Plant protecting and regulating compositions – Plant growth regulating compositions – Designated nonactive ingredient containing
Reexamination Certificate
2002-01-03
2004-01-20
Clardy, S. Mark (Department: 1616)
Plant protecting and regulating compositions
Plant growth regulating compositions
Designated nonactive ingredient containing
C424S489000, C424S499000, C424S500000, C424S501000, C424S502000, C514S959000, C516S001000, C516S114000, C516S922000, C516S928000
Reexamination Certificate
active
06680284
ABSTRACT:
The present invention describes a process for the preparation of pulverulent particle-reduced formulations with the aid of compressed gases.
A considerable number of substances such as active compounds, lacquers and additives often have only a very low solubility in water and in many organic solvents. The poor solubility of, especially, pharmaceutical active compounds is both a challenge to the pharmaceutical technologists, who attempt, using various formulation strategies, such as a reduction of the particle size and/or embedding in suitable additives, to achieve an improvement in solubility (Voigt, R., “Pharmazeutische Technologie” [Pharmaceutical Technology] 7th edition, Berlin: Ullstein Mosby, 1995), and for the active compound synthetic chemists, who attempt, by means of structural changes to the active compound molecules themselves, to improve their solubility without at the same time adversely affecting the active principles (Wermuth, C. G., “Preparation of Water-Soluble Compounds by Covalent Attachment of Solubilizing Moieties” in The Practice of Medicinal Chemistry, New York: Academic Press, pp. 755-776, 1996).
In pharmaceutical technology procedures, classical strategies for the reduction of the particle size and/or for the embedding of the active compound molecules in a solubility- or absorption-promoting matrix are predominant (Muranishi, S., Crit. Rev. Ther. Drug Carrier Syst. 7, 1-33 (1990)). Lipid vesicles, in particular liposomes, have also been proposed as active compound carriers (Lasic, D. D., J. Controlled Drug Release 48, 203-222 (1997)) which can bring about a specific improvement in the bioavailability of the active compounds after administration.
Many technological approaches, however, come up against their limits if a still acceptable bioavailability after administration is to be achieved for a poorly soluble active compound by a lowering of its particle size. To this end, a number of classical grinding techniques are admittedly available, such as, for example, with the aid of centrifugal force mills, pin beater mills, air-jet mills, ball mills, etc. (Voigt, R., “Pharmazeutische Technologie” [Pharmaceutical Technology] 7th edition, pp. 40, Berlin: Ullstein Mosby, 1995). These techniques, however, are often unsuitable for the realization of minimally achievable particle sizes and acceptable particle size distributions.
More recent technologies have therefore attempted to utilize the properties of compressed or supercritical gases for the preparation of micro- or nanoscale active compound particles (Howdle, S. et al. Proc. Int. Symp. Controlled Release Bioact. Mater. 25,972 (1998)), respectively, the following processes having gained acceptance:
1. The ‘RESS process’, in which the active compound is dissolved in the supercritical gas and then expanded through a fine nozzle and in the course of this “atomized”,
2. The ‘GASR process’, in which the dissolved active compound is precipitated from a solution by the gas and under pressure, and finally
3. The PGSS process, in which, inter alia, coprecipitates between the respective active compound and a carrier, such as, for example, a polymer, are sprayed from a solution saturated with gas.
German laid-open applications DE-A-197 13 096, DE-A-197 58 157 and DE-A-198 29 396, for example, describe the homogeneous introduction of active substances having different solubility properties into various emulsifier matrices formed from solutions, achieving with the aid of compressed gases a solvent exchange in a column system, which leads to homogeneous formulations of originally poorly soluble active substances.
These more recent processes for particle production with the aid of compressed or supercritical gases, however, can only be employed if the active compounds can be brought into solution at least partially in the compressed gas itself or completely in a solvent. Unfortunately, in the case of many active compounds, coating agents such as, for example, lacquers, but also construction chemicals, such as, in particular, concrete additives, this is not the case or only the case to an insignificant extent, such that these procedures can either not be employed or can only be employed uneconomically in practice.
It was thus an object of the present invention to make available a process for the preparation of pulverulent particle-reduced formulations with the aid of compressed gases, with which poorly soluble or nonsoluble compounds can be formulated such that generally a significant improvement in the administrability and, in the case of bioactive substances, in particular a better bioavailability, are achieved.
“Particle-reduced” within the meaning of the present invention means that the proportion of particles having a diameter of >50 &mgr;m is lowered by >90% in relation to the starting material.
“Poorly soluble” within the meaning of the present invention means that at temperatures between 15 and 25° C., in particular at, for example, 20° C., for one part by mass of substance at least 100 parts by volume and preferably between 100 and 1000 parts by volume of solvent are needed (see also European Pharmacopeia, 3rd edition 1997, 1.3 monographs, p. 3).
This objective was achieved by a process in which
a) the solid compound to be formulated is homogeneously ground at elevated process pressures in the presence of compressed gas together with 10 to 99% by weight of a carrier material based on the total weight of the particle-reduced formulation of compound and carrier material, the carrier material being essentially soluble in the compressed gas, and
b) the compressed gas is then expanded by lowering the pressure, preferably to atmospheric pressure, and separated off from the homogenate, and the pulverulent particle-reduced formulation is recovered from the homogenate.
Surprisingly, it was possible to establish by means of the novel process that not only pulverulent particle-reduced formulations, but formulations are obtained which are completely homogeneous, i.e. formulations which quantitatively contain the compound to be formulated, that is the actual active compound, and which moreover no longer comprise particles which can be detected by light microscopy. This was not to be expected in this clarity.
Solid compounds to be formulated are understood within the meaning of the invention as meaning poorly soluble or nonsoluble compounds, in particular compounds which are poorly soluble or nonsoluble in a compressed gas in the absence of a carrier material. These are preferably bioactive compounds and in particular pharmaceutical and cosmetic active compounds; but also other poorly soluble substances whose solubility or bioavailability is to be improved can be employed. According to definition, pharmaceutical active compounds are substances which are suitable in medicinal therapy and diagnosis. In the present process, pharmaceutical compounds are preferably employed which can generally be administered topically, transdermally, perorally, parenterally and by inhalation, intravenously, intramuscularly, subcutaneously, intraperitoneally or intranasally. Cosmetic active compounds are as a rule understood as meaning substances which are applied to the skin.
Preferred solid compounds to be formulated within the meaning of the present invention, however, can also be poorly soluble or nonsoluble agrochemicals, such as, in particular, biocides (herbicides, fungicides, insecticides) or active compounds which are used as ‘plant growth regulators’ (PGR).
Lacquers or their constituents having poor solubility and certain concrete additives, i.e. construction chemicals, generally also come under the definition of the solid compound according to the invention.
Substances or substance mixtures in which the solid compound to be formulated can be embedded are typical carrier materials according to the invention. In this case, the proportion of carrier material can vary within wide ranges, the proportion, however, essentially being determined by the flowability of the formulation.
Proportions of the carrier material w
Heidlas Jürgen
Ober Martin
Wiesmüller Johann
Clardy S. Mark
Degussa - AG
Fulbright & Jaworski L.L.P.
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