Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1998-09-09
2001-01-09
Kishore, Gollamudi S. (Department: 2625)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S489000, C514S110000
Reexamination Certificate
active
06171599
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing a novel solid dispersion of a 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-[benzyl(phenyl)amino]ethyl ester hydrochloride-ethanol solvate (1:1) (hereinafter referred to as “efonidipine hydrochloride”) which has an antihypertensive activity, and to oral preparations containing this solid dispersion.
BACKGROUND ART
Efonidipine hydrochloride which is an active ingredient of a pharmaceutical preparation produced by the present invention is a 1,4-dihydropyridine-5-phosphonic acid derivative of the formula:
and it is a compound which is useful as a medication for circulatory organs having a vasodilative activity and an antihypertensive activity owing to a calcium antagonism.
Efonidipine hydrochloride is a slightly-soluble medication, and has, therefore, a poor absorbability. In order to increase the absorbability, there are a method in which particles of an original medication are subjected to supermicro-particle powdering and a wettability or a dispersibility is improved, and a method in which a solubility of an original medication is improved by formation of a solid dispersion. A method in which a solid dispersion is formed by rendering a medication amorphous attracts special attention. The solid dispersion is a substance obtained by dispersing a medication into a carrier in a monomolecular state. In this dispersion, the medication 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 absorbability.
In a method of producing a solid dispersion of efonidipine hydrochloride, it is known that efonidipine hydrochloride and hydroxypropylmethylcellulose acetate succinate (hereinafter referred to as “HPMC-AS”) is dissolved in an organic solvent, and the solvent is removed from the resulting solution through drying under reduced pressure, spray-drying, freeze-drying or the like to form a powdery or particulate product, or the solution is spray-coated on a particulate pharmaceutical excipient as a core through fluidized bed coating, centrifugal fluidized bed coating, pan coating or the like, or the solution is added to a pharmaceutical excipient, and the mixture is kneaded, then dried and formed into a granular product [Japanese Patent Application Laid-open No. Hei 2-49728 (49728/1990), U.S. Pat. No. 4,983,593 and European Patent No. 344,6031].
The method described in these references is excellent as a method of improving a solubility and an absorbability of efonidipine hydrochloride. However, it was problematic in that since a large amount of an organic solvent is used, the production cost is high, and the solvent sometimes remains in the medication.
DISCLOSURE OF INVENTION
The present inventors have assiduously conducted investigations to overcome the problems involved in this conventional method, and have consequently found a process for producing a solid dispersion containing efonidipine hydrochloride, which comprises subjecting a mixture of efonidipine hydrochloride and HPMC-AS to a step A of heat treatment at from 85 to 140° C. or mechanochemical treatment at from 0 to 140° C., and then to a step B of dipping treatment into a water-containing solution, impregnation treatment with a water-containing solution or contacting treatment with a water vapor-containing gas; or treating the above-mentioned mixture with a hot steam at from 100 to 140° C. and a high pressure.
Further, the present inventors have found a process for producing a solid dispersion in which in the heat treatment in the step A, the mixture of efonidipine hydrochloride and HPMC-AS is subjected to high frequency heating at from 80 to 160° C. without the need of the step B.
The heat treatment in the step A is conducted in the temperature range of which the upper limit is a temperature at which efonidipine hydrochloride is not deteriorated by decomposition. Such a temperature is, for example, between 85° C. and 140° C., preferably between 85° C. and 120° C., more preferably between 90° C. and 120° C. The heat treatment time is between 20 minutes and 120 minutes, preferably between 20 minutes and 90 minutes. Further, the heating can be conducted at from 85° C. to 160° C. by adding a thermostabilizer to the above-mentioned mixture.
The heating can be conducted not only through ordinary hot-plate heating or steam heating but also through infrared heating or far infrared heating.
When high frequency heating is employed as heat treatment in the step A, it is conducted at, for example, from 80° C. to 160° C., preferably at from 80° C. to 140° C., more preferably at from 90° C. to 130° C. for from 1 minute to 60 minutes, preferably for from 5 minutes to 20 minutes. Further, the heating can be conducted at from 80° C. to 180° C. by adding a thermostabilizer to the above-mentioned mixture.
The mechanochemical treatment is conducted in the temperature range of which the upper limit is a temperature at which efonidipine hydrochloride is not deteriorated by decomposition. Such a temperature is, for example, between 0° C. and 140° C., preferably between 0° C. and 80° C., more preferably between 15° C. and 60° C. The mechanical energy treatment under the same energy conditions as the above-mentioned heat treatment is conducted usually for from 1 minute to 120 minutes, preferably for from 3 minutes to 90 minutes in view of the quality control, the uniformity and the energy saving. In this mechanochemical treatment, care must be taken to avoid the local increase in the temperature. Further, the heating from outside is not particularly required. Still further, the treatment can be conducted at from 0° C. to 160° C. by adding a thermostabilizer.
A solid dispersion having not only an improved wettability of the surface of the solid dispersion but also a superior absorbability can be formed by dipping treatment into a water-containing solution, impregnation treatment with a water-containing solution or contacting treatment with a water vapor-containing gas in the step B. This method can increase the molecular motion between the amorphous substance of efonidipine hydrochloride and HPMC-AS, making it possible to increase a micro-dispersion and to delocalize the localized amorphous substance of efonidipine hydrochloride.
The water-containing solution which is used in the above-mentioned method is water per se or an aqueous solution of an inorganic material, a surfactant or an organic solvent such as ethanol or the like. The water vapor-containing gas refers to a water vapor containing a vapor of an organic solvent such as ethanol or the like, air, oxygen, hydrogen and/or nitrogen.
Instead of the two-step treatment, namely, the step A including the heat treatment or the mechanochemical treatment for conversion to an amorphous state and then the step B including the dipping treatment into the water-containing solution, the impregnation treatment with the water-containing solution or the contacting treatment with the water vapor-containing gas, the step A of conversion to the amorphous state and the step B of the micro-dispersion can also be conducted at the same time by treating a mixture of efonidipine hydrochloride and HPMC-AS with a hot steam at from 100 to 140° C. and high pressure.
Meanwhile, in the case of the high frequency heating in the step A, the high frequency directly vibrates the water molecule to delocalize the localized amorphous substance of efonidipine hydrochloride and increase the micro-dispersion simultaneously with the conversion of efonidipine hydrochloride to the amorphous state through the heat treatment, whereby the stability and the absorbability of the amorphous substance can be increased without using the step B.
In the production of the solid dispersion, the stability can be further increased by adding a thermostabilizer. Further, oral preparations of efonidipine hydrochloride can be produced upon using the solid dispersion of the pr
Bunrin Toyohiko
Miyamoto Misao
Nishiyama Tetsuyuki
Oda Toshihisa
Okabe Toshio
Kishore Gollamudi S.
Nissan Chemical Industries Ltd.
Oliff & Berridg,e PLC
Ware Todd D
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