain microcapsules for which the coating agent is a polymer with a substantially polar nature.
Another object of the present invention is to provide novel microcapsules which are distinguished in particular from those which have been described above by their physical characteristics and by the absence of residual solvent in the coating layer.
The invention therefore firstly relates to a method for preparing microcapsules comprising an active substance coated with a layer of polar polymer, characterized in that it comprises the following stages:
suspending an active substance in a solution of substantially polar polymer in an organic solvent, the active substance being insoluble in this solvent,
the said substantially polar polymer being insoluble in liquid CO
2
or CO
2
in the supercritical state,
the said organic solvent being soluble in liquid CO
2
or supercritical CO
2
,
bringing the suspension into contact with liquid CO
2
or supercritical CO
2
, so as to desolvate in a controlled way the substantially polar po
Benoit Jean-Pierre
Richard Joel
Thies Curt
Jacobson, Price, Holman & Spern, PLLC
Mainlab
McQueeney P. E.
Page Thurman K.
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