Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
1998-02-06
2002-10-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S772000, C514S772100, C514S772200, C514S777000, C514S781000, C524S002000, C524S211000, C424S484000, C424S486000, C424S487000, C424S488000, C424S489000, C424S500000, C424S501000
Reexamination Certificate
active
06462093
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a technique for effectively utilizing a sparingly-water soluble medical substance, particularly to a method for producing a solid dispersion using a novel method for converting it to the amorphous state. This technique can be used in the field in which a medical substance should be eluted, for example, the fields of agricultural chemicals, perfumery and cosmetics, and medical treatment, particularly medical treatment.
BACKGROUND ART
For designing pharmaceutical preparations for oral administration, it is important to increase biological availability of sparingly water-soluble medical substance by improving their solubility and absorptivity from the viewpoint of efficacy and safety of pharmaceutical preparations.
As a measure to increase the biological availability of a sparingly water-soluble medical substance, there are a method in which particles of a medical substance are subjected to supermicro-particle powdering and a wettability or a dispersibility is improved, and a method in which a solubility of an original medical substance is improved by formation of a solid dispersion. A method in which a solid dispersion is formed by rendering a medical substance amorphous attracts special attention. The solid dispersion is a substance obtained by dispersing a medical substance into a carrier in a monomolecular state. In this dispersion, the medical substance is retained in a completely amorphous state. In general, an amorphous form is, compared to a crystal form, in a high energy state, and is therefore expected to have a high absorptivity.
The methods of producing a solid dispersion are roughly classified into a solvent method, a melting method (a heating method), a melting-solvent method, a mechanochemical method, and the like.
The solvent method comprises dissolving in an organic solvent both of a medical substance and a water-soluble polymer base which serves as an amorphous state-stabilizing agent and then, in the presence of core granules or as it is, distilling off the solvent to obtain a solid dispersion. This method is excellent in improvement of solubility of a sparingly water-soluble medical substance. It is, however, disadvantageous in that a high production cost is required because a large amount of an organic solvent is used and that there is a case in which the solvent remaining in the pharmaceutical preparation is concerned.
The melting method (the heating method) utilizes depression of the melting point of a mixture of a medical substance and a water-soluble polymer base which serves as an amorphous state-stabilizing agent. It comprises kneading both materials under heating at the temperature lower than their melting points, allowing the medical substance to disperse in a molecular state, followed by cooling, solidifying, and pulverizing the mixture.
The melting method is excellent in that no organic solvent is used. However, some sparingly water-soluble medical substances are not converted to the amorphous state sufficiently by adding only an amorphous-state stabilizing agent as a solid dispersion carrier.
Further, in order to completely convert a medical substance to the amorphous state, it is necessary to knead the mixture at a high temperature but lower than the melting points of the medical substance and the solid dispersion carrier. Thus, there are some cases that not only the medical substance is decomposed and the carrier is deteriorated but also the medical substance is not converted to the amorphous state sufficiently.
For example, in the method where a medical substance and a water-soluble polymer base which serves as an amorphous state-stabilizing agent are melted under heating to utilize depression of the melting point of the mixture, the melting point is depressed at most about 10° C. and a high temperature is still necessary for the heat treatment. In addition, since many polymer bases are originally amorphous, its apparent melting viscosity is high and micro-dispersity of the medical substance and the water-soluble polymer is poor. Thus, some medical substances cannot be converted to the amorphous state sufficiently.
An attempt has been made to melt a medical substance under heating together with a low molecular weight compound such as phosphatidylcholine as an amorphous state-inducing agent in place of a water-soluble polymer base as a solid dispersion carrier. However, in this method, the heat treatment may possibly cause decomposition and denaturation of a medical substance. Further, when the temperature of the heat-treated product is cooled to the room temperature, it is concerned that the resulting product shows such poor stability that it hardly keeps its amorphous state.
The mechanochemical method (treatment) comprises using mechanical energy such as compression, shearing, and friction to enhance a medical substance in a solid state to become amorphous and to improve dispersion of the resulting amorphous medical substance to the carrier, thereby obtaining a solid dispersion. Specifically, the treatments includes mixing and pulverization with a ball mill, treatment with a planetary mill, treatment with a compression press, mixing treatment with a shear roll, and the like.
The mechanochemical treatment alone is difficult to completely convert a sparingly water-soluble medical substance to the amorphous state even when an amorphous state-stabilizing agent is added to a medical substance. This may be because the level of mechanical energy is low. In such a case, a specific machine is sometimes required (WO 92/18106).
As described above, it has been desired to develop a method for obtaining a solid dispersion of a sparingly water-soluble medical substance in a complete amorphous state inexpensively compared with the conventional methods in an industrial scale.
DISCLOSURE OF THE INVENTION
As a result of intensive investigation to overcome the problems of the conventional methods, the present inventors have found a method for converting a sparingly water-soluble medical substance to the amorphous state which comprises mixing these components of (1) a sparingly water-soluble medical substance, (2) an amorphous state-inducing agent and (3) an amorphous state-stabilizing agent, and subjecting the resulting mixture to heat treatment or mechanochemical treatment. Further, it has been found that high-frequency heating is preferred as the heat treatment to the conventional heating by a heater or steam.
In addition, the inventors have found a method of converting a sparingly water-soluble medical substance to the amorphous state which comprises mixing two components of (1) a sparingly water-soluble medical substance and (3) an amorphous state-stabilizing agent and subjecting the mixture to high-frequency heating.
Furthermore, it is possible to produce a pharmaceutical preparation of a sparingly water-soluble medical substance containing a solid dispersion obtained by the method of converting the medical substance to the amorphous sate according to the present invention.
The (1) sparingly water-soluble medical substance used in the present invention is a medical substance that has extremely low water-solubility and is hardly absorbed from the intestine, tunica mucosa nasi, rectum, and the like. It is difficult to improve absorptivity of such medical substances by the conventional techniques for formulating them into the pharmaceutical preparations. Absorptivity of these medical substances can be improved by converting them to the amorphous state. Examples of the sparingly water-soluble medical substances include dihydropyridine compounds such as nifedipine, nicardipine, hydrochloride, or the like, phenacetin, digitoxin, diazepam, phenytoin, tolbutamide, theophylline, griseofulvin, chloramphenicol, and the like.
The (2) amorphous state-inducing agent used in the present invention can be any compound capable of depressing the melting point of the mixture of it with a medical substance. A crystalline compound is particularly preferred. This is a compound having functions and properties to change crystal-lattic
Miyamoto Misao
Oda Toshihisa
Di Nola-Baron Liliana
Nissan Chemical Industries Ltd.
Page Thurman K.
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