WO2002089851A1

WO2002089851A1 - Method for making host-client complexes

Info

Publication number: WO2002089851A1
Application number: PCT/FR2002/000798
Authority: WO
Inventors: Michel Perrut; Jennifer Jung; Fabrice Leboeuf; Isabelle Fabing
Original assignee: Separex (Societe Anonyme)
Priority date: 2001-03-06
Filing date: 2002-03-06
Publication date: 2002-11-14

Abstract

The invention concerns a method for making particles containing at least an active principle, said particles being formed by an assembly of molecular complexes each consisting of a molecule of active principle inserted in a host molecule. The method is characterised in that it comprises steps which consist in: placing in a pressurised chamber (1) at least an active principle and a host molecule powder, or a mixture thereof; introducing in said chamber (1) a fluid, consisting of a liquefied gas or a fluid at supercritical pressure, for a time interval sufficient for diffusing the active principle within the powder of the host molecule and for forming an active principle/host molecule complex, and in recovering the powder consisting of the active principle/host molecule complex.

Description

PROCESS FOR MANUFACTURING HOST-CUSTOMER COMPLEXES

The present invention relates to a process for the manufacture of particles consisting of at least one active principle inserted into a “host” molecule, in particular of the cyclodextrin type.

It is known that the pharmaceutical industry, but also the cosmetic industry and agrochemistry, require new formulations in order to improve the effectiveness of certain molecules of therapeutic, dermatological or phytosanitary interest. These industries are also looking for ways to increase the solubility in biological media of insoluble active ingredients, or very poorly soluble, in order to increase their bio-availability, reduce the doses administered and therefore reduce side effects. They also seek to avoid the loss of biological activity due to problems of instability in aqueous media or during storage in the presence of oxygen, air humidity or light. In order to solve these problems, it has been proposed to use different excipients, without however leading to satisfactory solutions.

Various methods have been proposed making it possible to manufacture particles consisting of an active principle which is inserted into a matrix, in order to protect it against various degradations, physical or chemical, or to facilitate its solubilization in aqueous solutions.

For several years now, new host molecules have been used which are capable of forming a complex molecular in which they enclose a molecule of an active principle. Cyclodextrin-type host molecules are thus known which are currently experiencing promising development in the pharmaceutical industry. These molecules, of natural origin, resulting from the enzymatic degradation of starch, are produced industrially and have the advantage of being biodegradable. Cyclodextrins are natural host molecules whose cyclic form allows them to "capture" a wide variety of solid, liquid or gaseous substances leading to the formation of "supermolecules".

Such “capture” of the active principles is generally used to modify the physicochemical properties of the molecules captured and in particular their solubility, their stability and their reactivity. In addition, many chemical groups (methyl-, hydroxypropyl-, carboxymethyl-, acetyl-, sulfobutylether-) can be grafted onto natural cyclodextrins by reaction with hydroxyl groups, modifying the interactions with trapped substances. The random position and type of substitution makes these so-called “modified” cyclodextrins amorphous, which contributes to greatly increasing their solubility in water and in organic solvents. Mention may thus be made of 1 hydroxypropyl-β-cyclodextrin which is very soluble in water (greater than 2000 g / l), while not being hygroscopic; it does not change the surface tension of the water where it is dissolved and it is also soluble in methanol and ethanol. In addition, it is recognized that this molecule can be used in oral, parenteral, nasal, transdermal, vaginal or rectal administration.

The present invention relates to a new process making it possible to carry out the insertion at the molecular level of an active principle, of interest in particular pharmaceutical, cosmetological, dietetic or phytosanitary, in a porous matrix consisting of a host molecule, in particular of cyclodextrin type or modified cyclodextrin, and to produce fine particles of this molecular complex, using a process using a fluid consisting either of a liquefied gas, or of a fluid at supercritical pressure.

It will be recalled first of all that the bodies are generally known under three states, namely solid, liquid or gas and that one passes from one to the other by varying the temperature and / or the pressure. However, there is a point beyond which it is possible to pass from the liquid state to the gas or vapor state without going through a boiling point or, conversely, through a condensation, but continuously. This point is called the critical point.

It is also known that a fluid in the supercritical state is a fluid which is in a state 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 of the critical points represented on a diagram (pressure, temperature) in the case of a mixture. Such a fluid has, for many substances, a high solvent power which is incommensurate with that observed for this same fluid when it is in the state of compressed gas.

The same is true of so-called “subcritical” 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, (cf. Michel PERRUT -The techniques of the Engineer "Extraction by supercritical fluid, J 2 770- 1 to 12, 1999 ”). In the following, a fluid at supercritical pressure will denote a fluid brought to a pressure higher than its critical pressure, whether it is in supercritical or subcritical state as defined above.

The significant and modular variations in the solvent power of liquefied gases and fluids at supercritical pressure as well as the high diffusivity of the molecules dissolved within these fluids, in comparison with the diffusivity of the same molecules dissolved in a liquid solvent are of elsewhere used in many extraction processes (solid / fluid), fractionation (liquid / fluid), analytical or preparative chromatography, treatment of materials (ceramics, polymers), generation of particles, or even as a setting medium in chemical or biochemical reactions. It should be noted that the physicochemical properties of carbon dioxide as well as its critical parameters (critical pressure: 7.4 MPa and critical temperature: 31 ° C) make it a preferred solvent in many applications, especially since it does not present 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, and certain halogenated hydrocarbons.

By numerous patents and scientific publications, it is known that liquefied gases, and especially fluids at supercritical pressure, and particularly supercritical carbon dioxide, are widely used to produce very fine powders of “micron” or “submicronic” sizes to dissolve very quickly or which can be used by ingestion through the respiratory tract. Fluids at supercritical pressure are also used with a view to obtaining very fine complex particles formed from mixtures of different morphologies of the active principle and of an excipient.

Most of the systems described in patents and publications apply to an encapsulation of the matrix type, which consists in integrating an active substance in a support in particular of alginate type, cellulose derivatives, waxes, triglycerides, polysaccharides, or acrylic polymers. A distinction will be made between microspheres, which consist of an active principle dispersed within an excipient, and microcapsules which are composed of a core of active substance surrounded by a continuous envelope.

The so-called “RESS” technique (Debenedetti P., Journal of Controlled Release, 24, 1993, p.27-44 - Debenedetti P., Journal of Supercritical Fluids, 7, 1994, p. 9-29) on the dissolution of the active principle and of the excipient in the fluid at supercritical pressure. The atomization of this supercritical solution allows the formation of microspheres. However, this technique is limited by the poor solubility of most polymers and active substances in supercritical fluids.

The so-called anti-solvent processes, known under the designations “SAS, SEDS, PCA, or ASES” allow the formation of composite micro-particles. They describe the contacting of organic solutions of active ingredients and of excipient with a supercritical fluid. Different patents describe various means of bringing the different fluids into contact: Introduction of the supercritical fluid into the organic solution (US-A-5,360,478), separate spraying of the organic solution and the supercritical fluid (DE-A-3,744 patents .329, US-A-5,043,280), use of coaxial nozzles with two or three inlets (patents WO 95/01221, WO 96/00610).

The so-called “PGSS” process makes it possible to encapsulate active principles by spraying at low pressure with a mixture of active principle excipient saturated with a supercritical fluid (patents EP-A-0744992, WO 95/21688).

Supercritical fluids also allow encapsulation of the membrane type by inclusion of active principles in liposomes (US-A-5,700,482).

It has been proposed, in the French patent application filed under No. 00.13393, to insert into a host molecule, in particular of the cyclodextrin type, at least one principle active by putting the latter in solution in a first solvent, the host molecule itself being in solution in a second solvent, then by bringing these solutions into contact with a fluid at supercritical pressure so as to reduce the solvent power of the liquid solvents and precipitating, by anti-solvent effect, the host molecules which are dissolved therein, and finally by extracting the residual solvents by means of a fluid at supercritical pressure and by evacuating the fluid / solvent mixture. The present invention aims, for its part, to provide a process for the preparation of particles consisting of at least one active principle, insoluble or very sparingly soluble in aqueous solutions, and which is dispersed in molecular form in a matrix consisting of a host molecule, in particular of the cyclodextrin type, using a liquefied gas or a fluid at supercritical pressure.

The present invention thus relates to a process for the manufacture of particles containing at least one active principle, these particles being formed from a set of molecular complexes each consisting of a molecule of active principle inserted into a host molecule, characterized in that '' it includes the steps of:

- placing in an enclosure under pressure at least one active principle and a powder of host molecule, or a mixture of these,

- introduce into this enclosure a fluid, consisting of a liquefied gas or a fluid at supercritical pressure, for a sufficient time for the active principle, diffuses within the host molecule powder and an active principle / host molecule complex is formed,

- recover the powder consisting of the active ingredient / host molecule complex. The present invention is advantageous in that it makes it possible to avoid using an organic solvent, thus eliminating any risk linked to the presence of organic solvent residues in the particles obtained. However, when the active principle is very slightly soluble in the liquefied gas or the fluid at supercritical pressure, the kinetics of complexation may be too long to be conceivable economically. It may then be necessary to improve this solubility and accelerate complexation by dissolving an organic co-solvent in the liquefied gas or the fluid at supercritical pressure, according to the technique conventionally used in extraction by supercritical fluid.

According to a variant, the active principle, or the mixture of active principles, and the matrix consisting of a host molecule, for example of the cyclodextrin type, may be premixed using conventional means for mixing powders, and the resulting mixture may be introduced into the enclosure into which the liquefied gas or the fluid at supercritical pressure will then be admitted. Preferably, the particles of host molecule will have a diameter between 1 μm and 100 μm, and those of active principle will have a diameter between 0.1 μm and 500 μm, this active principle being of food, pharmaceutical, cosmetic, agrochemical interest. or veterinarian. Furthermore, and although another gas can be used, the liquefied gas or the fluid at supercritical pressure will favorably consist of carbon dioxide, optionally added with a volatile organic solvent of the light hydrocarbon, alcohol, ester, ketone type. , ether or halocarbon.

Preferably, the powder consisting of the active principle-molecule-host complex will be recovered by filtration of the fluid leaving the enclosure. The powder can also be recovered by simultaneously drawing off the liquefied gas, or the liquid at supercritical pressure, and the powder by means of a recovery port provided in the bottom of the enclosure, by means of depressurization of it. According to the invention, the host molecule may consist of at least one cyclodextrin of the α-cyclodextrin type, or β-cyclodextrin or γ-cyclodextrin. It may also consist of at least one cyclodextrin modified by grafting a chemical group, in particular of the methyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, carboxymethyl-β type. -cyclodextrin, or acetyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin.

The host molecule may also consist of at least one cyclodextrin modified by grafting a chemical group.

Various embodiments 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 block diagram of an installation for producing particles of at least one active principle inserted into a host molecule, in particular, of the cyclodextrin type. FIG. 2 is a view in axial section of an alternative embodiment of an enclosure of the type used in the example shown in FIG. 1.

This device essentially consists of an enclosure 1, intended to be pressurized, which is supplied with fluid, liquefied or at supercritical pressure, by a pipe 2 connected to a storage tank 3 by means of a pump 4 and a heat exchanger 5, the latter making it possible to bring the liquefied fluid to the desired pressure and temperature. The pressure vessel 1 is provided at its upper part with an outlet 9 allowing the fluid to be removed without the powder, and at its lower part with an outlet 10 allowing the mixture of fluid and powder to be removed , which outputs can be either one or the other, connected to a regulating valve 11, to cyclonic separators 13, and to tapping elements 14, by means of a filter 12. The last separator 13 is connected to the storage tank 3 via a condenser 15.

The upper part of the enclosure 1 includes means for introducing the host molecule and the active principle. These means may consist of a simple cover or of a supply pipe 16, as shown in FIG. 1.

In one embodiment, the mixture consisting of a fluid and the powder obtained at the end of the operation is discharged through the outlet 10. The powder-charged fluid is partially expanded to the recycling pressure through the control valve 11 and reheated in the cyclone separators 13, after filtration through the filter 12. The fluid is recycled by liquefaction in the condenser 15 and returns to the fluid reservoir 3. The fluid is made up into a liquid or gaseous state by a supply 18. The powder is collected in the filter 12.

According to a particularly advantageous variant from the economic point of view of the invention, represented in FIG. 2, the enclosure 1 is provided with a stirring device, which can, for example, consist of a turbine with vertical axis 6 driven by an electric motor 7, and a magnetic drive system 8, which is particularly suitable for use under high pressure.

In order to illustrate the present invention, two examples of implementation will be described below on a pilot-size installation having an operating pressure of 30 Mpa and a temperature range from 0 ° C to 150 ° C, and which was carried out according to the diagram of Figures 1 and 2, the enclosure 1 being provided with a stirring turbine 6 rotating at 60 revolutions per minute.

Carbon dioxide has been used as a liquefied gas and as a fluid at supercritical pressure. The pump 4 was a membrane pump authorizing a flow rate of 6 kg / h to 20 kg / h of carbon dioxide at 30 MPa, the fluid reservoir 3 having a total volume of 2 liters, the pressure vessel 1 being constituted by a tubular container of vertical axis with a diameter of 0.1m and a total volume of 4 liters, endowed with a conical bottom of angle 30 ° emerging through an outlet 10 with a diameter of 4mm.

At the end of the operation, the mixture of fluid and powder was evacuated by outlet 10 and filtered in a glass fiber fabric filter with a porosity close to 1 μm, installed in a pressure vessel 12. The powder obtained has was characterized by conventional means of particle size distribution (laser granulometer), HPLC analysis for the content of active principle and differential micro-calorimetry (DSC) analysis for the evaluation of the complexing yield of the active principle by reduction or disappearance of the thermal peak relating to the free active principle. Example 1: By means of the installation thus described, a powder of complex particles formed from a steroid, prednisolone, and a matrix, consisting of a powder of ydroxypropyl-β-cyclodextrin, was produced by brought into contact with stirring for 30 minutes of 20 g of active principle and 90 g of matrix in the presence of supercritical carbon dioxide at 28 Mpa and 40 "C. After emptying the enclosure under pressure 1, it was recovered from the filters 12 a powder whose characteristics were as follows: - particle size distribution: Almost identical to that of the initial matrix powder, diameter between 10 μm and 120 μm and average diameter by mass of 65 μm.

- mass composition: 18% of prednisolone and 82% of hydroxypropyl-β-cyclodextrin, - degree of complexation of the active principle: approximately 90%.

Example 2:

By means of the installation thus described, a powder of complex particles formed from an anti-inflammatory, ibuprofen, and hydroxypropyl-β-cyclodextrin was generated by contacting with stirring for 8 minutes 10 g of active ingredient and 90 g of matrix in the presence of liquefied carbon dioxide at 6 Mpa and 20 "C. The installation was then drained and a powder, the characteristics of which are as follows:

- particle size distribution: Almost identical to that of the initial matrix powder, diameter between 10 μm and 120 μm and average diameter by mass of 65 μm, - mass composition: 9.8% of ibuprofen and 90.2% of hydroxypropyl -β-cyclomedextrin.

- degree of complexation of the active principle: approximately 95%. According to the invention, it is possible, before the powder recovery stage, to evacuate the fluid until the pressure in the enclosure becomes equal to atmospheric pressure.

Finally, during the diffusion stage, the various elements present in the enclosure may be subjected to agitation.

Claims

1.- Method for manufacturing particles containing at least one active principle, these particles being formed from a set of molecular complexes each consisting of a molecule of active principle inserted into a host molecule characterized in that it comprises the stages consisting at :

- placing in an enclosure (1) under pressure at least one active principle and a powder of host molecule, or a mixture of these,

- Introducing into this enclosure (1) a fluid, consisting of a liquefied gas or a fluid at supercritical pressure, for a sufficient time so that the active principle diffuses within the powder of host molecule and that a complex active ingredient host molecule is formed,

- recover the powder made up of the active ingredient host molecule complex.

2.- Method according to claim 1 characterized in that, prior to the powder recovery step, the fluid is discharged until the pressure in the enclosure (1) becomes equal to atmospheric pressure.

3. - Method according to claim 1 characterized in that 1 'one performs the recovery step by performing a simultaneous withdrawal of the liquefied gas, or liquid at supercritical pressure, and the powder by means of a recovery port provided in the bottom of one enclosure (1), by means of depressurization thereof.

4. - Method according to one of the preceding claims, characterized in that the powder is recovered consisting of complex active principle host molecule by filtration of the fluid leaving the enclosure (1).

5.- Method according to one of the preceding claims, characterized in that the fluid consists of carbon dioxide.

6.- Method according to one of the preceding claims, characterized in that the fluid consists of carbon dioxide added with a volatile organic solvent of light hydrocarbon type, alcohol, ester, ketone, ether or halocarbon.

7. - Method according to one of the preceding claims, characterized in that the host molecule consists of cyclodextrin of the α-cyclodextrin type, or β-cyclodextrin or γ-cyclodextrin.

8.- Method according to one of claims 1 to 6 characterized in that the host molecule consists of at least one modified cyclodextrin of the methyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, methyl-β- cyclodextrin, hydroxypropyl type -β-cyclodextrin, carboxymethyl-β-cyclodextrin, acetyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin.

9. - Method according to one of claims 1 to 6, characterized in that the host molecule consists of at least one cyclodextrin modified by grafting of a chemical group.

10.- Method according to one of the preceding claims, characterized in that the active ingredient is chosen from compounds of pharmaceutical, cosmetic, dietetic or phytosanitary interest.

11.- Method according to one of the preceding claims, characterized in that at least one active principle and at least one host molecule are intimately mixed before being introduced into one enclosure (1) under pressure.

12.- Method according to one of the preceding claims, characterized in that, during the diffusion step, the various elements present in the enclosure (1) are subjected to stirring.