Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-11-03
2004-02-10
Zeman, Mary K. (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C127S034000, C514S911000, C514S970000, C530S350000, C530S351000, C530S397000, C530S399000, C530S354000, C424S489000, C424S085100, C424S085200, C424S094100, C424S094300, C424S094600, C424S499000, C424S500000, C435S810000
Reexamination Certificate
active
06689755
ABSTRACT:
The present invention relates to a rapid and readily reproducible process for stabilizing biologically active substances by combining the biologically active substance with a stabilizing mixture and drying the resulting mixture into a dry, amorphous product by means of convection drying. The invention also relates to the amorphous, microscopically homogeneous products which are obtained by this process, are in the form of powders and have a uniform geometric, in particular spherical, shape. The invention furthermore relates to the use of substance mixtures for stabilizing biologically active material, in particular proteins by means of spray drying.
BACKGROUND OF THE INVENTION
It is well known that proteins, especially human proteins, can be stabilized in solid preparations by a large number of substances, preferably by sugars or combinations of sugars and amino acids.
Various processes and formulations for producing dry, biologically or therapeutically active materials are described. By dry materials are meant substances and substance mixtures which have a residual moisture content not exceeding 8% (g/g), preferably not exceeding 4% (g/g), particularly preferably not exceeding 2%. Freeze-drying processes are widely used for producing such formulations [F. Franks, Cryo Lett. 11, 93-110, (1990); M. J. Pikal, Biopharm. 3 (9), 26-30 (1990); M. Ilora, Pharm. Research 8 (3), 285-291 (1992); F. Franks, Jap. J. Freezing Drying 38, 15-16, (1992)] but have the specific disadvantages of freeze-drying. They consume large amounts of energy, require the use of refrigerants, some of which are environmentally harmful (frigens), and are time-consuming because it is often necessary to remove relatively large volumes of ice by sublimation. The freezing step necessary for freeze-drying may be destabilizing for a large number of substances, especially for proteins. This process is therefore not applicable at all to some biological materials.
Alternatives to freeze drying for producing dry protein preparations are processes which dry the material by using heat and/or vacuum [F. Franks, R. M. H. Hatley: Stability and Stabilization of Enzymes; Eds. W. J. J. von den Teel, A. Harder, R. M. Butlaar, Elsevier Sci. Publ. 1993, pp. 45-54; B. Roser, Biopharm, 4 (9), 47-53 (1991); J. F. Carpenter, J. H. Crowe, Cryobiol. 25, 459-470 (1988)]. Examples which may be mentioned in this connection are vacuum drying with or without use of elevated temperature, spray-drying processes in a wide variety of modifications, including combined use of vacuum and spraying techniques, and drum drying and other thin-film drying processes.
J. F. Carpenter, J. H. Crowe, Biochemistry 28, 3916-3922 (1989); K. Tanaka, T. Taluda, K. Miyajima, Chem. Pharm. Bull. 39 (5), 10-94 (1991), DE 35 20 228, EP 0 229 810, WO 91/18091, EP 0 383 569 and U.S. Pat No. 5,290,765 describe preparations which contain sugars or sugar-like substances. However, the production of dry, carbohydrate-containing preparations by means of freeze or vacuum drying, especially of sugar preparations, is associated with disadvantages in the state of the art. These include, inter alia, high energy consumption for drying to an acceptable residual moisture content, extended process times at low drying temperatures, formation of highly viscous, water-containing masses (called “rubber”) or glassy melts whose glass transition temperatures are below room temperature. The disadvantages described above significantly influence the stability of biological materials in such preparations.
It is also evident from the literature cited above that preparations suitable for stabilizing proteins should have glassy, that is to say amorphous, structures whose glass transition temperature is above the intended storage temperature. The glass transition temperature (Tg) is the temperature at which an amorphous or partially crystalline solid is converted from the glassy state into the fluid or viscous state and vice versa. This involves drastic changes in the viscosity and, associated therewith, in the diffusion coefficient and the kinetic mobility of the biological materials. Physical characteristics such as hardness and modulus of elasticity are changed, as are the thermodynamic functions of volume, enthalpy and entropy. The glass transition temperature of, for example, a sugar-containing composition and its residual water content are physically linked together in such a way that increasing residual amounts of water lead to declining glass transition temperatures and vice versa. It is thus possible to infer from measurement of the glass transition temperature, for example by differential scanning calorimetry (DSC), whether a preparation has a residual water content suitable for stabilization or, as stated above, a drying process is successful or not. Besides determining the glass transition temperature by means of DSC, the presence of amorphous structures can also be proved by means of X-ray diffraction investigations., optical and electron microscopic examinations.
It was therefore desirable to provide fully amorphous ancillary substance structures for biological or pharmaceutically active materials so that the embedded biological materials can also be kept stable at room temperature and over a long period. The ancillary substance structures should have a low residual moisture content which can be adjusted intentionally, and have a glass transition temperature which is as high as possible.
WO 97/15288 describes a process for stabilizing biological materials by means of drying processes without freezing, with which partially amorphous ancillary substance structures are obtained. The drying was carried out as vacuum drying (at slightly elevated temperatures <50° C.), although inhomogeneous products are obtained.
WO 96/32096 describes the production of a homogeneous, dispersible powder, which contains a human protein, carbohydrates and/or amino acids and other ancillary substances, for inhalation by means of spray drying. However, it has emerged that amorphous products are not obtained in any of the examples.
EP 0 682 944 Al describes lyophilisates with pharmaceutically acceptable ancillary substances, consisting of a phase with the protein in amorphous mannitol and a second phase with crystalline alanine. However, these formulations cannot stabilize the biological materials sufficiently well over a lengthy period.
SUMMARY OF THE INVENTION
The present invention is based on the object of developing a mild, flexible, readily reproducible, rapid and economic drying process for embedding biological materials, especially human proteins, and of finding stabilizing matrices suitable for this process. It is intended that it be possible with this process to produce fully amorphous and homogeneous products which allow stabilization of the biological materials over a long period.
The present invention relates to a rapid and readily reproducible process for stabilizing biologically active substances by combining the biologically active substance with a stabilizing mixture and drying the resulting mixture into a dry, amorphous product by means of convection drying. The invention also relates to the amorphous, microscopically homogeneous products which are obtained by this process, are in the form of powders and have a uniform geometric, in particular spherical, shape. The invention furthermore relates to the use of substance mixtures for stabilizing biologically active material, in particular proteins by means of spray drying.
DETAILED DESCRIPTION OF THE INVENTION
The object of the invention, of providing an efficient process for producing amorphous preparations which contain biological materials, is achieved by means of convection drying, in particular by means of spray drying, wherein the air inlet temperature is from about 50 C. to about 300 C. and with the mixtures of at least one zwitterion with polar or apolar radical or a mixture of at least one zwitterion with polar or apolar radical and a carbohydrate. The aforementioned mixtures may also contain ancillary substances suc
Gabel Rolf-Dieter
Mattern Markus
Winter Gerhard
Wirl Alexander
Woog Heinrich
Boehringer Mannheim GmbH
Johnston George W.
Prior Kimberly J.
Rocha-Tramaloni Patricia S.
Zeman Mary K.
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