Processes are provided for the preparation of orally administrable, yellow and powdery compositions essentially consisting of particles composed of a homogeneous mixture of an amorphous Cefditoren pivoxil substance with a water soluble high-molecular additive. These compositions can be produced by dissolving crystalline Cefditoren pivoxil substance and the water-soluble high-molecular additive in an aqueous solution of an acid, then neutralizing the resultant solution, to co-precipitate the product, and drying the thus precipitated product, followed by recovering the product in the form of the above-mentioned particles.

This invention relates to an orally administrable and powdery composition consisting essentially of a number of particles each comprising a crystallographically stable and amorphous cephalosporin. More specifically, this invention relates to a novel, orally administrable and powdery composition consisting essentially of particles which each have a uniform internal texture within each particle and each are formed from a homogeneous mixture of an amorphous and water-soluble substance of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl) ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, that is, Cefditoren pivoxil (a generic name), with a water-soluble, high-molecular additive, for example, a water-solubilized derivative of cellulose. This invention further relates to processes for the preparation of the novel, orally administrable and powdery composition as above-mentioned.
The cephem compound known under the generic name xe2x80x9cCefditorenxe2x80x9d is the compound which is represented by the following formula (A)
and which compound was at first named as 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer) (refer to Japanese Patent Publication Hei 3-64503 specification, U.S. Pat. No.4,839,350 and European Patent No.0175610 specification).
Cefditoren pivaloyloxymethyl ester is a pro-drug known under the generic name xe2x80x9cCefditoren pivoxilxe2x80x9d and is the compound represented by the following formula (B)
Cefditoren pivoxil is also known in the name of xe2x80x9c(xe2x88x92)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl esterxe2x80x9d and is described on page 317 of the literature xe2x80x9cMerck Indexxe2x80x9d, the 12th Edition to be a pale yellow-colored powdery substance melting at 127xcx9c129xc2x0 C. Another chemical name of the compound xe2x80x9cCefditoren pivoxilxe2x80x9d is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.
Cefditoren pivoxil, when orally administered, can be well absorbed by the digestive tracts, within which Cefditoren pivoxil is hydrolyzed into Cefditoren. It is known that Cefditoren is an antibiotic substance possessing an extremely broad antibacterial spectrum but a low toxicity and Cefditoren is very excellently useful for the therapeutic treatment and prevention of diseases which are caused by gram-positive and gram-negative bacteria. At present, Cefditoren pivoxil is widely utilized as an orally administrable pro-drug for the therapy.
We, the present inventors, had made investigations with the intention of obtaining a highly pure product of Cefditoren pivoxil, and as a result, we already succeeded in obtaining Cefditoren pivoxil in the form of an orthorhombic crystalline substance (at a purity of: 97xcx9c98%) of a melting point of 206xcx9c215.7xc2x0 C. (with decomposition), by adopting a certain particular process (refer to International Open-Laying Publication No. WO98/12200 of PCT application No. PCT/JP97/03340, issued on Mar. 26, 1998). This orthorhombic crystalline substance of Cefditoren pivoxil shows such advantages that it has a high purity, a high thermal stability and a high storage-stability under high-humidity conditions, but still it shows such disadvantage that it itself is not so suitable for the purpose of oral administrations due to its poor solubility in water.
In general, for such medicinal compounds which are sparingly soluble in water, it is well known that the solubility or the dissolution speed of the sparingly water-soluble compounds in water can exert a great influence on the absorption in vivo of said compounds. Thus, many reports were presented on how to improve the water-solubility of such medicinal compounds which are sparingly soluble in water. One of the reported proposals is a method in which a medicinal compound sparingly soluble in water is converted into an amorphous substance, thus to improve the solubility of the compound in water. It is known that an amorphous substance generally has a higher solubility in water, as compared with that of the corresponding crystalline substance. It is therefore expectable that if the orthorhombic crystalline substance of Cefditoren pivoxil sparingly soluble in water is converted into an amorphous substance which is of a higher solubility in water, there may be afforded such a water-soluble and highly pure product of Cefditoren pivoxil which is capable of exhibiting its therapeutic efficacy to a full extent.
We have therefore further prosecuted diligently our investigations in order to solve the problem of converting the crystalline Cefditoren pivoxil into an amorphous substance having a higher water-solubility. As a result, we have now found that there can successfully be prepared an orally administrable, yellow-colored powdery composition consisting essentially of such particles which each have a uniform internal texture or tissue within each particle and which each are formed from a homogeneous mixture of the amorphous Cefditoren pivoxil substance having a high water-solubility and a high thermal stability, with a water-soluble high-molecular additive, when use is made of such a process which comprises dissolving a crystalline Cefditoren pivoxil in an acidic aqueous solution containing a water-soluble high-molecular additive, for example, a water-solubilized derivative of cellulose and an acid dissolved therein, thereby to form an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular additive and the acid dissolved therein, then slowly adding to the resultant acidic aqueous solution an aqueous solution of an inorganic base to neutralize said acidic aqueous solution to a neutral or a substantially neutral pH value, with co-precipitating Cefditoren pivoxil and said water-soluble high-molecular additive simultaneously from said aqueous solution during the neutralization operation, then washing the deposited precipitate with an aqueous solution of the water-soluble high-molecular additive, drying the washed precipitate, and recovering the resulting particulate product so dried. This invention has been established on the basis of these findings mentioned above.
Thus, according to a first aspect of this invention, there is provided an orally administrable, yellow-colored powdery composition consisting essentially of solid particles which each are formed of a homogeneous mixture of a crystallo-graphically stable, amorphous and water-soluble substance of Cefditoren pivoxil with a water-soluble high-molecular additive, and which particles have a uniform, internal texture within each particle, characterized in that said yellow-colored powdery composition consists essentially of the solid particles each formed of the homogeneous mixture of (i) the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil, namely 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, with (ii) the water-soluble high-molecular additive which is either such a pharmaceutically acceptable, water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose, methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol, that the water-soluble high-molecular additive (ii) contained in the above-mentioned solid particles is present in said particles in a proportion of 0.5%xcx9c5% based on the weight of the Cefditoren pivoxil substance, that said particles fuse at a temperature of 120xc2x0 C. or higher, but do not show any definite melting point, that the amorphous substance of Cefditoren pivoxil (i) contained in said particles does not show any peak of the angle of diffraction in a X-ray powder diffractometry chart of said particles but exhibits in its infrared absorption spectrum (as measured by pelleted potassium bromide method) a substantially broader peak of absorption at a wave number of 1750 cmxe2x88x921, as compared with the sharp peak of absorption exhibited by the orthorhombic crystalline substance of Cefditoren pivoxil at a wave number of 1750 cmxe2x88x921 in the infrared absorption spectrum, and that the amorphous substance of Cefditoren pivoxil (i) contained in said particles can be dissolved in an acidified water containing hydrochloric acid (pH 1.2) at a solubility of at least 4 mg/ml of Cefditoren pivoxil at 37xc2x0 C. and has a crystallographical stability such that said amorphous Cefditoren pivoxil substance does not involve crystallization when stored at 40xc2x0 C. for 4 months in a sealed container under dry conditions.
One preferred example of the powdery composition according to the first aspect of this invention is such a composition consisting essentially of particles each formed of a homogeneous mixture of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with the water-soluble high-molecular additive which is hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose or polyvinylpyrrolidone, and which additive as blended is present in a proportion of 1%xcx9c3% based on the weight of the Cefditoren pivoxil.
Further, in respect of the respective solid particles which each are formed of the homogeneous mixture of the amorphous Cefditoren pivoxil with the water-soluble high-molecular additive and which are present in the powdery composition according to the first aspect of this invention, we have now observed, under a polarizing microscope of 400 magnifications or under an electron microscope, the surface texture or tissue of said solid particles, and we have found that the surface of each particle has a simple and uniform texture or tissue. We cannot find any presence of independent and separate grains of either Cefditoren pivoxil or the high-molecular additive in the surface of each particle.
In the powdery composition according to the first aspect of this invention, the water-soluble high-molecular additive which is to be mixed with the amorphous Cefditoren pivoxil, and which is the water-solubilized cellulose derivatives, or pluran, carraqeenan, polyvinylpyrrolidone or an arginic acid ester of polypropylene glycol, may be of a grade thereof which usually is used and incorporated in the formulations of medicines as a binder or a suspending agent. Among the water-soluble high-molecular additives to be usable in the composition of the first aspect of this invention, the water-solubilized derivatives of cellulose are particularly preferred. As the water-solubilized derivatives of cellulose, there may be used hydroxypropylmethyl cellulose (abbreviated as HPMC), hydroxypropylmethyl cellulose phthalate (abbreviated as HPMCP), hydroxypropyl cellulose (abbreviated as HPC), methyl cellulose (abbreviated as MC), carboxymethyl cellulose calcium salt or carboxymethyl cellulose sodium salt. The use of hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) or methyl cellulose (MC) is particularly preferred.
In the homogeneous mixture which constitutes the solid particles present in the powdery composition of the first aspect of this invention, and which is composed of the amorphous Cefditoren pivoxil and the water-soluble high-molecular additive, the proportion of the water-soluble high-molecular additive to be incorporated therein may be in a range of 0.5%xcx9c5%, preferably in a range of 1%xcx9c3% based on the weight of Cefditoren pivoxil.
Further, we have tried to measure the melting point of the solid particles present in the composition of the first aspect of this invention, by placing the particles in a melting point-measuring apparatus. As a result, we have found that these solid particles fuse at 120xcx9c150xc2x0 C. with decomposition, but do not show any one definite melting point.
We have further carried out the measurement of powder X-ray diffraction of the solid particles present in the composition of the first aspect of this invention, by placing the particles in a X-ray powder diffraction apparatus (Rigaku Denki K. K. : Geigerflex 2027). Upon analysis of the pattern of the resulting X-ray diffraction chart of said X-ray powder diffraction, it is shown that no peak is appearing in the angle of diffraction, indicating that the Cefditoren pivoxil substance existing in said solid particles is amorphous in nature.
We have further carried out a measurement of infrared absorption spectrum of the solid particles present in the composition of the first aspect of this invention, by mixing the solid particles with an amount of potassium bromide, compressing the resultant mixture to pelletize the same, and then placing the resulting pellet into an infrared absorption spectrometer. In the spectrum chart thus obtained, the infrared absorption spectrum of the Cefditoren pivoxil substance present in said powder exhibits at a wave number of 1750 cmxe2x88x921 an absorption peak which is substantially broader than such a sharp absorption peak that the orthorhombic crystalline substance of Cefditoren pivoxil exhibits at a wave number of 1750 cmxe2x88x921 in its infrared absorption spectrum.
We have also made a measurement of powder X-ray diffraction of the previously stored solid particles present in the composition of the first aspect of this invention, by placing and storing said solid particles in a sealed container under a dry air atmosphere at 40xc2x0 C. for 4 months, followed by measuring the powder X-ray diffraction of the stored particles in the powder X-ray diffraction apparatus used as above. Analysis of the pattern of the resulting powder X-ray diffraction chart did not indicate any peak in the angle of diffraction in the chart. Thus, it is demonstrated that the Cefditoren pivoxil present in the particles stored as above has remained in the amorphous state and that it is crystallographically stable and can maintain the amorphous state even after the storage thereof for a long period of time.
We presume that in the composition of this invention, the water-soluble high-molecular additive co-existent in admixture with the Cefditoren pivoxil in the solid particles can possess a function capable of inhibiting the molecules of Cefditoren pivoxil from undergoing their crystallization.
The solid particles present in the composition of this invention have an average particle diameter within the range of 0.5 xcexcxcx9c100 xcexc.
The solid particles present in the composition of this invention were tested for the measurement of their water-solubility as shown in Test Example given hereinafter. It was thus found that the amorphous Cefditoren pivoxil contained in said particles was soluble in an acidified water of pH 1.2 containing about 0.1 N hydrochloric acid (corresponding to the artificial gastric juice specified in Japanese Pharmacopedia) and had a solubility of at least 4 mg/ml in the acidified water at 37xc2x0 C.
Furthermore, we have proceeded our further investigation. Thus, when we carry out, for the purpose of producing the particles of the powdery composition of the first aspect invention, the process which comprises the steps of completely dissolving a crystalline Cefditoren pivoxil in an acidic aqueous solution containing and having dissolved therein a water-soluble high-molecular additive and an acid, thereby to prepare an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular additive and the acid all dissolved therein, then slowly adding to the resulting acidic aqueous solution so prepared an aqueous solution of an inorganic base, thereby to neutralize the acidic aqueous solution to a neutral pH value or a substantially neutral pH value, allowing, during the neutralization operation, Cefditoren pivoxil and the first-mentioned water-soluble high-molecular additive to co-precipitate simultaneously from said aqueous acidic solution, separating and then washing the deposited precipitate with an aqueous solution of the first-mentioned a water-soluble high-molecular additive and subsequently drying the washed precipitate, we have now found that the aforesaid process can be carried out in such one modified manner that the first mentioned water-soluble high-molecular additive, which was contained in said acidic aqueous solution of the water-soluble high-molecular additive and the acid to be employed for the dissolution of Cefditoren pivoxil, and which is to be contained in the washing aqueous solution of the high-molecular additive for washing the deposited precipitate, is replaced by such a second, water-soluble high-molecular additive which is made of a compound different from said first-mentioned high-molecular additive, when it is intended to prepare a washing aqueous solution of the water-soluble high-molecular additive which is to be employed in the step of washing said deposited recipitate therewith, and thereby at least a portion of the second, water-soluble high-molecular additive present in so prepared the washing aqueous solution of the second additive as employed for the aforesaid washing step is allowed to transfer into the surface of the precipitate particles during said washing step. It has further been found that, when said washing step is conducted with said aqueous solution of the second-mentioned additive, followed by conducting the steps of recovering and drying the precipitate particles of which the surface have contained therein the second, water-soluble high-molecular additive as transferred from the washing aqueous solution employed in said washing step, there can be afforded such dried precipitate particles wherein the surface layer of each of said solid particles as collected is formed from a homogeneous mixture of the amorphous Cefditoren pivoxil with the first, water-soluble high-molecular additive and the second, water-soluble high-molecular additive, but wherein the central portion or core portion of each of the solid particles lying under the surface layer of the solid particles is formed from a homogeneous mixture of the amorphous Cefditoren pivoxil with the first, water-soluble high-molecular additive.
According to a second aspect of this invention, therefore, there is provided an orally administrable, yellow-colored powdery composition consisting essentially of particles which each substantially comprise mixtures of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with water-soluble high-molecular additive or additives, and which particles have a uniform, internal texture within each particle, characterized in that the yellow-colored powdery composition consists essentially of the particles each substantially comprising a mixture of (i) the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil, namely 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, with (ii) a first, water-soluble high-molecular additive which is either such a pharmaceutically acceptable, water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose, methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol, that the central portion or core portion of the respective particles which is lying under the surface layer of said respective particles is formed only from a homogeneous mixture of (i) the amorphous substance of Cefditoren pivoxil with (ii) the above-mentioned first, water-soluble high-molecular additive, but the surface layer of said particles is formed from a homogeneous mixture of (i) the amorphous substance of Cefditoren pivoxil with (ii) the first, water-soluble high-molecular additive and also with (iii) such a second, water-soluble high-molecular additive which is additionally incorporated and which second additive is made of a substance different from the above-mentioned first, water-soluble high-molecular additive present just in the central portion or core portion of said particles lying under said surface layer of the particle, and which second, water-soluble high-molecular additive is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone, that both the first, water-soluble high-molecular additive (ii) and the second, water-soluble high-molecular additive (iii) are present in a total proportion of them of 0.5%xcx9c5% based on the weight of the Cefditoren pivoxil substance contained in said particles, that said particles fuse at a temperature of 120xc2x0 C. or higher, but do not show any definite melting point, that the amorphous substance of Cefditoren pivoxil (i) contained in said particles does not show any peak of the angle of diffraction in a powder X-ray diffractometry chart of said particles but exhibits in its infrared absorption spectrum (as measured by pelleted potassium bromide method) a substantially broader peak of absorption at a wave number of 1750 cmxe2x88x921, as compared with the sharp peak of absorption exhibited by the ortho-rhombic crystalline substance of Cefditoren pivoxil at a wave number of 1750 cmxe2x88x921 in the infrared absorption spectrum, and that the amorphous substance of Cefditoren pivoxil (i) contained in said particles can be dissolved in an acidified water containing hydrochloric acid (pH 1.2) at a solubility of at least 4 mg/ml of Cefditoren pivoxil at 37xc2x0 C. and has a crystallographical stability such that said amorphous Cefditoren pivoxil substance does not involve crystallization when stored at 40xc2x0 C. for 4 months in a sealed container under dry conditions.
A first preferred example of the powdery composition according to the second aspect of this invention is such a composition, wherein the central portion or core portion of the particles constituting the composition, which is lying under the surface layer of the particles, is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropylmethyl cellulose, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropylmethyl cellulose and also with hydroxypropyl cellulose or methyl cellulose.
A second preferred example of the powdery composition according to the second aspect of this invention is such a composition, wherein the central portion or core portion of the particles constituting the composition, which is lying under the surface layer of the particles, is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropylmethyl cellulose, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with hydroxypropyl cellulose and also with hydroxypropylmethyl cellulose or methyl cellulose.
A third preferred example of the powdery composition according to the second aspect of this invention is such a composition, wherein the central portion or core portion of the particles constituting the composition, which is lying under the surface layer of the particles, is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with methyl cellulose, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with methyl cellulose and also with hydroxypropylmethyl cellulose or hydroxypropyl cellulose.
A fourth preferred example of the powdery composition according to the second aspect of this invention is such a composition, wherein the central portion or core portion of the particles constituting the composition, which is lying under the surface layer of the particles, is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with polyvinylpyrrolidone, but the surface layer of said particles is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with polyvinylpyrrolidone and also with hydroxypropylmethyl cellulose or hydroxypropyl cellulose or methyl cellulose.
The solid particles present in the composition of the second aspect of this invention have physical and physicochemical properties substantially the same as those of the solid particles present in the composition according to the first aspect of this invention.
Besides, the solid particles present in the composition according to the second aspect of this invention have been found to be such those that, when the surface of the particles are observed under a polarizing microscope or under an electron microscope, said surface has a simple and uniform, internal texture in each particle and does not substantially contain any independently separate grains of Cefditoren pivoxil, nor any independently separate grains of the water-soluble high-molecular additives in the surface texture or tissue of said particles.
Both of the powdery composition according to the first aspect of this invention and the powdery composition according to the second aspect of this invention are orally administrable, and they may be formulated in the form of tablets by blending said composition with excipient(s), for example, starch or talc, and/or binder(s), for example, gelatine or hydroxypropyl cellulose, and a suitable additive agent, and then compressing the resulting blend into tablets. Both of the powdery compositions according to the first and second aspects of this invention may also be formulated in the form of powdery preparations by blending such composition with a pharmaceutically acceptable powdery carrier, for example, starch or cellulose powder.
For a process for the preparation of the powdery composition according to the first aspect of this invention, there is provided, according to a third aspect of this invention, a process for the preparation of a yellow-colored powdery composition consisting essentially of particles which each are formed of a homogeneous mixture of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with a water-soluble high-molecular additive, and which particles have a uniform, internal texture within each particle, characterized in that the process comprises a step of dissolving an orthorhombic crystalline substance of Cefditoren pivoxil, namely 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, in an acidic aqueous solution which is containing a water-soluble high-molecular additive made of either such a water-solubilized derivative of cellulose as chosen from hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol as dissolved at a concentration of 0.05% to 1% (weight/weight basis), and which acidic aqueous solution is containing also hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid at a concentration of 0.1Nxcx9c12N of the acid, so that the amount of Cefditoren pivoxil dissolved in said acidic aqueous solution is in the range of 10 times to 130 times based on the whole weight of said water-soluble high-molecular additive contained in said acidic aqueous solution, and so that there is prepared an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular additive and the acid dissolved therein; a step of subsequently neutralizing the acidic aqueous solution so prepared by adding slowly thereto an aqueous solution or solutions of sodium or potassium hydroxide, sodium or potassium hydrogen carbonate, or sodium or potassium carbonate, singly or in combination, or an aqueous solution of ammonium hydroxide, with maintaining said acidic aqueous solution at a temperature of 10xc2x0 C. or below under stirring, and with the amount of the basic sodium or potassium compound or ammonium hydroxide to be added to said acidic aqueous solution being so adjusted that the resulting reaction solution after the neutralization shows a pH value of 6.5xcx9c7.1; and a step of continuing during the neutralization reaction the stirring of the aqueous solution containing Cefditoren pivoxil at a temperature of 10xc2x0 C. or below, to bring about co-precipitation of Cefditoren pivoxil and the water-soluble high-molecular additive simultaneously from the aqueous solution; a step of collecting by filtration or centrifugation, the so deposited precipitate from the resulting neutralization reaction mixture; a step of washing the collected precipitate with an aqueous solution of a water-soluble high-molecular additive made of the same substance as that of the first-mentioned water-soluble high-molecular additive and containing said additive dissolved in said solution at a concentration of 0.5%xcx9c10% (weight/weight basis), while at least a portion of said water-soluble high-molecular additive used here in the washing aqueous solution is allowed during the washing operation to transfer from the washing aqueous solution of the water-soluble high-molecular additive into the surfaces of the particles of said precipitate; and a step of then drying the washed precipitate, to afford the yellow-colored powdery composition consisting essentially of the particles each formed of the homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with the above-mentioned water-soluble high-molecular additive present in a proportion of 0.5%xcx9c5% based on the weight of the Cefditoren pivoxil substance.
In practicing the process of the third aspect of this invention, the acid present in the aqueous solution of the water-soluble high-molecular additive and the acid to be used for the dissolution of the crystalline Cefditoren pivoxil substance may preferably be hydrochloric acid, phosphoric acid, acetic acid or sulfuric acid. Particularly, hydrochloric acid is preferred. The concentration of the acid in said aqueous solution may be within a range of 0.1Nxcx9c12N, with a range of 0.5Nxcx9c2.0N being particularly preferred.
The step of dissolving the crystalline Cefditoren pivoxil substance in the acidic aqueous solution containing said water-soluble high-molecular additive and acid may preferably be carried out at a temperature of 10xc2x0 C. or lower. The dissolution of the crystalline Cefditoren pivoxil substance may preferably be effected with taking a period of time of 10xcx9c60 minutes therefor. By adopting these operation conditions, it is necessary to make the Cefditoren pivoxil substance dissolved completely in the aqueous solution of the water-soluble high-molecular additive and the acid.
Next, there is effected the step of neutralizing the resulting aqueous solution of the Cefditoren pivoxil, water-soluble high-molecular additive and acid, with an inorganic base. The aqueous solution of an inorganic base used for this neutralization step may preferably be an aqueous ammonium hydroxide solution, namely aqueous ammonia, or aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium hydrogen carbonate solution or aqueous potassium hydrogen carbonate solution. Aqueous ammonia is particularly preferred. The concentration of the inorganic base in the aqueous solution of the inorganic base may be in a range of 0.1Nxcx9c14N, but the base concentration in a range of 0.5Nxcx9c2.0N is particularly preferred. An aqueous solution of one inorganic base may be used in combination with an aqueous solution of another inorganic base. The addition of the aqueous solution of the inorganic base is preferably carried out slowly, while maintaining the neutralization reaction mixture at a temperature of 0xc2x0 C.xcx9c10xc2x0 C. The addition may preferably be effected dropwise. The time to be taken for the neutralization reaction may be 5 minutesxcx9c24 hours and preferably 5 minutesxcx9c10 hours. During the neutralization reaction, it is preferred that the amount of the inorganic base added is so controlled that the resulting reaction mixture shows a pH value of 6.5xcx9c7.0 at the completion of the neutralization. With the progress of the neutralization reaction, Cefditoren pivoxil and the water-soluble high-molecular additive are allowed to be co-precipitated simultaneously from the aqueous solution, resulting in the deposition of solid precipitate. This precipitate is composed of a mixture of Cefditoren pivoxil with the water-soluble high-molecular additive.
After the completion of the neutralization reaction, the precipitate is then collected from the resulting neutralization reaction mixture. The collection of the precipitate may be effected by filtration, for example, filtration under a reduced pressure, or by centrifugation, in a conventional manner.
Next, the precipitate so collected is subjected to the step of washing it at a temperature of 10xc2x0 C. or below with an aqueous solution containing such a water-soluble high-molecular additive which is of the same compound as the high-molecular additive just co-precipitated and thus included in said precipitate and which high-molecular additive is present at a concentration of 0.5%xcx9c10% (weight %) in said aqueous solution. By this washing operation, the salts having attached to the precipitate can be removed, and at least a portion of the water-soluble high-molecular additive present in the washing aqueous solution is allowed to transfer into the surface of the precipitate particles from the washing aqueous solution of the water-soluble high-molecular additive during the washing operation. If a plain water were used for the step of washing the precipitate, a portion of the water-soluble high-molecular additive which has been included and contained in the precipitate could be washed away therefrom. In such a possible case, the particles of the powder which could be obtained after a drying of the precipitate so washed with the plain water would be undesirable as the target product wanted, because the content of the water-soluble high-molecular additive in the particles should be unsuitably lower than the desirable one. Such undesirable product is inappropriate in that the Cefditoren pivoxil component contained therein can show some tendency to crystallize out.
The precipitate which has received the washing step as above is then dried in a conventional way. The drying step is preferably carried out at a temperature of 30xc2x0 C. or lower under a reduced pressure. Thus, as the dried final product, there can be afforded a powdery composition consisting essentially of solid particles which each are formed of a homogeneous mixture of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil and the water-soluble high-molecular additive as mixed in a proportion of 0.5%xcx9c5% (weight %) of said additive, based on the weight of the Cefditoren pivoxil substance.
Preferably, the process of the third aspect of this invention may be effected by such a process comprising a step of dissolving the orthorhombic crystalline substance of Cefditoren pivoxil in an acidic aqueous solution which is containing such a water-soluble high-molecular additive as chosen from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone as dissolved at a concentration of 0.05% to 1% (weight/weight basis) and which acidic aqueous solution is containing also hydrochloric acid or phosphoric acid at a concentration of 0.5Nxcx9c2.0N of the acid, so that the amount of Cefditoren pivoxil dissolved in said acidic aqueous solution is in a range of 10 times to 100 times based on the whole weight of said water-soluble high-molecular additive contained in said acidic aqueous solution, and so that there is prepared an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular additive and the acid dissolved therein; a step of subsequently neutralizing the so prepared acidic aqueous solution containing Cefditoren pivoxil, by adding slowly thereto a 1Nxcx9c2N aqueous sodium hydroxide solution or/and a 1Nxcx9c2N aqueous sodium hydrogen carbonate solution, or by adding slowly thereto a 1Nxcx9c2N aqueous ammonium hydroxide solution, with maintaining said acidic aqueous solution at a temperature of 5xc2x0 C. or below under stirring, until said acidic aqueous solution is neutralized to a pH value of 6.5xcx9c7.0; a step of continuing during the neutralization reaction the stirring of the resulting neutralization reaction mixture at a temperature of 5xc2x0 C. or below, to bring about co-precipitation of Cefditoren pivoxil and the water-soluble high-molecular additive simultaneously from said aqueous solution; a step of collecting the so deposited precipitate from the resulting neutralization reaction mixture; a step of washing the collected precipitate with an aqueous solution of a water-soluble high-molecular additive made of the substance same as that of the first-mentioned water-soluble high-molecular additive and containing said additive dissolved in said solution at a concentration of 0.5%xcx9c10% (weight/weight basis); and a step of then drying the washed precipitate, to afford the yellow-colored powdery composition consisting essentially of the particles each formed of a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with the above-mentioned water-soluble high-molecular additive present in a proportion of 1%xcx9c3% based on the weight of the Cefditoren pivoxil substance.
For a process for the preparation of the powdery composition of the second aspect of this invention, there is provided, according to a fourth aspect of this invention, a process for the preparation of a yellow-colored powdery composition consisting essentially of particles which each comprise mixtures of a crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with water-soluble high-molecular additive or additives, and which particles have a uniform, internal texture within each particle, characterized in that the process comprises a step of dissolving an orthorhombic substance of Cefditoren pivoxil in an acidic aqueous solution which is containing a first water-soluble high-molecular additive made of either such a water-solubilized derivative of cellulose as chosen from hydroxy-propylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose, methyl cellulose and a pharmaceutically acceptable alkali metal salt or alkaline earth metal salt of carboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol as dissolved at a concentration of 0.05%xcx9c1% (weight/weight basis) and which acidic aqueous solution is containing also hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid at a concentration of 0.1Nxcx9c12N of the acid, so that the amount of Cefditoren pivoxil dissolved in said acidic aqueous solution is in a range of 10 times to 130 times based on the whole weight of said first water-soluble high-molecular additive contained in said acidic aqueous solution, and so that there is prepared an acidic aqueous solution containing Cefditoren pivoxil, the first, water-soluble high-molecular additive and the acid dissolved therein; a step of subsequently neutralizing the so prepared acidic aqueous solution, by adding slowly thereto an aqueous solution or solutions of sodium or potassium hydroxide, sodium or potassium hydrogen carbonate, or sodium or potassium carbonate, singly or in combination, or by adding slowly thereto an aqueous solution of ammonium hydroxide, with maintaining said acidic aqueous solution at a temperature of 10xc2x0 C. or below under stirring, and with the amount of the basic sodium or potassium compound or ammonium hydroxide to be added to said acidic aqueous solution being so adjusted that the reaction solution after the neutralization shows a pH value of 6.5xcx9c7.1; a step of continuing during the neutralization reaction the stirring of the aqueous solution containing Cefditoren pivoxil at a temperature of 10xc2x0 C. or below, to bring about co-precipitation of Cefditoren pivoxil and the first, water-soluble high-molecular additive simultaneously from the aqueous solution; a step of collecting by filtration or centrifugation the so deposited precipitate from the resulting neutralization reaction mixture; a step of washing the collected precipitate with such an aqueous solution which is containing a second, water-soluble high-molecular additive made of a substance different from the above-mentioned first, water-soluble high-molecular additive contained in said acidic aqueous solution containing Cefditoren pivoxil, and which aqueous solution is containing said second high molecular additive dissolved therein at a concentration of 0.5%xcx9c10% (weight/weight basis), while at least a portion of said second water-soluble high-molecular additive used here in the washing aqueous solution is allowed during the washing operation to transfer from the washing aqueous solution of the second water-soluble high-molecular additive into the surfaces of the particles of the precipitate; and a step of then drying the washed precipitate, to afford the yellow-colored powdery composition consisting essentially of such particles which each contains Cefditoren pivoxil, and of which the central portion or core portion of each particle is formed only from a homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with the first water-soluble high-molecular additive present in a proportion of 0.5%xcx9c5% based on the weight of said Cefditoren pivoxil substance, and of which the surface layer of each particle is formed from a homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of Cefditoren pivoxil with said first water-soluble high-molecular additive and also with said second water-soluble high-molecular additive.
The process of the fourth aspect of this invention may be carried out in the same manner as the process of the third aspect of this invention.
The process of the fourth aspect of this invention is preferably effected by such a process comprising a step of dissolving the orthorhombic crystalline substance of Cefditoren pivoxil in an acidic aqueous solution which is containing such a water-soluble high-molecular additive as chosen from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone as dissolved at a concentration of 0.05%xcx9c1% (weight/weight basis) and which acidic aqueous solution is containing also hydrochloric acid or phosphoric acid at a concentration of 0.5Nxcx9c2.0N of the acid, so that the amount of Cefditoren pivoxil dissolved in the acidic aqueous solution is in a range of 10 times to 100 times based on the whole weight of said first water-soluble high-molecular additive contained in said acidic aqueous solution, and so that there is prepared an acidic aqueous solution containing Cefditoren pivoxil, the water-soluble high-molecular additive and the acid dissolved therein; a step of subsequently neutralizing the so prepared acidic aqueous solution containing Cefditoren pivoxil, by adding slowly thereto an aqueous 1Nxcx9c2N sodium hydroxide solution or/and an aqueous 1Nxcx9c2N sodium hydrogen carbonate solution or by adding slowly thereto an aqueous 1Nxcx9c2N ammonium hydroxide solution, with maintaining the acidic aqueous solution at a temperature of 5xc2x0 C. or below under stirring, until the acidic aqueous solution is neutralized to a pH value of 6.5xcx9c7.0; a step of continuing the stirring of the neutralization reaction mixture at a temperature of 5xc2x0 C. or below during the neutralization reaction, to bring about the co-precipitation of Cefditoren pivoxil and said first water-soluble high-molecular additive simultaneously from the aqueous solution; a step of collecting the deposited precipitate from the resulting neutralization reaction mixture; a step of washing the collected precipitate with such an aqueous solution which is containing, as the second water-soluble high-molecular additive made of a substance different from the above-mentioned first water-soluble high-molecular additive, such a water-soluble high-molecular additive as chosen from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone, and which aqueous solution is containing said second high-molecular additive dissolved therein at a concentration of 0.5%xcx9c10% (weight/weight basis), while at least a portion of the second water-soluble high-molecular additive used here in the washing aqueous solution is allowed during the washing operation to transfer from said aqueous solution of the second water-soluble high-molecular additive into the surfaces of the particles of the precipitate; and a step of then drying the washed precipitate, to afford the yellow-colored powdery composition consisting essentially of such particles of which the central portion or core portion of each particle is formed only from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with said first water-soluble high-molecular additive, and of which the surface layer of each particle is formed from a homogeneous mixture of the amorphous substance of Cefditoren pivoxil with said first water-soluble high-molecular additive and also with said second water-soluble high-molecular additive.

Composition comprising a crystallographically stable, amorphous cephalosporin and processes for the preparation thereof


An opening is made in a surface intercepting a wave propagating through space. An image of an object is formed on an intermediate surface from the wave passing through this opening. After wave conversion, that is to say, after the entity of a wave is converted into a detectable wave from which a two-dimensional image can be picked up, an image is picked up with a two-dimensional image pick-up device. Distortion caused by the two-dimensional image pick-up device is corrected using a calibration grid pattern provided on the intermediate surface. The intermediate surface provides a wave converting function, distortion calibrating function, distortion-free wide field of view ensuring function, and wave entity converting function, and a place of detection elements themselves.

Hitherto, images of particular objects have been formed using light or other electromagnetic waves in various fields of science and technology. Image-forming systems using opening, which have been developed from the concept of a pinhole, are fundamental systems for such image formation. Light and other electromagnetic waves, which are examples of wave motion, have a characteristic that no distortion occurs in spatial projection.

Apparatus and method for intermediate image-formation of information propagating as wave motion passing through open hole and for image pick-up


A communication device is provided in the present invention. The communication device comprises an oscillation signal source, a tunable capacitor array, a frame counter; and a control module. The control module is configured to jointly or separately control the tunable capacitor array and the frame counter to compensate a first frequency offset of the oscillation signal source when the communication device operates in a first mode, and to jointly or separately control the tunable capacitor array and the frame counter to compensate a second frequency offset of the oscillation signal source when the communication device operates in a second mode.

1. Field of the Invention
The invention relates in general to a frequency offset correction technique for an oscillation signal source, and more particularly to a technique for correcting a frequency offset of an oscillation signal source caused by a loading amount.
2. Description of the Related Art
Most electronic systems are equipped with at least one oscillation signal source (e.g., a crystal oscillator) that provides clock signals as references for circuit operations. How to maintain a stable output frequency of an oscillation signal under all circumstances is an important issue. For example, a frequency drift may arise in output signals of an oscillation signal source when an ambient temperature changes. To prevent functions of an electronic system from being affected by environmental factors, a frequency offset compensating mechanism is essential in electronic systems.
Accompanied by advancements in electronic-related technologies, wireless communication apparatuses in all diversities are becoming increasingly popular. Circuits in current wireless communication apparatuses generally need two types of reference clock signals—system clock signals and real-time clock signals. System clock signals have a higher frequency (usually in MHz range), and are fundamental signals that many circuits refer to for operations. Real-time clock signals have a lower frequency (usually in kHz range), and mainly serve for assisting a wireless communication apparatus to count a real time (e.g., current hour, minute and second) to facilitate the wireless communication apparatus to synchronize and/or communicate with other wireless systems such as base stations. In a conventional hardware configuration, two sets of oscillation signal sources, having different oscillation frequencies and respectively outputting system clock signals and real-time signals, are arranged in the same wireless communication apparatus.
To reduce hardware costs, in another conventional approach, system clock signals and real-time clock signals are designed to share the same oscillation signal source. FIG. 1 is an example showing a partial schematic diagram of such type of electronic system. In the example, system clock signals have a frequency of 26 MHz, and real-time clock signals have a frequency of 32 kHz. The output frequency of an oscillation signal source 12 is 26 MHz and the output signal is provided to a buffer amplifier 14 and a frequency divider 16. The buffer amplifier 14 provides the amplified 26 MHz signals to its subsequent circuits (e.g., a baseband circuit) to serve as system clock signals. The frequency divider 16 divides the 26 MHz signal to generate signals having a 32 kHz frequency. A frame counter 17, coupled to one of the outputs of the frequency divider 16, counts the number of 32 kHz pulses from the frequency divider 16, and changes its output signal when the counting result reaches a predetermined threshold. The frame counter 17, which may be regarded as another frequency divider, outputs signals to control the system events.
In practice, the electronic system in FIG. 1 may be a mobile phone. In order to have proper operations, the mobile phone has to be synchronized to a base station which provides communication services. The synchronization is accomplished by decoding and tracking the difference between local clocks and the clocks in the base station. In the event that the clock signals of the mobile phone become inaccurate (e.g., when a frequency offset arises due to an ambient temperature change), settings of a coarse-tuning capacitor array 18A and/or a fine-tuning capacitor array 18B may be adjusted (i.e., equivalent to changing a loading amount of the oscillation signal source 12) to correct the output frequency of the oscillation signal source 12.
It is well-known to those skilled in the art that a mobile phone enters from a normal operation mode to a low power consumption standby mode at a predetermined interval. To lower the overall power dissipation, in the low power consumption mode, the buffer amplifier 14 and its subsequent circuits that utilize the system clock signals are turned off. The tuning capacitor arrays are set to their low capacitance state. It is apparent that the corresponding loading amounts that the oscillation signal source 12 needs to drive are different between the normal operation mode and the low power consumption mode. The change in the loading amount also causes a frequency offset in output signals of the oscillation signal source 12, leading the frequency of the real-time clock signals to deviate from 32 kHz in the low power consumption mode. However, as the mobile phone in the low power consumption mode does not synchronize with the base station, reference information for correcting the frequency offset cannot be acquired. Thus, when the frequency offset becomes too excessive, the "real time" that is determined based on the real-time clock signals may significantly deviate from the desired value causing the mobile phone to return to the normal operation mode either too early or too late potentially failing the communication with a base station.

Communication device and control method thereof


A keyboard illumination system comprises a computer device having a plurality of liquid crystal displays (LCDs). The system also comprises a display controller adapted to change an electrical state of at least one of the LCDs for providing a predetermined level of illumination by the at least one LCD for illuminating at least a portion of a keyboard of the computer device.

Computer devices, such as notebook or laptop computers, are increasingly being used in places such as automobiles, planes, classrooms, and outside. However, the surrounding environment is not always a suitable working environment for the computer device, and insufficient lighting conditions further detract from a user's ability to adequately utilize the computer device.

Hewlett-Packard Development Company, L.P.


A clock line over-protection circuit (28) carried on an interface card (16) for interfacing synchronous clock line (20), power line (22), DC common line (24) and data line (26) between a host computer (12) and a plurality of data link modules (14) with a plurality of associated controlled devices (18) including a series resistor (52) interconnected between a clock disable switch (52) and a clock signal generating amplifier (48) and a current sensor circuit (64, FIG. 3) connected across the series resistor (50) to produce a current sensor signal on an output (62). The current sensor signal is integrated by an over-current protection circuit (58, FIG. 4) to produce an over-current detection signal that varies with the difference in the clock line current magnitude during clock signal phases of opposite polarity. A clock switch control circuit (54) actuates the clock disable switch (52) to turn off and to protectively disconnect the clock line (20) and the data link modules (14) coupled therewith from the clock signal generating amplifier (48). A latch (170, FIG. 6) maintains the clock disable switch (52) in the protective off state until reset and a circuit (110, 126) provides hysteresis to the clock switch control circuit (54) to prevent resetting while the over-current condition persist.

1. Field of the Invention:
This invention generally relates an over-current protection circuit and, more particularly, to an over-current protection circuit especially adapted for protecting a synchronous clock line bus employable in industrial control systems and an industrial system employing same.
2. Description of the related art including information disclosed under 37 C.F.R. 1.97-1.99:
Industrial control systems, such as the parallel bus digital control systems shown in U.S. Pat. No. 4,808,994 issued Feb. 28, 1989, to Riley for "LOGIC INTERCHANGE SYSTEM" and shown in U.S. Pat. No. 5,553,070, issued Sep. 3, 1996, to Riley for "DATA LINK MODULE FOR TIME DIVISION MULTIPLEXING CONTROL SYSTEM", have networks with extensive bus cables. These busses, bus lines, or lines, in an industrial setting, span the factory floor between a host computer or other data termination point and a plurality of data link modules. The data link modules, in turn, are connected with one or more associated controllable devices which are controlled to perform an active function in response to data on the data line or to convey data onto the data line. Because of the factory floor environment, such network bus lines are vulnerable to cuts and resultant short circuits, or shorts.
Accordingly, in such networks it is known to provide over-current protection circuits. These over-current protection circuits detect current in the data bus line circuitry and automatically protectively break the data line circuit in the data bus when the current exceeds a preselected maximum current threshold level to protect the data bus and the associated circuitry.
The data bus, or data line, is an open drain circuit and only conducts current when active. Therefore, excess current in the data line is detected by a current sinking device at an interface circuit, or interface card, only during a clock sync period when all the loads on the data line are inactive, and the total normal load on the data line is known. This enables selection of the correct maximum current threshold level regardless of the number of control modules or the topology in which they are arranged, such as daisy chain, star, loop, loop with branches, trunk, trunk with branches, single branch, etc.
However, the clock line circuit is not open drain but rather has a so-called, totem-pole output that sinks and sources current only at the clock source at the interface card and is free running except during the periodic sync pulse. Consequently, the in-rush current in the charging and discharging of the network clock line varies with the many variations of the wiring topologies and variations in the load. The maximum current threshold level detection method successfully employed with respect to the data line is therefor not well adapted to use with respect to protecting the data line against excessive currents. The level at which the maximum, current threshold level should be set is indeterminate due to the current sinking being performed at the plurality of loads on the line.
Because of this circumstance, the known technique of relying upon absolute current levels to detect a short circuit condition on the clock line results in either false detecting of over-current conditions or in permitting existence of an excess current condition sufficiently long enough to stress the clock driver circuit.
In order to over come this problem, another technique has been known to be employed to prevent over-current conditions in the clock line. In this other technique the clock voltage waveform is monitored to compare the "incoming" clock with the "out-going" clock. The incoming clock is the signal seen on the bus cable at the clock source on the interface card 16. The out-going clock is "expected" clock as generated. Disadvantageously, the implementation of this comparison technique requires complex hardware implementation, exposes the components to destructive excess current, or requires a separate microprocessor to control. This method is also subject to false triggering by electrical noise.

Clock line over-current protector and industrial control system employing same


A method and arrangement in a telecommunications system comprising a data transmission path (8), the arrangement comprising devices (1, 21, 221 to 22n) and data being transmitted on the data transmission path between the devices in messages (4, 9) cyclically, whereby one or more of the devices (1, 221 to 22n) are arranged, during one or more first turns, respectively, to set the timing of their own cyclic traffic between cyclic traffic detected on the data transmission path; and one or more of the devices (1, 21, 221 to 22n) are arranged, during a second turn, to transmit a message not belonging to the cyclic traffic to the data transmission path on the basis of at least one determined occurrence time slot of the cyclic traffic such that the message does not collide with messages of the cyclic traffic which occur in the determined at least one occurrence time slot.

The invention relates to a method and an arrangement for arranging traffic in a telecommunications system, and particularly in a telecommunications system wherein data is transmitted cyclically.
An example of a telecommunications system wherein data transmission takes place cyclically according to certain cycle times is a common industrial automation system comprising a programmable logic controller (PLC or a "SoftPLC", which refers to replacing an execution unit of the programmable logic with an application program to be run in a computer to execute commands of the logic program), related actuators and sensors or other devices and a bus connecting the same, e.g. a Profibus or the like. Typically, the internal telecommunication of such a system is cyclic such that the transmitter of data, e.g. a PLC, transmits a certain (same) message at certain intervals according to a corresponding cycle time, in other words a cycle time refers to a time between the starting moments of the transmission of two such successive messages. The message is delivered to a device connected to the bus, and the device typically replies by transmitting a reply message. When the cycle time is sufficiently short, in practice data may thus be transferred in real time e.g. between a PLC and an actuator, so that e.g. the real-time state information or the like of the actuator is available to the PLC. Such cycles usually occur several at the same time, each cycle having a certain cycle time. The cycle times of different cycles may differ from one another or they may be equal in length. Furthermore, in such a system, a message cycle is usually always initiated by a device operating as a master, such as a PLC, while other devices (slave devices) only reply to the messages received from the master device. In such a case, each message cycle has a predetermined transfer time on a data transmission path, thus enabling collisions between different messages, i.e. simultaneous transmissions on to the data transmission path, to be prevented.
In some processes, however, a need also exists to communicate from one slave device to another, i.e. slave-to-slave communication is needed. Typically this takes place through a master device such that the master device asks a first slave device for the necessary information and writes the received reply to a second slave device. A problem with the above-described solution is that such a procedure unnecessarily consumes the capacity of the data transmission path used as well as the processor capacity of the master device since communication between slave devices always takes place through a master device.

Method and arrangement of arranging traffic in telecommunications system


A method of processing waste gas exhausted from chemical vapor deposition equipment, which entails:. a) contacting a waste gas containing viscous substances with a filtering aid agent, PA1 b) passing the waste gas containing the viscous substances exhausted from the chemical vapor deposition equipment, and which has been contacted with the filtering aid agent, through a filtering and dust collecting unit, whereby the viscous substances are condensed with the filtering aid agent on the filtering and dust collecting unit, and PA1 c) removing the condensed matter from the surface of the filter, thereby preventing clogging thereof.

1. Field of the Invention
The present invention relates to a method and apparatus for processing waste gas exhausted from chemical vapor deposition (CVD) equipment whereby a dust and/or viscous substances are separated and removed from the waste gas exhausted from the CVD equipment.
2. Description of the Prior Art
CVD is one of the semiconductor processing techniques used to form a thin film. In the CVD technique, one or more compounds such as halides, sulfides, or hydrides or other simple gases containing the elements for comprising the thin film to be formed are supplied onto a substrate so that the desired thin film is deposited on the substrate by means of a chemical reaction (such as thermal decomposition, oxidation, reduction, polymerization, vapor phase reaction, etc. at a high temperature) occurring in a vapor phase or on the surface of the substrate. As the CVD technique is based on a chemical reaction, it is possible to form a thin film of a wide variety of elements. It is also possible to obtain an arbitrary composition by properly selecting the combination of materials used for the vapor phase reaction. Therefore, the CVD technique can be used to synthesize a film having an entirely new structure and/or composition which has not been known conventionally. The CVD technique has a further advantage that a thin film can be formed at a temperature much lower than the melting point of the film material.
For example, the CVD technique is used to form a SiO.sub.2 film on a Si substrate or the like by supplying a raw material such as SiH.sub.4 (mono-silane) or tetraethoxysilane (TEOS) onto the substrate. The CVD equipment exhausts waste gas that includes not only the unreacted gas which made no contribution to the formation of the film but also dust, such as particles of SiO.sub.2, and by-products of the film formation process such as alcohol, aldehyde, and highly viscous polysiloxane, etc. Many of these components in the waste gas are hazardous and therefore, it is prohibited to directly release the waste gas into the atmosphere so as to protect humans and the environment from any negative effects.
There are various known techniques for processing the waste gas exhausted from CVD equipment. For example Japanese Patent Laid-Open No. 5-261232 discloses as a wet-type apparatus, a scrubber for processing the waste gas exhausted from atmospheric-pressure CVD equipment which is adapted to spray cleaning water containing an anionic surface-active agent or nonionic surface-active agent through a shower nozzle of the scrubber.
Japanese Patent Laid-Open No. 3-229609 discloses a dry-type apparatus for processing the waste gas exhausted from CVD equipment in such a manner that the solid components contained in the waste gas exhausted from the CVD equipment are collected in the form of particles and disposed of, wherein the waste gas is cooled without using a water shower so that the particles are deposited on the surface of a plurality of layers of wire mesh provided in an exhaust path of the waste gas, and the particles are sucked up and disposed of by a vacuum cleaner.
However, in the wet technique disclosed in Japanese Patent Laid-Open No. 5-261232, the apparatus produces waste containing dust and highly toxic gas, and thus an after-treatment is required. In the example disclosed in Japanese Patent Laid-Open No. 3-229609, the technique requires an apparatus for cooling the waste gas at a rate of 4 to 5 m.sup.3 /min for each piece of CVD equipment so that the solid particles are changed into a powder form. For example, when waste gas containing a great amount of dust and highly-viscous substances such as polysiloxane produced during an atmospheric-pressure CVD process is collected and recovered, the highly-viscous substances are deposited on the surface of the wire mesh, and it is very difficult to remove the deposited highly-viscous substances by means of suction using a vacuum cleaner. Furthermore, the highly-viscous substances also deposit on the inner wall of the pipe connected to the vacuum cleaner, which leads to a reduction in its suction capabilities. Therefore, this technique cannot provide high efficiency in waste gas processing.
It is therefore an object of the present invention to provide a method and apparatus for processing waste gas exhausted from CVD equipment which overcomes the above described problems.

Method for processing waste gas exhausted from chemical vapor and deposition equipment


A CEL material (11) is formed such that a first region (11a) thereof which is formed on a concave portion of a semiconductor substrate (1) is sufficiently thicker than a second region (11b) thereof which is formed on the other region. Light (4) is directed from above to the CEL material (11) for a predetermined period of time to render only the thin second region pervious to light to thereby expose part of a photoresist (2) which is under the second region (11b) by the illumination. Subsequently, the semiconductor substrate (1) is immersed in an appropriate solvent to remove only part of the photoresist (2) which is under the first region (11a). The part of the photoresist (2) which is under the second region 11b remains unremoved.. The photoresist (2) can be patterned with the shape of the concave portion of the semiconductor substrate (1) accurately reflected therein.

1. Field of the Invention
The present invention relates to a method of patterning an organic macromolecular film such as a photoresist.
2. Description of the Background Art
FIGS. 17 to 19 are cross-sectional views showing a conventional method of patterning a photoresist which is formed on a semiconductor substrate having an uneven surface. The method will be discussed hereinafter with reference to FIGS. 17 to 19.
Initially, a semiconductor substrate 1 which has concave portions formed on the surface thereof is coated all over with a negative photoresist 2, as shown in FIG. 17.
As shown in FIG. 18, shade masks 3 are disposed in regions corresponding to the concave portions above the semiconductor substrate 1. Light 4 is directed from above the shade masks 3 to the photoresist 2 to polymerize (expose) only part of the photoresist 2 above which the shade masks are absent and which is formed on the smooth surface of the semiconductor substrate 1.
The semiconductor substrate 1 is immersed in an appropriate solvent, so that only part of the photoresist 2 which is on the concave portions and is not illuminated is removed, and the part of the photoresist 2 which is polymerized by the illumination remains unremoved.
By forming the photoresist 2 only on the region other than the concave portions of the semiconductor substrate 1 by the use of the shade masks 3, a diffusion processing can be performed only on the concave portions of the semiconductor substrate 1. An example of the processing performed on the concave portion of the semiconductor substrate 1 is disclosed in FIG. 5 of Japanese Patent Application Laid-Open No. 62-160776.
The conventional method of the type in which the photoresist 2 is patterned on the region other than the concave portions of the semiconductor substrate has been carried out by disposing the shade masks 3 above the semiconductor substrate 1 and directing light from above the shade masks 3 to the photoresist 2. In this method, however, it is difficult to accurately dispose the shade masks 3 in the regions corresponding to the concave portions of the semiconductor substrate 1. There has been a problem that the organic macromolecular film cannot be accurately patterned in corresponding relation to the concave portions.
Another problem is that, when the light 4 enters under the shade masks 3 as shown in FIG. 20, part of the photoresist 2 which should not be illuminated is polymerized so that the pattern accuracy of the photoresist 2 remarkably deteriorates.

Method of patterning organic macromolecular film


Apparatus and associated methodology contemplating a portable sheet metal folding apparatus that folds a sheet metal panel profile into a different predetermined shape, the profile having straight elements joined together by arcs. The apparatus has consecutive roller die sets configured to perform a series of folds on a first element of the profile toward a second element of the profile. Each roller die set has opposing roller dies operably contacting only the first and second elements, not contacting any arc. The opposing roller dies are arranged to define a minimal gap between them equal to or more than the radius of the arc joining the first and second elements together. The gap provides a material relief space that is sized to clearingly permit the arc to positionally shift during folding to relieve stress and strain.

Numerous types of structural webs are made in the construction industry by joining sheet metal panels together. Roof assemblies in pre-engineered buildings, for example, are large structural webs with requisite load and weather-element resistance.
A popular type of roof has standing seams, such as the standing seams 25 depicted in FIG. 1. Adjacent sheet metal panels 24 are overlapped and then seamed together to form a weathertight joint between them, the standing seam 25. To make the standing seam 25, light gauge (22 to 24 gauge) sheet metal panels are first rollformed, in a factory or field rollforming machine, to produce upstanding cross-sectional profiles along both sides ("sidelaps"). Typically, these rollforming machines have about 12 to 16 forming stands containing about 18 to 28 die roller sets. The frame can be about 12 to 20 feet long, the forming stands being distributed along the frame. A sidelap is progressively formed as the sheet metal passes through all of the forming stands. At least some of the die roller sets can be rotated by a drive train while they are pressed against the sidelaps, frictionally engaging the sheet metal to move it through the forming stands.
FIG. 3, for example, depicts a rollformed female sidelap 34 along one side of the panel 24. The female sidelap 34 has a characteristic retention cavity at its distal end. As discussed in detail below, the female sidelap 34 consists of a number straight elements having respective lengths, connected together by arcs (curved segments) having respective radii. A generally trapezoidal transition is also rollformed into the panel 24, connecting the female sidelap 34 to the interior portion of the panel 24. A male sidelap 36 and a mirror-image trapezoidal transition is rollformed into the other side of the panel. The male sidelap 36 has a characteristic protuberant element at its distal end.
The differently-shaped sidelaps 34, 36 and transitions are manufactured with different tooling setups in the rollforming machine. The panel is ready for use after both sidelaps 34, 36 have been rollformed. FIG. 5 depicts how a female sidelap 342 (of a panel 242) can be placed around a male sidelap 361 (of another panel 241). The protuberant element of the male sidelap 361 interlocks with the retention cavity of the female sidelap 342, and otherwise the elements and arcs are configured so that the sidelaps 342, 361 nest in a closely mating relationship. In these illustrative embodiments, the sidelaps 342, 361 have been overlapped with a retention clip 38 sandwiched between them. The clip 38 is used to connect the sidelaps 342, 361 to the underlying roof structurals.
After the sidelaps 342, 361 have been overlapped and interlocked, at times with one of the clips 38 sandwiched therebetween, a portable seaming machine can be used to seam them together into the weathertight standing seam 25. An illustrative configuration of the standing seam 25 is depicted in FIG. 6. The standing seam 25 fixes the adjacent panels together so that they do not displace with respect to each other, even at high loading. Seamed together, the panels form a structural web having considerable diaphragm strength that is well suited for constructing a roof, while also suited to position and stabilize the underlying support structure in the roof assembly.
However, ordinary process variations can make seaming problematic. For example, part-to-part dimensional variations can result from machine setup or operating error during manufacturing. For example, referring back to FIG. 5, if one of the elements in the profile is longer than expected, that can become problematic in maintaining the desired closely nesting and interlocking relationships during seaming. In conventional rollforming processes, this kind of dimensional variation can lead to creating compressive forces acting on the elements that can plastically distort them and the arcs between them. These kind of distortions, and the associated ripple-effect stresses and strains, compound and propagate to cause distortions in other elements and arcs in the profile. This can defeat the goal of creating a standing seam with the advantageous closely mating and interlocking relationships of the elements and arcs. Similar failures can occur due to other types of ordinary process variations, such as sheet metal material properties like thickness, yield strength, grain structure, and the like. Improvements are needed that compensate for these difficulties in forming a reliable and robust standing seam. It is to those improvements that embodiments of this technology are directed.


Disclosed is a distortion compensation circuit that reduces the time for convergence of distortion compensation data, without impairing any stability of distortion compensation. The circuit includes an error computation and compensation data updating section that repeats a computation in which errors between an input orthogonal baseband transmission signal and a feedback signal obtained by demodulating part of the output from a power amplifier are computed to obtain error data and values obtained by multiplying this error data by step coefficients are added to distortion compensation data before updating, thereby computing distortion compensation data after updating. Distortion compensation data for compensation of nonlinear distortion is thus updated. Step coefficients are stored in a step coefficient data memory with respect to each of different input signal amplitude values. Step coefficients corresponding to an input signal amplitude value computed by an amplitude computation section are output from the memory to multipliers.

1. Field of the Invention
The present invention relates to a distortion compensation circuit which is used in a wireless transmitting apparatus such as a base station in a wireless communication system to make compensation for a distortion caused in amplification means such as a power amplifier which amplifies an input signal.
2. Description of the Related Art
In a wireless transmitting apparatus in a wireless communication system, it is ideal to use a power amplifier having linearity with respect to all amplitude components in order to minimize adjacent-channel-leakage power as small as possible. A power amplifier having good linearity with respect to a wide amplitude component range, however, is large in scale and high-priced and has large power consumption. In some case, therefore, there is no way other than a power amplifier having nonlinearity with respect to large-amplitude components while having good linearity with respect to small-amplitude components. If an amplitude component of a power level higher than the mean power level is amplified by using such a power amplifier, adjacent-channel-leakage power is increased.
Then, various distortion compensation techniques have been proposed for the purpose of reducing adjacent-channel-leakage power due to nonlinearity of power amplification means. Typical examples of such distortion compensation techniques are feedforward method, Cartesian feedback method, and the predistortion method. It is difficult to improve the efficiency of an amplification system using the feedforward method because of the need for an error amplifier. Recently, distortion compensation made by the Cartesian feedback method or the predistortion method capable of distortion compensation in a base band on a digital orthogonal coordinate system has been studied from the viewpoint of achieving cost-reduction and efficiency-improvement effects. (See, for example, Japanese Patent Laid-open Nos. 8-78967 and 8-251246).
In the Cartesian feedback method, however, the amount of improvement in distortion is proportional to the loop gain and it is, therefore, difficult to increase the bandwidth in which a distortion improvement effect can be achieved in increasing the distortion improvement effect and maintaining the loop stability in feedback. In a mobile communication system, therefore, the predistortion method capable of increasing the bandwidth is effectively used. A description will be given of the predistortion method.
FIG. 9 is a block diagram showing an example of a configuration of a wireless transmitting apparatus having a conventional predistortion-type distortion compensation circuit. This wireless transmitting apparatus has a transmission data generation unit 1, digital-to-analog (D/A) converters 31 and 32, a quadrature modulator 4, a reference signal generation unit 5, a power amplifier 6, a directional coupler 7, and a distortion compensation circuit 30. The distortion compensation circuit 30 is constituted by a nonlinear distortion compensation computation section 2, a quadrature demodulator 8, an analog-to-digital (A/D) converters 91 and 92, an amplitude computation section 10, and an error computation and compensation data updating section 91.
The nonlinear distortion compensation computation section 2 performs computation for distortion compensation on digital orthogonal baseband transmission signals I and Q from the transmission data generation unit 1 by performing complex multiplication of these signals on the basis of distortion compensation data (amplitude compensation data K and phase compensation data θ). Orthogonal baseband transmission signals I′ and Q′ after distortion compensation computation are converted into analog orthogonal baseband signals by the D/A converters 31 and 32. The quadrature modulator 4 modulates the analog orthogonal baseband signals into a orthogonally modulated signal with a signal from the reference signal generation unit 5. The orthogonally modulated signal is power amplified by the power amplifier 6 to be output as a radio frequency (RF) output.
Part of the output from the power amplifier 6 is fed back to the quadrature demodulator 8 by the directional coupler 7 to be demodulated into analog orthogonal baseband signals with the signal from the reference signal generation unit 5. The analog orthogonal baseband signals are converted into digital orthogonal baseband signals I″ and Q″ by the A/D converters 91 and 92. The error computation and compensation data updating section 91 updates the distortion compensation data by comparing the feedback digital orthogonal baseband signals I″ and Q″ and the orthogonal baseband signals I and Q from the transmission data generation unit 1 and using as an address an amplitude value from the amplitude computation section 10. The nonlinear distortion compensation computation section 2 makes distortion compensation on the basis of the updated distortion compensation data.
In the arrangement shown in FIG. 9 as an example of a predistortion-type distortion compensation circuit, a power value which is the second power of the amplitude value may be used as an address instead of the amplitude value from the amplitude computation section 10.
FIG. 10 shows a configuration of the error computation and compensation data updating section 91 shown in FIG. 9. As shown in FIG. 10. the error computation and compensation data updating section 91 is constituted by an error computation section 12, an error compensation data memory 13, a distortion compensation data memory 14, multipliers 211 and 212, and adders 221 and 222.
The error computation and compensation data updating section 91 repeats a computation in which errors between orthogonal baseband signals I and Q, which are input signals, and orthogonal baseband signals I″ and Q″, which are obtained by demodulating part of the output from the power amplifier 6, are computed to obtain error data and values obtained by multiplying this error data by step coefficients α and β are added to the distortion compensation data (amplitude compensation data Kn and phase compensation data θn) before updating, thereby computing new distortion compensation data (amplitude compensation data Kn+1 and phase compensation data θn+1). In this manner, the distortion compensation data for compensation for nonlinear distortion is updated.
Since the distortion compensation data varies depending on the amplitude value of the input signals, the distortion compensation data corresponding to a certain amplitude value is updated only when the amplitude value of the input signals becomes equal to the certain amplitude value. In the following description, if the number of times the distortion compensation data corresponding to the certain amplitude value is updated (referred to) is n, the amplitude value of the input signals when it becomes equal to the certain amplitude value at the nth time is expressed as rn.
The error computation section 12 compares the input signals I and Q having the amplitude value rn and the feedback signals I″ and Q″ on a polar coordinate system, thereby computes an amplitude error Ea(rn) and a phase error Ep(rn), also computes a value Ea(rn)/rn by dividing the amplitude error Ea(rn) by the amplitude value rn of the input signals, and outputs the computed errors and the value Ea(rn)/rn as error data to the error compensation data memory 13.
The error compensation data memory 13 is a rewritable memory for temporarily storing error data computed by the error computation section 12 by using as an address the amplitude value rn computed by the amplitude computation section 10.
The multiplier 211 performs a computation which is multiplication of the phase error Ep(rn) from the error compensation data memory 13 by the predetermined step coefficient β, and outputs the result of this computation. The multiplier 212 performs a computation in which the value Ea(rn)/rn from the error compensation data memory 13, i.e., the value obtained by dividing the amplitude error Ea(rn) by the amplitude value rn, is multiplied by the predetermined step coefficient α, and outputs the result of this computation.
The adder 221 performs a computation in which phase compensation data θn before updating, output from the distortion compensation data memory 14, is added to the result of computation from the multiplier 211, and outputs the result of this computation to the distortion compensation data memory 14 as phase compensation data θn+1 after updating. The adder 222 performs a computation in which amplitude compensation data Kn before updating, output from the distortion compensation data memory 14, is added to the result of computation from the multiplier 212, and outputs the result of this computation to the distortion compensation data memory 14 as amplitude compensation data Kn+1 after updating.
The distortion compensation data memory 14 outputs to the nonlinear distortion compensation computation section 2 amplitude compensation data Kn and phase compensation data θn corresponding to the amplitude value rn from the amplitude computation section 10, and newly stores, as compensation data corresponding to the amplitude value rn of the input signals, distortion compensation data (amplitude compensation data Kn+1 and phase compensation data θn+1) after updating from the adders 221 and 222.
The operation of the error computation and compensation data updating section 91 in this conventional distortion compensation circuit 30 will be described with reference to FIG. 10.
It is assumed that the amplitude of the input signals at a certain point in time is rn and amplitude compensation data and phase compensation data which are distortion compensation data corresponding to the amplitude value rn and which is stored in the distortion compensation data memory 14 at the corresponding time are Kn and θn, respectively. The error computation section 12 compares input signals I and Q having the amplitude value rn and feedback signals I″ and Q″ on the polar coordinate system, thereby computes amplitude error Ea(rn) and phase error Ep(rn), and also computes Ea(rn)/rn. This error data is temporarily stored in the rewritable error compensation data memory 13 with rn used as an address.
If the amplitude value of the input signals at the next time when it becomes equal to rn is rn+1, amplitude compensation data Kn+1 and phase compensation data θn+1 corresponding to the amplitude value rn+1 are obtained by the multipliers 211 and 212 and the adders 221 and 222 performing the following repeated computation processing by referring to amplitude compensation data Kn and phase compensation data θn stored in the distortion compensation data memory 14 using the amplitude value rn as an address.Kn+1=Kn+α·{Ea(rn)/rn}θn+1=θn+β·Ep(rn)  (1)
The distortion compensation data in the rewritable distortion compensation data memory 14 is updated to the distortion compensation data obtained by the above-described processing with the amplitude value as an address, and the nonlinear distortion compensation computation section 2 shown in FIG. 9 performs complex multiplication on the basis of the distortion compensation data updated at successive times, thus realizing adaptive distortion compensation control.
Each of the multiplication coefficient α in the repeated computation processing on amplitude compensation data by the equation (1) shown above and the multiplication coefficient β in the repeated computation processing on phase compensation data is a step coefficient in repeated computation independent of the convergence value and having an influence on the convergence time and stability. Ordinarily, a certain fixed value is used as the multiplication coefficient.
If each step coefficient is set to a smaller value, the convergence time before the completion of convergence of distortion compensation data to the optimum value is increased, as shown in FIG. 11A. However, if each step coefficient is set to a larger value for the purpose of reducing the convergence time, distortion compensation data vibrates instead of converging with stability, as shown in FIG. 11B. In setting the step coefficients, therefore, values selected as the step coefficients are optimized by considering the convergence time and stability. However, the optimum values vary depending on the amplitude of the input signals. In the conventional distortion compensation circuit, the step coefficients in repeated computation for obtaining distortion compensation data are set constant regardless of the magnitude of the amplitude value of the input signals and, therefore, are not necessary optimum values with respect to some amplitude value when they are optimum with respect to another amplitude value. Consequently, it is not possible to achieve a reduction in convergence time while improving the stability of distortion compensation with respect to all amplitude values.
As described above, the conventional distortion compensation circuit has a problem in that, since the step coefficients in repeated computation for obtaining distortion compensation data are set to constant values regardless of the amplitude value of input signals, it is not possible to reduce the convergence time while maintaining the stability of distortion compensation.


An object of the present invention is to provide a cytotoxic assay using a new established fish cell line. The invention attained according to the object is a cytotoxic assay, wherein an evaluation of toxicity of a specimen is performed on the basis of its toxicity to an established cell line originated from sturgeon, preferably a STIP-1 cell line (FERM BP-8421) and a STIP-3 cell line (FERM BP-8422). Furthermore, another object of the present invention is to provide a new established cell line expected to be used in the diagnosis of viral infection disease of sturgeon and so on. The invention attained according to the object is an established cell line originated from a sturgeon eyeball, particularly a STIP-1 cell line (FERM BP-8421) and a STIP-3 cell line (FERM BP-8422).

1. Field of the Invention
The present invention relates to a cytotoxic assay of various kinds of specimens, such as chemical compounds and heavy metals. Furthermore, the present invention relates to a new established cell line expected to be used in the diagnosis of viral infection disease of sturgeon.
2. Background Art
Heretofore the toxicity tests of quality of various specimens such as chemical compounds or heavy metals (zinc, cadmium, copper, arsenic, cobalt, molybdenum, nickel, lead, selenium, chromium, tin, and mercury and so on) have been done with individual animals. However, the method using the individual animals suffers a problem of too much time and expense as well as that from a viewpoint of animal protection. In late years, therefore, toxicity assays that utilize established cell lines (culture cells) (i.e., cytotoxic assays), have been considered.
It is desirable to perform the toxicity test of a specimen in an aqueous environment with an established cell line derived from a fish origin. The toxicity assays using RTG-2 cells which are cells of a fibroblastic established cell line originated from a rainbow trout ovary and FHM cells which are cells of an epithelial established cell line originated from fathead minnow have been considered. However, these methods are not adequate in an aspect of sensitivity. In addition, there is a problem that a growth rate is late and a growth temperature range is small as for the RTG-2 cell, which can not be always satisfactory in an aspect of convenience.
In late years, aquaculture skills continue a remarkable development in increasing the number of fish species which can be cultivated and improving the stabilities in supply. On the other hand, there is a problem of the death of a culture fish by an infection disease caused by, such as bacteria or viruses. In particular, the fact is that there is no measure effective to such a problem even though viral infection disease after leads to a large quantity of deaths. For viral infection disease, it becomes important how early it is checked.
For the diagnosis of viral infection, established cell lines having sensitivities against the virus that is responsible for viral infection in fishes are indispensable. As to the established cell line of fish origin, many established cell lines have been reported since RTG-2 cells which are of a fibroblastic established cell line originated from a rainbow trout ovary were established. However, many of these established cell lines are derived from fibroblastic origins but not epithelial origins. That is, most of them are isolat d, cultured and established from limited fish species such as salmon and carp. Consequently, at present, the diagnosis of viral infection or the isolation of virus itself are not always smoothly performed about a various kinds of fish species.
By the way, sturgeon is the ancient species that has lived for about 300000000 years, but its egg is valued high as caviar, and, also its meat has high utility value as edible, thus it is expected as future culture object fish. In such an aspect, there is an indispensable need for established cell lines to check viral infection disease of sturgeon. However, only a few reports have been published for the established cell lines of sturgeon, although for example, there is a report about the established cell lines of white sturgeon grouped in the genus Acipenser in "Transactions of the American Fisheries Society" 120: 528–534, 1991. Therefore, it is very important to establish a new established cell line expected to be used for the diagnosis of viral infection disease of sturgeon. The establishment of such a new established cell line will lead to a great advantage in the production of vaccine effective to viral infection disease of sturgeon and at the time of the cytotoxic tests of chemical compounds, heavy metals or the like.

Cytotoxic assay and new established cell line of sturgeon origin