WO2003086610A2

WO2003086610A2 - Method for production of a stable suspension of particles in a liquid

Info

Publication number: WO2003086610A2
Application number: PCT/FR2003/001206
Authority: WO
Inventors: Michel Perrut; Jennifer Jung; Fabrice Leboeuf
Original assignee: Separex
Priority date: 2002-04-15
Filing date: 2003-04-15
Publication date: 2003-10-23
Also published as: FR2838356B1; WO2003086610A3; FR2838356A1; AU2003262134A1

Abstract

The invention relates to a method for production of a suspension of solid particles of at least one product. The method is characterised in comprising the following steps: dissolution of the product in a compressed fluid, expansion of said solution by decompression means with simultaneous atomisation of a liquid in which the product is insoluble or poorly soluble and collection of the particles thus formed in suspension in the liquid.

Description

PROCESS FOR OBTAINING A STABLE SUSPENSION OF PARTICLES IN A LIQUID

The present invention relates to a process for obtaining a suspension of solid particles of products, pure or in mixture.

It is known that many industries use solids in pulverulent form or in the form of a suspension in a liquid, and these powders are present either in the form of simple particles consisting of only one component, or in the form of complex particles consisting of an active ingredient dispersed within a suitable coating, ie a core of a certain material and a coating of another material. The pharmaceutical industry, but also the cosmetics and agrochemical industry, require new formulations in order to improve the effectiveness of certain molecules of therapeutic, dermatological or phytosanitary interest. Thus, we are looking for ways to increase the solubility in biological media of insoluble or very poorly soluble active ingredients, in order to improve their bioavailability, reduce the doses administered and therefore reduce the side effects of these products.

In addition, it is sometimes advantageous to obtain a controlled dissolution of products within tissues or biological fluids such as blood or lymph. To do this, use is preferably made of either widely dispersed forms of the active ingredients having a dissolution rate much faster than the usual powders, or a type of micro-capsules or nano-capsules known as having a matrix structure, (sometimes called micro- spheres or nanospheres), which consist of a mixture as homogeneous as possible of the particles of active ingredient within an excipient. Ideally, the active ingredient is dissolved within the excipient. We are also looking for formulations suitable for new forms of administration of the active ingredients, particularly substitutes for injections by injections, preferably oral or, in some cases, pulmonary administration forms by inhalation of a powder, the particles of which must have well-defined characteristics allowing them to reach the pulmonary alveoli.

Among the most interesting methods for carrying out such a pulmonary administration, it will be noted in particular the spraying of a suspension of very fine particles in an aqueous medium. The use of such a suspension also makes it possible to avoid the collection and handling of very fine particles, which always constitutes an extremely difficult problem to solve on an industrial scale, especially with the constraints imposed in the pharmaceutical industry. .

It is known in the prior art that compressed fluids, and particularly supercritical carbon dioxide, make it possible to produce very fine powders, usable by ingestion through the respiratory tract. Compressed or supercritical fluids are also known to promote the production of complex particles consisting of the mixture of different morphologies of the active principle and of an excipient, such as micro-spheres or micro-capsules. We will first recall the different states of a fluid and its properties in each of these states. We know that bodies are generally known in three states, namely solid, liquid or gas and that we pass from one to the other by varying the temperature and / or the pressure. Besides the solid state, there is the liquid state and the gaseous state which are separated by the vaporization / condensation curve, and there is a point beyond which one can pass from the liquid state to the gaseous state. without going through a boil or, conversely, through a condensation, and this continuously: this point is called the critical point PC. The supercritical state is characterized either by a pressure and a temperature respectively higher than the pressure and the critical temperature in the case of a pure body, or by a representative point (pressure, temperature) located beyond the envelope critical points represented on a diagram (pressure, temperature) in the case of a mixture. It therefore has, for a very large number of substances, a high solvent power which is incommensurate with that observed in this same fluid in the state of compressed gas. The same is true of so-called "sub-critical" liquids, that is to say liquids which are in a state characterized either by a pressure greater than the critical pressure and by a temperature below the critical temperature in the case of a pure body, either by a pressure higher than the critical pressures and a temperature lower than the critical temperatures of the components in the case of a mixture (see on this subject the article of Michel PERRUT - The Techniques of the Engineer “ Extraction by supercritical fluid, J 2 770 - 1 to 12, 1999 ”). Variations significant and modular solvent power of supercritical fluids are also used in many extraction processes (solid / fluid), fractionation (liquid / fluid), analytical or preparative chromatography, treatment of materials (ceramics, polymers, ...) and particle generation. Chemical or biochemical reactions are also carried out in such solvents.

Note that the physicochemical properties of carbon dioxide and its critical parameters (critical pressure: 7.4 MPa and critical temperature: 31 ° C) make it the preferred solvent in many applications, especially since it does not has no toxicity and is available at very low prices in very large quantities. Other fluids can also be used under similar conditions, such as nitrous oxide, light hydrocarbons having two to four carbon atoms, ethers and certain halogenated hydrocarbons.

It will also be noted that water is generally very poorly soluble in most fluids at supercritical pressure as well as in the liquefied gases conventionally used, in particular in carbon dioxide under high pressure in which the water is soluble. only at a rate of 1 to 3 g / kg between 25 and 50 ° C. In the remainder of this text, the term “compressed fluid” will mean any fluid brought to a pressure substantially higher than atmospheric pressure and a fluid brought to a pressure greater than its critical pressure will be called supercritical pressure fluid, ie either a supercritical fluid proper, ie a liquid called subcritical as defined above. Of similarly, liquid gas will be called a liquid, consisting of a compound which is in the gaseous state at atmospheric pressure and at ambient temperature, brought to a pressure and to a temperature below its critical pressure and its critical temperature respectively.

From dozens of scientific and patent publications, as can be found in a recent publication by J. JUNG and M. PERRUT in The Journal of Supercritical Fluids, 20, 2001, p. 179 to 219, we know that we can obtain micro-particles, with a particle size generally between 1 and 10 μm, and nanoparticles with a particle size generally between 0.1 and 1 μm, using processes using supercritical fluids, such as the process known by the acronym RESS, described for example in patent US-A-4, 582, 731, consisting in very quickly relaxing a solution of a product at low pressure atomize in a compressed fluid, or the anti-solvent process known by different acronyms SAS, SEDS, PCA, ASES, and consisting in spraying a solution of the product to be atomized in an organic or aqueous solvent within a stream of fluid in supercritical state, described for example in patents US-A-5, 707, 634, EP-A-0 322 687 and US-A-5,043,280. Likewise, several processes aimed at generating microspheres according to the anti-solvent principle, or microcapsules using a fluid at supercritical pressure, a compressed gas or a liquefied gas, have been described in the patents and patent applications EP- A-0 322 687, WO- 95/01221, O-96/00610, EP-A-0 706 821, FR-2 753 639, FR-00. 000185, EP-A-0 744 992, WO-98/15348 and FR00.13393. The patents EP-A-0 322 687 and US-A-5, 043, 280, describe a family of processes making it possible to prepare microspheres by bringing a liquid solution of the active ingredient and the excipient into contact with a supercritical fluid, applying, without naming it, the anti-solvent concept.

We know that the RESS process is only applicable to molecules soluble in the compressed fluid. Another method, described in patent EP-A-0 706 821 and in certain claims of patent application WO 98/15348, relies on the dissolution of the coating agent in the fluid at supercritical pressure. However, a person skilled in the art knows that the majority of the coatings used for forming microcapsules are insoluble in most such fluids, which considerably limits the practical scope of this process. A fortiori, the process described in several articles by the team of P. Debenedetti, (including for example: P. Debenedetti, J.. Tom, SD Yeo, GB Lim "Application of Supercritical Fluids for the Production of Sustained Delivery Devices ", Journal of Controlled Release, 24, 1993, 27-44), consisting in spraying a solution of the coating agent and of the active ingredient in the fluid at supercritical pressure, has even much more limited applications. However, recent patents and publications teach that the RESS process finds a more interesting field of application if the usual fluids at supercritical pressure, such as carbon dioxide or light hydrocarbons, are not used, but a fluid having significantly greater solvent power vis-à-vis polar molecules. It is notably the case of dimethyl ether as it has been described in several patents including American patent application No. US20010000143, or PCT patent application WO 99/52504 and American patent US-A-6, 299, 906. The diethyl ether has also been described as a solvent for inorganic products in an application similar to the RESS process intended for the projection of thin films. These two compounds and other ethers or derived products also having properties similar to these two compounds, can be used in the process which is the subject of the present invention, although their highly flammable nature requires reinforced safety measures.

However, one of the problems linked to the very concept of the RESS process appreciably limits the field of application of the process, even and above all when a solvent is used in the form of a liquefied gas: The sudden decompression of the solution leads to significant cooling of the fluid and the formation of a two-phase medium with droplets of liquid within a gas phase, which prevents the formation of fine particles of regular particle size and often leads to the formation of films and deposits on the walls of the chamber spray. According to the prior art, the enthalpy of vaporization of the fluid must be provided by heating the solution before its decompression to temperatures such that the transition to the gaseous state of the decompressed fluid is complete without the formation of liquid droplets, this which is incompatible with the use of thermosensitive molecules which will be irreversibly altered by such heating. Also known from PCT application No. W0 97/14407 and from US Pat. No. 6,177,103 is a process in which the solution of an active principle in a compressed fluid is decompressed within a liquid phase aqueous comprising a surfactant.

One of the aims of the present invention is to propose a new process for obtaining a suspension consisting of very fine particles or micro-capsules / nano-capsules with matrix structure, with a diameter generally less than 20 μm, and often less than 1 μm, which are suspended in a liquid, and preferably in an aqueous medium, in which they are insoluble or very slightly soluble.

The present invention thus relates to a process for obtaining a suspension of solid particles of at least one product, characterized in that it comprises the steps consisting in: dissolving the product in a compressed fluid , expand this solution by means of decompression through which is sprayed, simultaneously, a liquid in which the product is insoluble or very poorly soluble, and collect the particles thus formed in suspension in the liquid.

According to the invention, the product to be sprayed is dissolved in a compressed fluid according to the techniques usually used by those skilled in the art, the compressed fluid being defined as it was said previously, that is to say under the form of a liquefied gas, a subcritical liquid or a supercritical fluid, chosen its solvent power vis-à-vis the product or the mixture used. This solution is then expanded through a device with a high pressure drop, for example a nozzle. spraying, to a spraying chamber maintained at a pressure much lower than that at which the dissolution took place. The fluid is then found in gaseous form, which causes a very strong decrease in its solvent power, and, consequently, the supersaturation of this fluid in solute and therefore the precipitation of this solute in the form of very fine particles.

According to the invention, and unlike the techniques used in the prior state of the art in which the operations described above are implemented, a liquid is also injected, via this same decompression device, in which the fluid and the solute are not soluble or are very slightly soluble under the conditions prevailing in the atomization chamber. The fluid which has become gaseous will therefore carry droplets of this liquid which will collect the solute particles generated during the decompression of the solution, which particles will find themselves dispersed within the liquid when it is separated from the gaseous fluid by any device usually used for such a separation, such as for example a gravity separator possibly provided with baffles, or, preferably, one or more cyclonic separators. It is understood that the difficulties of collecting very fine particles conveyed by a gaseous fluid have thus been avoided, as has been described in several patents proposing different solutions to this problem, such as in particular the French patents FR-A -2 802 445, FR-A-2 803 538, and FR-A-2 803 539. In addition, in a particularly advantageous variant, the liquid injected at the same time as the solution of the product or of the mixture to be atomized in the compressed fluid, will be previously heated to a sufficient temperature so that it thus provides the enthalpy required for vaporization. full of fluid upon decompression. This is particularly important when it is known that the conventional implementation of the RESS process requires intense prior heating of the solution in the compressed fluid, so that this fluid is completely vaporized after its decompression, otherwise droplets of this fluid would form. , ruining the formation of very fine particles. Such a problem is moreover particularly acute when the compressed fluid is a liquefied gas, such as for example dimethyl ether, the solution then having to be heated to more than 100 ° C. before spraying. However, many products are not compatible with such a treatment and are irreversibly altered by such heating which can therefore, according to the invention, be avoided.

According to a variant of the invention, the product to be sprayed can consist of a mixture of which, in certain particularly favorable cases, at least one of the constituents is a surfactant, which will contribute to ensuring the stability of the suspension of particles, generated during decompression, within this liquid. According to another particularly advantageous variant of the invention, the liquid used is a mixture containing at least one surfactant which will contribute to ensuring the stability of the suspension of the particles, generated during decompression, within this liquid. To this end, numerous surfactants can be used, from which one or those which are best suited to the suspension in question will be chosen, according to the rules known to those skilled in the art. According to another variant of the invention, the products to be sprayed consist of a mixture of active principles and of a coating agent consisting of a lipid or of a mixture of lipids, of a polymer or of a mixture of polymers, conventionally used in the pharmaceutical or cosmetic industries, so that the micro-capsules in suspension thus obtained are directly usable in presentations for therapeutic, cosmetic, veterinary or phytosanitary use.

According to a particularly advantageous implementation variant of the invention, solutions of each of the constituents are firstly produced in the compressed fluid, by percolation through several extraction autoclaves in which each of the constituents are arranged individually, then these solutions are mixed just before spraying, so as to obtain particles consisting of the mixture of constituents with a given composition.

In another embodiment of the invention, stable suspensions of particles are thus produced, more particularly intended for preparations for therapeutic use, and this in human or veterinary, cosmetic or phytosanitary pharmacy, these suspensions being able to be produced either in a medium aqueous, or in a non-aqueous organic medium, according to the needs and properties of the compounds constituting the particles to be kept in suspension. The powders obtained according to the invention have been found to be particularly effective for obtaining pharmaceutical formulations intended for inhalation, insofar as the droplets generated by a nebulization device transport these fine powders to the bottom of the pulmonary alveoli.

Surprisingly, unlike what is described in the prior art, the present invention allows the use of a wide variety of active agents and excipients, in particular, due to the fact that it it is not necessary to heat the solution in the compressed fluid prior to its decompression, the enthalpy required to bring the fluid to the gaseous state completely is largely provided by the sprayed liquid at the same time as the solution . In addition, the particles can be easily obtained in a sterile manner, provided that the liquid on the one hand and the product to be sprayed on the other are themselves sterile and that the recovery of the particles is carried out according to the usual rules of sterility. , the process itself being intrinsically sterile and in no way increasing the biological load of the products used. It will even be noted that, as widely described in the past, pressurized carbon dioxide and ethers are biocides, which can only, when used according to the present invention, facilitate the sterility of the operation, or even accidentally destroy microorganisms present in products.

According to the invention, it is possible in particular to use as compressed fluid, in addition to carbon dioxide, nitrous oxide, dimethyl ether, diethyl ether, or dimethoxymethane or also a hydrocarbon having between 2 and 10 carbon atoms, preferably between 2 and 5 carbon atoms. The compressed fluid may also consist of a mixture of these different elements. The liquid will preferably consist of an aqueous or organic medium.

According to the invention, it is also possible to use several autoclaves in parallel in which will be disposed different products making it possible to mix the solutions of these different products in the compressed fluid before spraying, so as to obtain particles of a given composition in each of these compounds.

The present invention also relates to a suspension of submicron particles characterized in that it is generated by a process according to the invention.

An embodiment of the present invention will be described below, by way of non-limiting example, with reference to the appended drawing in which: FIG. 1 is a schematic view of an installation making it possible to implement the method according to the invention.

Figure 2 is a schematic view in longitudinal section of a first embodiment of a spray nozzle used in the method according to the invention.

Figure 3 is a schematic view in longitudinal section of a second embodiment of a spray nozzle used in the method according to the invention. On the schematic installation shown in FIG. 1, a stream of compressed fluid from a reserve 1 is sent, by a pump 2 and a heat exchanger 3, which will bring it to the desired pressure and temperature, to a extraction autoclave 4 where a basket 6 containing an active agent is placed 5. The solution thus produced is decompressed in a decompression device 7 within an atomization chamber 8 which is maintained at a pressure much lower than that prevailing in the extraction autoclave 4, thus causing the precipitation of the active agent 5, in the form of particles. Is injected simultaneously, by the decompression device 7, a liquid supplied from a reservoir 16 by a pump 14 and passing through an exchanger 15 which will bring it to the desired pressure and temperature. The liquid droplets and the particles of active agent, possibly formed, are entrained by the current of the decompressed fluid and can thus be collected in cyclonic separators 11 and 12 and collected in the form of a liquid suspension at 10. The compressed gas freed of this liquid phase is then recycled or discharged at 13 into the atmosphere.

The autoclave 4, the atomization chamber 8, as well as the cyclonic separators 11 and 12 are provided with double envelopes in which a heat transfer fluid circulates allowing them to be maintained at the desired temperatures.

According to the invention, all or part of the liquid suspension thus collected can also be recycled by the pump 14 and the exchanger 15, particularly in the case where it is desired to obtain a suspension having a high concentration of solid particles.

According to a particularly advantageous variant of the invention, and as shown in FIG. 2, the pressure relief device consists of a spray nozzle 7 ', which is formed of two cylindrical and concentric tubes, namely an inner tube 20 and an outer tube 21 which ends in a convergent 19. The inner tube 20 is traversed by the solution of the product in the compressed fluid and the outer tube 21 by the liquid, so that the spraying of these two phases is carried out simultaneously with the benefit of the mechanical action linked to the brutal expansion of the compressed fluid within the liquid itself, as well as the addition of enthalpy by the liquid to allow the complete passage of the compressed fluid in the gaseous state.

According to another equally advantageous embodiment of the invention, a pressure relief device is used which consists of a spray nozzle 7 '' of different design, as shown diagrammatically in FIG. 3.

This nozzle 7 '' consists of an enclosure 22 in the center of which is provided a mixing chamber 23 into which opens a first line 24 for supplying the product in solution in the compressed fluid and a second line 25 for supplying liquid. An outlet 26 connects the mixing chamber 23 with the spraying chamber 8. Under these conditions, the solution and the liquid are brought into contact in the chamber 23 just before their injection into the atomization chamber 8 by the orifice 26. As it was in the previous embodiment, the spraying of these two phases is carried out simultaneously with the benefit of the mechanical action linked to the sudden expansion of the compressed fluid within the liquid itself, as well as the enthalpy contribution by the liquid to allow the complete passage of the compressed fluid in the gaseous state.

EXAMPLE OF IMPLEMENTATION In the example of implementation of the invention described below, equipment of pilot size was used in accordance with the principle diagram previously described with reference to FIG. 1. We used, in as a compressed fluid, dimethyl ether, at an operating pressure of 30 MPa and a temperature range capable of going from 0 to 120 ° C. The extraction autoclave 4 and the atomization chamber 8 had respective volumes of one and eight liters. The separators 11 and 12 consisted of cyclonic chambers with a volume of 200 ml. The atomization chamber 8 was provided with a nozzle 7 '', of the type shown in FIG. 3, and had two supply lines, namely a supply line 24 for the product in solution and a line 25 liquid supply, with diameters of 0.2 mm and 1 mm respectively, the mixing chamber 23 had a volume of 1 ml and its outlet orifice had a diameter of 0.2 mm. In such a device, 100 g of budenoside added with 2 g of a polysorbate type surfactant (Tween-80) were introduced into the extraction autoclave 4, and percolated through this autoclave of dimethyl ether with a flow rate of 2 kg / h at a temperature of 80 ° C and under a pressure of 5 Mpa. As shown in Figure 1, the solution of budenoside in dimethyl ether was brought through line 24 of nozzle 7 '' and, simultaneously, water at 90 ° C was fed at a rate of 2 kg / h through line 25. The two fluids mixed in the chamber of mixture 23 before relaxing through the orifice 26 in the atomization chamber 8. The latter as well as the cyclonic separators 11 and 12 were heated by a heat transfer fluid brought to 60 ° C and placed in direct communication with a vent line opening into the atmosphere. After half an hour of stabilized operation under these conditions, a liter of suspension was collected. After final degassing under vacuum for four hours, this suspension had a slightly grayish appearance and was perfectly stable. The Tyndall effect observed by lighting the bottle with a red laser beam demonstrated the presence of submicron particles. An aliquot of the suspension was analyzed by HPLC after complete re-dissolution in dichloromethane and led to a budesonide concentration of 9 g per liter. A measurement of the diameters of particles by laser granulometry was carried out at 24 h, then at 8 days, and finally at 30 days after the collection and it was found that the average diameter of 0.14 μm of the particles had not significantly varied over time.

Claims

1.- Method for obtaining a suspension of solid particles of at least one product, characterized in that it comprises the stages consisting in:

- dissolving the product in a compressed fluid, expanding this solution by means of decompression through which is sprayed simultaneously, a liquid in which the product is insoluble or very slightly soluble,

- Collect the particles thus formed in suspension in the liquid.

2.- Method according to claim 1, characterized in that the compressed fluid is carbon dioxide.

3.- Method according to claim 1, characterized in that the compressed fluid is chosen from the following elements: nitrous oxide, dimethyl ether, diethyl ether, dimethoxymethane.

4.- Method according to claim 1, characterized in that the compressed fluid is a hydrocarbon having between 2 and 10 carbon atoms, preferably between 2 and 5 carbon atoms.

5.- Method according to claim 1, characterized in that the compressed fluid consists of a mixture comprising at least two compounds chosen from carbon dioxide, nitrous oxide, dimethyl ether, diethyl ether, dimethoxymethane and a hydrocarbon having between 2 and 10 carbon atoms, preferably between 2 and 5 carbon atoms.

6.- Method according to one of the preceding claims characterized in that the liquid is an aqueous medium.

7.- Method according to one of claims 1 to 5, characterized in that the liquid is an organic medium.

8.- Method according to any one of the preceding claims, characterized in that the product to be sprayed consists of at least one active principle or of a formulation comprising at least one active principle of food, pharmaceutical, cosmetic interest, agrochemical or veterinary.

9.- Method according to any one of the preceding claims, characterized in that the product to be sprayed consists of a mixture of at least one active principle and of a coating agent consisting of at least one lipid, and / or at least one polymer, of the type used in the pharmaceutical, cosmetic, veterinary or phytosanitary industries.

10.- Method according to any one of the preceding claims, characterized in that the product to be sprayed and / or the liquid are added with a surfactant of the type capable of stabilizing the suspension of particles in the liquid.

11.- Method according to any one of the preceding claims, characterized in that several autoclaves are used in parallel in which are disposed different products making it possible to mix the solutions of these different products in the compressed fluid before spraying, so to obtain particles of a given composition in each of these compounds.

12.- Suspension of sub-micron particles characterized in that it is generated by a process according to any one of the preceding claims.