Title:  Process for making submicron particles

United States Patent:  6,299,906

Assignee:  Hoffmann-La Roche Inc. (Nutley, NJ)

Filed:  April 6, 1999

Foreign Application Priority Data:  Apr 09, 1998[EP] (98106534)

The present invention relates to a process for manufacturing a pulverous preparation of a submicron-sized biologically active compound comprising the steps of dissolving a biologically active compound under elevated pressure in a compressed gas, liquid or supercritical fluid containing a surface modifier; and rapidly expanding the compressed solution thereby precipitating the dissolved compound. An alternative process comprises dissolving the biologically active compound in compressed dimethylether, which may optionally contain a surface modifier; and spraying the compressed solution into an antisolvent phase, optionally containing a surface modifier, under vacuum, atmospheric pressure or elevated pressure. An optional third step involves converting the antisolvent phase into a pulverous preparation using conventional powder processing.

SUMMARY OF THE INVENTION

The object of the present invention is thus to provide a novel process for producing submicron-sized particles of a biologically active compound from a compressed gas, liquid or supercritical fluid, thus avoiding the above mentioned difficulties.

The process of the present invention is based on the use of compressed gas and fluids including supercritical technology yielding submicron-sized particles having a narrow size distribution and being stabilized by a surface modifier.

The process can be performed either batchwise or continuously and is applicable to a wide range of substances.

In a first aspect of the invention it has now been found that the above mentioned problems concerning the cosolvent can be avoided by using compressed dimethylether to solvate the biologically active compound.

In a second aspect of the invention it has now been found that the above mentioned problems of clogging can be avoided by stabilizing the supercritical solution by adding a surface modifier in the compressed gas solution.

The invention thus concerns a process for the manufacture of a pulverous preparation of a submicron-sized biologically active compound comprising as a first step, dissolving a biologically active compound under elevated pressure in a compressed gas, liquid or supercritical fluid containing a surface modifier. Alternatively, the biologically active compound may be dissolved in compressed dimethylether, which may optionally contain a surface modifier. The second step of the process comprises rapidly expanding the compressed solution of step (1) thereby precipitating the dissolved compound. Alternatively, the second step comprises spraying the compressed solution of step (1) into an antisolvent phase, which may optionally contain a surface modifier, under vacuum, atmospheric pressure or elevated pressure. A third step, which is optional, comprises converting the antisolvent phase into a pulverous preparation using conventional powder processing techniques.

Conventional powder techniques are for example spray drying and freeze drying.

In this manner the formation of submicron sized particles stabilized by a surface modifier is achieved.

The term "submicron-sized particles" embraces particles having a median diameter (Dv 0.5) within the range of 5 nm to 5 .mu.m, preferably 200 nm to 1 .mu.m.

In cases where the compressed fluid is compressed dimethylether, the use of surface modifier is optionally and can be added to the compressed fluid (step 1) or to the antisolvent phase.

However, where the compressed fluid is not dimethylether, a surface modifier must be added to the compressed fluid.

The term "surface modifier" in step (1) and in the antisolvent phase of the present process embraces common modifiers as described in "Pharmazeutische Technologie, 4. Edition, 1993, Georg Thieme Verlag Stuttgart, N. Y."

Examples of suitable surface modifiers are: natural surfactants such as e.g. gelatine, paraffin, cholesterol esters and triglycerides; non-ionic surfactants such as e.g. polyethylene glycol; anionic surfactants such as e.g. natrium dodecylsulfate; cationic surfactants such as e.g. quaternary ammonium compounds; block copolymers of ethylene oxide and propylene oxide available from BASF under the trade name Pluronic.RTM.; olyoxamines availaible under the tradename Tetronic .RTM.; polyoxyethylen sorbian fatty acid esters, e.g. Tween 20, 40, 60 and 80; Klucel EF, Eudragit E, Arlactel 40, Carbopol 940, PVP K50; Brij 96 and Aerosol OT.RTM..

Preferred surface modifiers are Brij 96.RTM. (polyethyleneglycolether of lauryl,-cetyl-, stearyl- and oleylalcohols, available from Atlas Chemie) and Aerosol OT.RTM. (sodium di-isooctylsulphosuccinate availaible from Wako Junyaku Corp).

In step (1) and in the antisolvent phase and the same modifier can be used.

As shown by H. Steffen (BT Gattefosse No. 81, 1988, pp. 45-53) the concentration of the surface modifier depends on the critical micelle concentration (CMC). The amount of surface modifier needed depends therefore on the CMC and the surface area of the particles.

The addition of a surface modifier to the compressed gas prior to the spraying has the advantage that

(i) nuclei and particles formed spontaneously in the pipes or--due to the pressure drop--in the region of the nozzle are immediately stabilized and their growth is hindered further, thereby preventing clogging,

(ii) the mixing of the precipitated particles and the surface modifier is improved by simultaneously spraying the solution of the drug and the surface modifier through the same nozzle,

(iii) the use of an antisolvent phase which neither solubilizes the drug nor the surface modifier is allowed.

Due to the presence of a surface modifier in the compressed gas, liquid or supercritical liquid the following advantages are achieved:

Differences in the pressure and temperature are counteracted by stabilizing any nuclei formed.

The pressure drop in the region of the nozzle can be accommodated without clogging.

The surface modifier is located very close to the region of particle formation and not distributed in the whole liquid.

It is possible to expand into a liquid phase, e.g. compressed CO₂, which is then evaporated by keeping the stabilization of the suspension. Thus, the additional step of spray drying is no longer necessary.

The term "compressed gas, liquid or supercritical fluid" embraces dimethylether, carbon dioxide, straight chain or branched C1-C6-alkanes or combinations thereof. Examples for said alkanes are ethane, propane, butane and isopropane and the like.

The term "biologically active compound" includes, but is not limited to pharmaceuticals such as those listed below:

Claim 1 of 14 Claims

What is claimed is:

1. A process for the manufacture of a pulverous preparation of a submicron-sized particulate Saquinavir comprising the steps of:

(1) dissolving Saquinavir under an elevated pressure in dimethyl ether in a supercritical stat of temperature and pressure containing a surface modifier; and

(2) rapidly expanding the compressed solution of step (1) thereby precipitating the dissolved Saquinavir as discrete submicron particles.

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