Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-04-06
2001-10-09
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C514S311000, C514S314000, C424S490000, C424S497000
Reexamination Certificate
active
06299906
ABSTRACT:
FIELD OF THE INVENTION
The invention provides a novel process for producing submicron-sized particles of a biologically active compound or pharmaceutical.
A number of different processes to produce very small particles of a pharmaceutical have been described. (e.g. Rapid Expansion (of) Supercritical (fluid) Solution (RESS), Gas Antisolvent (GAS), Particles (from) Gas Saturated Solution (PGSS), Supercritical Anti-Solvent (PRECIPITATION) (SAS)). These processes are described in Journal of Pharmaceutical Sciences Vol. 86, No. 8, August 1997, pp. 885-890 under the title “Pharmaceutical Processing with Supercritical Carbon Dioxide. Typically the drug is dissolved in a compressed gas and subsequently rapidly expanded mostly into atmospheric pressure. Due to the expansion conditions and to a high surface energy in the gas very small particle sizes, i.e., smaller than 1 &mgr;m are hard to achieve and to handle. It is well known that such high surface energy can only be handled by using a surface modifier to decrease the surface energy, to achieve stabilization of small particles in suspension. H. Sucker, P. Fuchs, P. Speiser, “Pharmazeutische Technologie”,2. Edition, 1991, Georg Thieme Verlag, Stuttgart/New York, pp 419-424; and Hans Steffen, BT Gattefossé No. 81, 1988, pp. 45-53, “Controlled Precipitation—a Method to Produce Small Drug Particles and to Increase Bioavaibility”.
International application WO 97/14407 describes a supercritical fluid/compressed fluid based process to produce submicron-sized particles of biologically active compounds, which process comprises the steps of:
(1) dissolving a water insoluble biologically active compound in a solvent thereof;
(2) spraying the solution of step (1) into a compressed gas, liquid or supercritical fluid in the presence of a surface modifier dispersed in an aqueous phase.
In another embodiment the process described in WO 97/14407 comprises the steps of:
(1) dissolving a water insoluble biologically active compound in a compressed fluid;
(2) spraying the compressed fluid of step (1) into an aqueous phase containing a surface modifier.
The process described in WO 97/14407 may be difficult to realise on an industrial scale for various reasons. On an industrial scale it is difficult to reach a uniform distribution of temperature in the connection tubes. Due to such variations in temperature, aggregation or flocculation of particles dissolved in the supercritical solution may occur causing clogging of the tubes or spraying-nozzles.
The solubility of most of the pharmaceutical compounds in liquid or supercritical CO
2
is very low even under high pressure. Therefore the use of additional cosolvents is proposed. Most of these cosolvents are liquids under atmospheric pressure. By spraying the solution containing the pharmaceutical into the liquid phase, e.g. aqueous phase, the fraction of the cosolvent in the liquid phase increases. Therefore, the solubility of the compound in the liquid phase also increases. This can destabilize the suspension on an industrial scale.
In addition, the recycling of the pressurized gas becomes more difficult and expensive using a cosolvent.
A pressurised gas with high solubility for pharmaceutical compounds would allow the process to be effected without the use of cosolvents.
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 &mgr;m, preferably 200 nm to 1 &mgr;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®; olyoxamines availaible under the tradename Tetronic ®; 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®.
Preferred surface modifiers are Brij 96® (polyethyleneglycolether of lauryl,-cetyl-, stearyl- and oleylalcohols, available from Atlas Chemie) and Aerosol OT® (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 Gattefossé 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:
Diffe
Bausch Alexander
Hidber Pirmin
Dawson Arthur D.
Epstein William H.
Hoffmann-La Roche Inc.
Johnston George W.
Kishore Gollamudi S.
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