MXPA00006722A - Crystallographically stable amorphous cephalosporin compositions and process for producing the same - Google Patents
Crystallographically stable amorphous cephalosporin compositions and process for producing the sameInfo
- Publication number
- MXPA00006722A MXPA00006722A MXPA/A/2000/006722A MXPA00006722A MXPA00006722A MX PA00006722 A MXPA00006722 A MX PA00006722A MX PA00006722 A MXPA00006722 A MX PA00006722A MX PA00006722 A MXPA00006722 A MX PA00006722A
- Authority
- MX
- Mexico
- Prior art keywords
- water
- soluble
- additive
- high molecular
- cefditoren
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 117
- 238000000034 method Methods 0.000 title claims description 31
- 150000001780 cephalosporins Chemical class 0.000 title description 3
- 239000000654 additive Substances 0.000 claims abstract description 171
- 230000000996 additive Effects 0.000 claims abstract description 165
- 239000002245 particle Substances 0.000 claims abstract description 165
- 239000007864 aqueous solution Substances 0.000 claims abstract description 149
- 239000002244 precipitate Substances 0.000 claims abstract description 134
- 239000008240 homogeneous mixture Substances 0.000 claims abstract description 83
- 239000002253 acid Substances 0.000 claims abstract description 32
- 238000001035 drying Methods 0.000 claims abstract description 10
- KMIPKYQIOVAHOP-YLGJWRNMSA-N Cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 claims description 305
- 229960004069 cefditoren Drugs 0.000 claims description 298
- 229950009297 Pivoxil Drugs 0.000 claims description 293
- 239000000126 substance Substances 0.000 claims description 193
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 193
- 239000000843 powder Substances 0.000 claims description 105
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 89
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 89
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 89
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 89
- 239000003929 acidic solution Substances 0.000 claims description 87
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 83
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 claims description 83
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 83
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 83
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 83
- 238000006386 neutralization reaction Methods 0.000 claims description 81
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 66
- 239000000243 solution Substances 0.000 claims description 50
- 230000002378 acidificating Effects 0.000 claims description 47
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 46
- -1 2-aminothiazol-4-yl Chemical group 0.000 claims description 46
- 229920000609 methyl cellulose Polymers 0.000 claims description 46
- 239000001923 methylcellulose Substances 0.000 claims description 46
- 235000010981 methylcellulose Nutrition 0.000 claims description 44
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 40
- 230000001264 neutralization Effects 0.000 claims description 40
- 238000005406 washing Methods 0.000 claims description 40
- 239000002344 surface layer Substances 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 229960002900 Methylcellulose Drugs 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 28
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 26
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 26
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 26
- 239000011541 reaction mixture Substances 0.000 claims description 26
- 238000002441 X-ray diffraction Methods 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 22
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- 229920002678 cellulose Polymers 0.000 claims description 16
- 239000001913 cellulose Substances 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 16
- 238000010521 absorption reaction Methods 0.000 claims description 15
- 238000000862 absorption spectrum Methods 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 15
- 239000000908 ammonium hydroxide Substances 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- IOLCXVTUBQKXJR-UHFFFAOYSA-M Potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 229940113118 Carrageenan Drugs 0.000 claims description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 235000010418 carrageenan Nutrition 0.000 claims description 9
- 239000000679 carrageenan Substances 0.000 claims description 9
- 229920001525 carrageenan Polymers 0.000 claims description 9
- 230000005591 charge neutralization Effects 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 8
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 8
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 8
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000010936 aqueous wash Methods 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 7
- 238000002844 melting Methods 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 239000000428 dust Substances 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 229920001451 Polypropylene glycol Polymers 0.000 claims description 5
- 238000005119 centrifugation Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000005712 crystallization Effects 0.000 claims description 5
- 239000001184 potassium carbonate Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 238000001228 spectrum Methods 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- 239000001187 sodium carbonate Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229960003975 Potassium Drugs 0.000 claims description 3
- 238000000975 co-precipitation Methods 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 150000003112 potassium compounds Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims 3
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 claims 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- 238000004140 cleaning Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims 1
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 abstract description 6
- 229960002142 cefditoren pivoxil Drugs 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 6
- 230000003472 neutralizing Effects 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 229920003169 water-soluble polymer Polymers 0.000 abstract 2
- 239000010419 fine particle Substances 0.000 description 107
- 238000007792 addition Methods 0.000 description 30
- 238000000634 powder X-ray diffraction Methods 0.000 description 25
- 229960000443 hydrochloric acid Drugs 0.000 description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 15
- 238000004090 dissolution Methods 0.000 description 12
- 150000007529 inorganic bases Chemical class 0.000 description 12
- 238000005259 measurement Methods 0.000 description 6
- 210000001519 tissues Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000008239 natural water Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrugs Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UKRMLMLMUQODDB-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-methyloct-2-enoate Chemical compound CCCCCC=C(C)C(=O)OCOC(=O)C(C)(C)C UKRMLMLMUQODDB-UHFFFAOYSA-N 0.000 description 1
- 240000002234 Allium sativum Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- KMIPKYQIOVAHOP-LRHAYUFXSA-N CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)C=CC2=C(N=CS2)C)C(=O)O)C1=O)C=1N=C(SC=1)N Chemical compound CON=C(C(=O)NC1[C@@H]2N(C(=C(CS2)C=CC2=C(N=CS2)C)C(=O)O)C1=O)C=1N=C(SC=1)N KMIPKYQIOVAHOP-LRHAYUFXSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 210000004051 Gastric Juice Anatomy 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000035492 administration Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- RECVMTHOQWMYFX-UHFFFAOYSA-N oxygen(1+) dihydride Chemical compound [OH2+] RECVMTHOQWMYFX-UHFFFAOYSA-N 0.000 description 1
- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Abstract
Yellow and powdery compositions consisting of particles composed of a homogeneous mixture of amorphous cefditoren pivoxil with a water-soluble polymer additive and being orally administrable. These compositions can be obtained by dissolving the amorphous cefditoren pivoxil and the water-soluble polymer in an aqueous solution of an acid, neutralizing, coprecipitating, and then drying the thus obtained precipitate followed by the recovery of the product.
Description
DESCRIPTION A compound comprising an amorphous, crystallographically stable cephalosporin and processes for the preparation thereof. Technical Field This invention relates to an orally administered powder compound, which consists essentially of a number of particles, each composed of a crystallographically stable amorphous cephalosporin. More specifically, this invention relates to a novel, orally administrable and powdered compound, consisting essentially of particles, which have a uniform internal texture within each particle and each is formed of a homogeneous mixture of an amorphous substance and soluble in water of 7- [(z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [(z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem -4-pivaloyloxymethyl ester of carboxylic acid, that is, Cefditoren pivoxil (generic name), with an additive of high molecular concentration, for example, a water-soluble cellulose derivative. This invention also relates to processes for the preparation of the new compound, orally administrable in powder form as mentioned above. Foundation Technique The cefe compound known under the generic name Cefditoren "is the compound represented by the following
And whose compound was first named as 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4 carboxylic acid (non-isomer, cis-isomer) (refer to Japanese Patent Publication, specification Hei 3-64503, specification of the
U.S. Patent No. 4,839,350 and European Patent
No. 0175610). The pivaloyloxymethyl ester Cefditoren is a prodrug known under the generic name of "pivoxil Cefditoren" and is the compound represented by the following formula (B)
Cefditoren pivoxil is also known as w. { -) - (6R, 7R) -7- [(Z) -2- (2-aminothiazol-4-yl) -2-methoxy-9-eneacetamido] -3- [(Z) -2- (4-methylthiazole-5- ilo) ethenyl] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester "and is described on page 317 of the information" Merck index ", 12th edition to make a pale yellow powder substance that melts at 127-129 ° C. Another chemical name of the compound" pivoxil Cefditoren "is 7- [(Z) -2- (2-aminothiazole -4-yl) -2- ethoxyiminoacetamido] -3- [(Z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4-pivaloyloxymethyl ester of carboxylic acid When administered orally pivoxil Cefditoren, can be absorbed well through the digestive tracts, within which pivoxil Cefditoren is hydrolyzed within Cefditoren It is known that Cefditoren is an antibiotic substance that has an extremely broad antibacterial spectrum but low toxicity and Cefditoren It is very useful for the treatment therapeutic and prevention of diseases that are caused by the gram-positive and gram-negative bacteria. Currently, pivoxil Cefditoren, is widely used as a prodrug that can be administered orally for therapy. We, the current inventors, have conducted research with the intention of obtaining a highly pure product of pivoxil Cefditoren, and as a result, we have had satisfactory results in obtaining pivoxil Cefditoren in the form of an orthorhombic crystalline substance (at a purity of: 97 -98%) of a melting point of 206-215.7 ° C (with decomposition), by adopting a certain particular process (refer to PCT International Open Placement Publication No. 098/12200 of PCT Application No. PCT / JP97 / 03340, issued March 26, 1998) this orthorhombic crystalline substance of pivoxil Cefditoren, shows such advantages that it has a high purity, high thermal stability and high storage stability under high humidity conditions, but still shows the disadvantage that by itself it is not suitable for the purpose of oral administrations because of its poor solubility in water. Revelation of the Invention In general, for such medicinal compounds which are poorly soluble in water, it is well known that the speed of solubility or dissolution of poorly soluble compounds in water, in water can exert a great influence on the in vivo absorption of said compounds. Subsequently, various reports were presented on how to improve the solubility in the water of said medicinal compounds, which are poorly soluble in water. One of the proposals reported is a method in which a poorly soluble medicinal compound is converted into water, into an amorphous substance, in order to improve the solubility of the compound in water. It is known that an amorphous substance generally has greater solubility in water, as compared to the corresponding crystalline substance. Therefore, it is expected that if the orthorhombic crystalline substance of pivoxil Cefditoren is poorly soluble in water, it becomes an amorphous substance, which is more soluble in water, then a water-soluble and highly pure product of pivoxil Cefditoren can be obtained, which is able to show its therapeutic efficacy to its maximum extent. Therefore, we have diligently carried out our investigations to solve the problem of converting crystalline Cefditoren pivoxil into an amorphous substance that has greater solubility in water. As a result we have now discovered that an orally administrable, yellow powdery compound can be successfully prepared, consisting essentially of such particles wherein each of them has a uniform internal texture or tissue within each particle and of which each It is formed of a homogeneous mixture of the amorphous substance pivoxil Cefditoren which has a high solubility in water and a high thermal stability, with a highly molecular and water soluble additive, when said process is used which comprises dissolving a pivoxil Cefditoren in a aqueous acidic solution containing a highly molecular soluble water-soluble additive, for example, a water-soluble cellulose derivative and an acid dissolved therein, thus forming an acidic aqueous solution containing pivoxil Cefditoren, the highly molecular additive soluble in water and the acid dissolved in it, after slowly adding to the aqueous acidic solution, a solution n aqueous solution of an inorganic base to neutralize said acidic aqueous solution to a neutral or substantially neutral pH value, with co-precipitated pivoxil Cefditoren and such highly soluble water-soluble additive, simultaneously of said aqueous solution during the neutralization operation, subsequently washing the deposited precipitate with an aqueous solution of the water-soluble high molecular additive, drying the washed precipitate, and coating the resulting particulate product which was dried. This invention was established based on the findings mentioned above. Then, "in accordance with the first aspect of this invention, there is provided an orally administrable, yellow-colored powder compound consisting essentially of solid particles which are formed of a homogeneous mixture of a crystallographically stable, amorphous and water-soluble substance of pivoxil Cefditoren with a highly molecular additive soluble in water, and whose particles have a uniform internal texture within each particle, which is characterized in that the yellow-colored powder compound consists essentially of solid particles, where each is formed of a mixture homogeneous of (i) the substance is crystallographically stable, amorphous and soluble in water of pivoxil Cefditoren, ie 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [( Z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4-pivaloyloxymethyl ester of carboxylic acid, with (ii) the highly molecular soluble water-soluble additive, which is a soluble cellulose derivative in ag ua, pharmaceutically acceptable as chosen from hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, methylcellulose and acceptable alkali metal salt or alkaline earth metal salt of carboxymethylcellulose or pluran, carrageenan, polyvinylpyrrolidone or an ester of glycol polypropylene glycolic acid, that the highly molecular soluble water additive (ii) contained in the particles solid particles mentioned above is present in such particles, in a proportion of 0.5% -5%, based on the weight of the pivoxil substance Cefditoren, that said particles are fused at a temperature of 120 ° C or higher, but do not show any point of definitive fusion, that the amorphous substance of pivoxil Cefditoren (i) contained in such particles, does not show any maximum point of the diffraction angle in an X-ray diffraction diagram of such particles, but shows in its infrared absorption spectrum, (as measured by the compressed potassium bromide method) a maximum point substantially broader entity of absorption at a wave number of 1750 cm "1, as compared to the well defined maximum absorption point presented by the orthorhombic crystalline substance of pivoxil Cefditoren at a wave number of 1750 cm" 1 in the spectrum of infrared absorption, u that the amorphous substance of pivoxil Cefditoren
(i) content in said particles, it can be dissolved in a hydrochloric acid containing acidified water (pH 1.2) at a solubility of at least 4 mg / dL / ml of pivoxil
• Cefditoren at 37 ° C and has a crystallographic stability, so that the substance of pivoxil Cefditoren amorphous does not involve crystallization when stored at 40 ° C for 4 months in a sealed container under drying conditions. A preferred example of a powder composition according to the first aspect of this invention is a compound consisting essentially of particles, each formed of a homogeneous mixture of a crystallographically stable, amorphous and water soluble substance of pivoxil. Cefditoren with the water-soluble high molecular additive which is hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose or polyvinylpyrrolidone and whose additive, as mixed, is present in a proportion of 1% ~ 3% based on the weight of the pivoxil Cefditoren. Further, with respect to the respective solid particles, wherein each is formed of the homogeneous mixture of the amorphous pivoxil Cefditoren with the additive of high molecular content, soluble in water and which is present in the powder composition, in accordance with the First aspect of this invention, we have now observed, under a polarized light microscope of 400 magnifications or under an electron microscope, the texture of the surface or tissue of such particles, and we have found that the surface of each particle has a single texture or uniform tissue. We could not find any presence of independent and separated grains of either the pivoxil Cefditoren or the additive with high molecular content on the surface of each particle. In the powder composition, according to the first aspect of this invention, the water-soluble and high-molecular-weight additive, which is to be mixed with the amorphous pivoxil Cefditoren, and which are water-soluble cellulose derivatives, or pluran, carrageenan, polyvinylpyrrolidone or an arginine glycol polypropylene acid ester, can be of a degree thereof, which is commonly used and incorporated into the medicine formulations as a binder or a suspending agent. Among the water-soluble high molecular content additives, which can be used in the composition of the first aspect of this invention, the water-soluble cellulose derivatives are those which are mainly preferred. As the cellulose derivatives solubilized in water, hydroxypropylmethylcellulose (abbreviated as HPMC), hydroxypropylmethylcellulose phthalate (abbreviated as HPMCP), hydroxypropylcellulose (abbreviated as HPC), methylcellulose (abbreviated as MC), calcium salt of carborximethylcellulose or sodium salt of carboxymethylcellulose. The use of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) or methylcellulose (MC) is preferred. In the homogeneous mixture, which constitutes the solid particles present in the powder composition of the first aspect of this invention, and which is composed of amorphous pivoxil Cefditoren and the water-soluble high molecular content additive, the proportion of additive of High molecular content, soluble in water, will be incorporated in it, perhaps in a range of 0.5% ~ 5%, preferably in a range of 1% ~ 3% based on the weight of the pivoxil Cefditoren. In addition, 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 discovered that these solid particles are fused at 120 ~ 150 ° C with decomposition, but do not show any defined melting point. We have also carried out the measurement of the X-ray powder diffraction of the solid particles present in the composition of the first aspect of this invention, by placing the particles in a powder X-ray diffraction apparatus (Rigaku Denki KK: Geigerflex 2027). Based on the analysis of the pattern of the X-ray diffraction diagram of said *** X-ray powder diffraction, it can be noticed that no maximum point appears in the diffraction angle, indicating that the substance of pivoxil Cefditoren that exists in the particles, is amorphous by nature. We have also carried out a measurement of the 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, by concentrating the resulting mixture to compress the same , and then by placing the resulting tablet in an infrared absorption spectrometer. In the spectrum table that was obtained, the infrared absorption spectrum of the pivoxil substance Cefditoren present in said powder, exhibits at a wave number of 1750"1, a maximum absorption point which is substantially wider than a point well-defined absorption maximum, that the orthorhombic crystalline substance of pivoxil Cefditoren presents in a wave number of 1750"1 in its infrared absorption spectrum. We have also carried out a measurement of the X-ray diffraction in the powder of the previously stored solid particles, present in the composition of the first aspect of this invention, by placing and storing such particles in a sealed container in a dry air atmosphere. , at 40 ° C for 4 months, followed by measurement of the X-ray diffraction in the powder of the particles stored in the powder X-ray diffraction apparatus that was previously used. The analysis of 1 pattern of the resulting X-ray powder diffraction graph did not indicate any maximum point in the diffraction angle in the graph. Then it was demonstrated that the pivoxil Cefditoren present in the particles stored as mentioned above, had remained in an amorphous state and that it is cryographically stable and can maintain the amorphous state after storage thereof for a long period of time.
We assume that in the composition of this invention, the additive of high molecular content, soluble in water and coexisting in the mixture in the pivoxil Cefditoren in the solid particles, may possess a function capable of inhibiting the molecules of the pivoxil Cefditoren after passing its crystallization . The solid particles present in the composition of this invention have an average particle diameter within the range of 0.5 μ ~ 100 μ. The solid particles present in the composition of this invention were tested by measuring their solubility in water as shown in the Test Example given below. Subsequently it was discovered that the amorphous pivoxil Cefditoren contained in said particles was soluble in acidified water of pH 1.2 which contained approximately 0.1 N hydrochloric acid (corresponding to the artificial gastric juice specified in the Japanese Pharmacopoeia). And it had a solubility of at least 4 mg / ml in acidified water at 37 ° C. In addition, we proceed with our additional investigation. Then, when we carry it out, for the purpose of producing the particles of the powder composition of the first aspect of the invention, the process comprising the steps of completely dissolving a crystalline pivoxil Cefditoren in an aqueous acidic solution containing and dissolving in It is an additive with a high molecular content, soluble in water and an acid, in order to prepare an aqueous acidic solution containing pivoxil Cefditoren, the additive with high molecular content, soluble in water and the acid dissolved in it, then adding slowly to the solution acidic aqueous solution that was prepared, an aqueous solution of an inorganic base, to neutralize the aqueous acidic solution to a neutral pH value or a substantially neutral pH value, thus allowing during the neutralization, that the pivoxil Cefditoren and the additive with high molecular content , soluble in water that was mentioned first, precipitate together and simultaneously of the solu acidic aqueous solution, separating and then washing the deposited precipitate with an aqueous solution of the additive with high molecular content, soluble in water that was mentioned first and subsequently drying the washed precipitate, now we have observed that the aforementioned process can be carried out in such a modified form that the first additive with high molecular content, soluble in water mentioned, which was contained in the aqueous acidic solution of the additive with high molecular content, soluble in water and the acid that would be used for the dissolution of the pivoxil Cefditoren, and the which will be contained in the aqueous washing solution of the additive with high molecular content, soluble in water to wash the deposited precipitate, is replaced by a second, additive with high molecular content, soluble in water which is formed of a compound different from the first additive with high molecular content, soluble in water mentioned, when you want to prepare a solution water ion of the water-soluble additive with high molecular content, which will be used in the washing step of the precipitate deposited therein, and at least a part of the second additive with high molecular content, soluble in water is allowed to present in the aqueous washing solution of the second additive, as used for the aforementioned washing step, is transferred onto the surface of the precipitate particles during the washing step. It has also been discovered that, when the washing step is carried out with the aqueous solution of the second additive mentioned, followed by the conduction of the steps of recovery and drying of the particles of the precipitate of which the surface contained the second. additive with high molecular content, soluble in water as it was transferred from the aqueous wash solution that was used in said washing step, then said particles can be obtained from the dehydrated precipitate, wherein the surface layer of each of the solid particles As it was collected, it is formed of a homogeneous mixture of amorphous Cefditoren pivoxil with the first additive with high molecular content, soluble in water and the second additive with high molecular content, soluble in water, but where the central and neutral part of each of the particles solid particles lie beneath the surface layer of the solid particles, a homogeneous mixture of amorphous pivoxil Cefditoren is formed with the first additive with high molecular content, soluble in water. According to a second aspect of this invention, there is provided an orally administrable, yellow-colored powder composition, consisting essentially of particles, wherein each of them substantially comprises mixtures of a crystalline stable amorphous and soluble pivoxil Cefditoren substance at water with the additive or additives with high molecular content, soluble in water, and whose particles have a uniform internal texture within each particle, characterized in that the composition yellow color powder consists essentially of particles where each comprises a mixture of (i) the substance of crystallographically stable, amorphous and water soluble pivoxil Cefditoren, ie 7- [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacitamido] -3- [(Z) -2- (4-Methylthiazol-5-yl) ethenyl] -3-cephem-4-pivaloyloxymethyl ester of carboxylic acid, with (ii) a first additive with high molecular content, soluble in water which is a derivative of pharmaceutically acceptable cellulose, solubilized in water, as chosen from hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, methylcellulose and an acceptable alkali metal salt or alkaline earth metal salt of carboxymethylcellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol, which the central or neutral part of the respective particles which lies beneath the surface layer of said respective particles, is formed only of a homogeneous mixture of (i) the amorphous substance of pivoxil Cefditoren with (ii) the first additive with high molecular content, soluble in water mentioned above, but the surface layer of said particles is formed of a homogeneous mixture of (i) the amorphous substance of pivoxil Cefditoren with (ii) the first additive with high molecular content, soluble in water and also with (iii) the second additive with high molecular content, luble in water which is additionally incorporated and whose second additive is made of a substance different from the first additive with high molecular content, soluble in water mentioned above present just in the central or neutral part of the particles that lie under the surface layer of the particle, and whose second additive with high molecular content, soluble in water is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone, which both the first additive with high molecular content, soluble in water (ii) as the second additive with high content molecular, water-soluble (iii) are present in a total proportion of them of 0.5% ~ 5% based on the weight of the pivoxil substance Cefditoren contained in the particles, that such particles are fused at a temperature of 120 ° C or greater, but do not show any defined melting point that the pivoxil substance Cefditoren amorphous (i) contained in such particles, n or shows no maximum point of the diffraction angle in an X-ray diffraction diagram for dust of such particles, but has a substantially higher peak in its infrared absorption spectrum (as measured by the compressed potassium bromide method) greater absorption at a wave number of 1750"1, as compared to the well defined maximum absorption point that presented the orthorhombic crystalline substance of pivoxil Cefditoren at a wave number of 1750 cm" 1 in the infrared absorption spectrum, and that the amorphous substance of pivoxil Cefditoren (i) contained in such particles can be dissolved in acidified water containing hydrochloric acid (pH 1.2) at a solubility of at least 4 mg / ml of pivoxil Cefditoren at 37 ° C and has a crystallographic stability that said pivoxil substance Cefditoren amorphous does not involve crystallization when stored at 40 ° C for 4 months in a sealed container b Garlic drying conditions. A first preferred example of the powder composition, according to the second aspect of this invention, is a composition, wherein the central or neutral part of the particles forming the composition, which lie under the surface layer of the particles, is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylmethylcellulose, but the surface layer of the particles is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylmethylcellulose and also with hydroxypropylcellulose or methylcellulose. A second preferred example of the powder composition according to the second aspect of this invention is a composition, wherein the central or neutral part of the particles forming the composition which lies under the surface layer of the particles, it is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylmethylcellulose, but the surface layer of said particles is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylcellulose and also with hydroxypropylmethylcellulose or methylcellulose. A third preferred example of the powder composition according to the second aspect of this invention is a composition, wherein the central or neutral part of the particles forming the composition, which lies beneath the surface layer of the particles, is form of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with methylcellulose, but the surface layer of such particles is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with methylcellulose and also with hydroxypropylmethylcellulose or hydroxypropylcellulose. A fourth preferred example of the powder composition according to the second aspect of this invention, is a composition wherein the central or neutral part of the particles forming the composition, which lies beneath the surface layer of the particles, is form of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with polyvinylpyrrolidone, but the surface layer of the particles, is formed of a homogeneous mixture of an amorphous substance of pivoxil Cefditoren with polyvinylpyrrolidone and also with hydroxypropylmethylcellulose or hydroxypropylcellulose or methylcellulose. 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. Furthermore, the solid particles present in the composition, according to the second aspect of this invention, turned out to be those which, when the surface of the particles is observed under a polarized light microscope or under an electron microscope, said surface has an internal texture simple and uniform in each particle and does not substantially contain any separated grain independently of the pivoxil Cefditoren, nor separate grains independently of the additives with high molecular content, soluble in water in the texture or tissue of the surface of said particles. Both the powder composition, according to the first aspect of this invention, and the powder composition, according to the second aspect of this invention, are administered orally, and can be formulated in tablet form by mixing the composition with the composition. excipient (s), for example, starch or talc, and / or binder (s), for example, gelatin or hydroxypropylcellulose and a suitable additive people, and then compressing the resulting mixture into tablets. The two powder compositions according to the first and second aspects of this invention can also be formulated in the form of powder preparations by mixing the composition with a pharmaceutically acceptable powder carrier, for example, starch or cellulose powder. For the process of preparing the powder composition according to the first aspect of this invention, a process for the preparation of a yellow powder composition, consisting essentially of particles which are formed of a homogeneous mixture of a crystallographically stable, amorphous and water soluble substance, is provided according to a third aspect of this invention. of pivoxil Cefditoren with an additive with high molecular content, soluble in water and whose particles have a uniform internal texture within each particle, characterized in that the process comprises a step of dissolving a crystalline orthorhombic substance of pivoxil Cefditoren, ie 7- [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [(Z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4 -Thyloyloxy ethyl ester of carboxylic acid, in an aqueous acidic solution which contains an additive with high molecular content, soluble in water made of a water-soluble cellulose derivative, as chosen from hydroxypropylmethylcellulose, ft of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and an alkali metal salt or pharmaceutically acceptable alkaline earth metal salt of carboxymethylcellulose or pluran, carrageenan, polyvinylpyrrolidone or an ester of glycol polypropylene glycol, as dissolved in a concentration of 0.05% to 1% ( on a weight / weight basis), and whose aqueous acidic solution also contains hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid at a concentration of 0. IN ~ 12N of the acid, so that the amount of pivoxil Cefditoren dissolved in said aqueous acidic solution is in the range of 10 to 130 times, based on the total weight of the additive with high molecular content, soluble in water contained in the aqueous acidic solution, and so that an aqueous solution is prepared Acidic containing pivoxil Cefditoren, the additive with high molecular content, soluble in water and the acid dissolved in this one; a step to subsequently neutralize the aqueous acidic solution which was prepared, by slowly adding thereto, an aqueous solution or solutions of sodium or potassium hydroxide, sodium or potassium hydrogen carbonate, or sodium or potassium carbonate, simple or combined, or an aqueous solution of ammonium hydroxide, keeping the aqueous acidic solution at a temperature of 10 ° C or lower, under agitation, and with the amount of the basic compound of sodium or potassium or of ammonium hydroxide to be added to the acidic aqueous solution which is adjusted so that the solution of the resulting reaction, after neutralization, shows a pH value of 6.5 ~ 7.1; and a step to continue during the neutralization reaction, the agitation of the aqueous solution containing pivoxil Cefditoren at a temperature of 10 ° C or lower, to cause the joint precipitation of pivoxil Cefditoren and pivoxil Cefditoren and the additive with high molecular content , soluble in water, simultaneously from the aqueous solution; a step of collecting by filtration or centrifugation the precipitate deposited from the resulting neutralization reaction mixture; a step for washing the collected precipitate with an aqueous solution of an additive with high molecular content, soluble in water made of the same substance as the additive with high molecular content, soluble in water that was mentioned first and containing such additive dissolved in the solution at a concentration of 0.5% ~ 10% (based on weight / weight), while allowing at least a part of the additive with high molecular content, soluble in water that is used in the aqueous wash solution, during the washing operation for transferring from the aqueous washing solution, the additive with high molecular content, soluble in water on the surfaces of the particles of such precipitate; and a step for drying the washed precipitate, and obtaining the yellow powder composition, consisting essentially of the particles, which are formed of the homogeneous mixture of the crystallographically stable, amorphous, water-soluble substance of pivoxil Cefditoren with the additive with high molecular content, "water soluble mentioned above, present in a part of 0.5% ~ 5% based on the weight of the substance pivoxil Cefditoren.In practicing the process of the third aspect of this invention, the acid present in the solution of the additive with high molecular content, soluble in water and the acid to be used for the dissolution of the substance pivoxil Cefditoren crystalline, can preferably be hydrochloric acid, phosphoric acid, acetic acid or sulfuric acid Particularly, hydrochloric acid is preferred. The concentration of the acid in the aqueous solution can be within a range of 0. IN ~ 12N, with a range of 0.5N ~ 2. ON which is the one that is particularly preferred. The step for dissolving the substance of crystalline pivoxil Cefditoren in the aqueous acidic solution, which contains the additive with high molecular content, soluble in water and acid, can be carried out preferably at a temperature of 10 ° C or lower. The dissolution of the substance pivoxil Cefditoren crystalline can be carried out preferably by taking a period of time of 10 ~ 60 minutes for it. When adopting these operating conditions, it is necessary to make the substance pivoxil Cefditoren completely dissolve in the aqueous solution of the additive with high molecular content, soluble in water and acid. Subsequently, the step of neutralizing the resulting aqueous solution of pivoxil Cefditoren, additive with high molecular content, soluble in water and acid, with an inorganic base is carried out. The aqueous solution of an inorganic base which is used for this neutralization step may preferably be an aqueous solution of ammonium hydroxide, ie aqueous ammonia, or aqueous solution of sodium hydroxide, aqueous solution of potassium hydroxide, aqueous solution of carbonate of sodium hydrogen or aqueous solution of potassium sodium carbonate. Aqueous ammonia is the one that is particularly preferred. The concentration of the inorganic base in the aqueous solution of the inorganic base can be in a range of 0. ÍN ~ 14N, but the base concentration in a range of 0.5N ~ 2. ON is the one that is particularly preferred. An aqueous solution of an inorganic base can 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 0 ° C ~ 10 ° C. The addition can preferably be carried out dropwise. The time that the neutralization reaction will take may be 5 minutes ~ 24 hours and preferably 5 minutes ~ 10 hours. During the neutralization reaction, it is preferred that the amount of the inorganic base added be controlled such that the resulting reaction mixture shows a pH value of 6.5 ~ 7.0 upon completion of the neutralization. With the progress of the neutralization reaction, the pivoxil Cefditoren and the additive with high molecular content, soluble in water are controlled so that they simultaneously precipitate simultaneously from the aqueous solution, resulting in the deposition of the solid precipitate. This precipitate is composed of a mixture of pivoxil Cefditoren with the additive with high molecular content, soluble in water. After finishing the neutralization reaction, the precipitate is collected from the resulting neutralization reaction mixture. The collection of the precipitate can be carried out by filtration, for example filtration under a reduced pressure or by centrifugation in a conventional manner. Then, the precipitate that was collected is subjected to the washing step at a temperature of 10 ° C or lower with an aqueous solution containing an additive with high molecular content, soluble in water that is of the same compound as the additive with high content. molecular, soluble in water precipitated together and that is then included in said precipitate and whose additive of high molecular content is present in a concentration of 0.5% ~ 10% (% by weight) in said aqueous solution. By means of this washing operation, the salts that were added to the precipitate, can be eliminated and at least a part of the additive with high molecular content, soluble in water present in the aqueous washing solution is allowed to be transferred inside the surface of the particles of the precipitate from the aqueous wash solution of the additive with high molecular content, soluble in water during the washing operation. If natural water were used for the step of washing the precipitate, a part of the additive with high molecular content, soluble in water, which has been included and contained in the precipitate, could be washed completely from it. In such a possible case, the dust particles that can be obtained after the drying of the precipitate that was washed with the natural water, would be undesirable as the desired target product, because the content of the additive with high molecular content, soluble in water in the particles would be inadequately less than what was desired. Said undesirable product is inappropriate in that the component of the pivoxil Cefditoren contained therein may show a certain tendency to crystallize. The precipitate which has received the washing step, as indicated above, is subsequently dried in a conventional manner. The drying step is preferably carried out at a temperature of 30 ° C or lower under reduced pressure. Then, as the final product that was dried, a powder composition consisting essentially of solid particles, which are formed of a homogeneous mixture of a crystallographically stable, amorphous and water soluble substance, of the pivoxil Cefditoren and the additive can be obtained. with high molecular content, soluble in water, such as was mixed in a proportion of 0.5% ~ 5% (% by weight) of said additive, based on the weight of the substance pivoxil Cefditoren. Preferably, the process of the third aspect of this invention can be carried out through a process comprising a step of dissolving the orthorhombic crystalline substance of the pivoxil Cefditoren in an aqueous acidic solution, which contains an additive with high molecular content, soluble in water as chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone as dissolved in a concentration of 0.05% to 1% (based on weight / weight) and whose aqueous solution Acidic acid also contains hydrochloric acid or phosphoric acid at a concentration of 0.5N ~ 2.0N of the acid, so that the amount of pivoxil Cefditoren dissolved in said aqueous acidic solution is in a range of 10 to 100 times based on the total weight of the acid. additive with high molecular content, soluble in water contained in the aqueous acidic solution, and then an aqueous acidic solution containing pivoxil Cefditoren, the additive with high molecular content, soluble in water and the acid dissolved in it is prepared; a step to subsequently neutralize prepared acidic aqueous solution containing pivoxil Cefditoren, by slowly adding eto an aqueous solution of 1N ~ 2N sodium hydroxide and / or an aqueous solution of sodium hydrogen carbonate ÍN ~ 2N, or by slowly adding to it an aqueous solution of ammonium hydroxide, keeping aqueous acidic solution at a temperature of 5 ° C or lower as agitation is carried out, until acidic aqueous solution is neutralized to a pH value of 6.5 ~ 7.0; a step to continue during neutralization reaction agitation of resulting neutralization reaction mixture at a temperature of 5 ° C or lower, to cause co-precipitation of pivoxil Cefditoren and additive with high molecular content, soluble in water, simultaneously from aqueous solution; a step for collecting precipitate collected from resulting neutralization reaction mixture; a step for washing collected precipitate with an aqueous solution of an additive with a high molecular content, soluble in water made of same substance as additive with high molecular content, soluble in water that was mentioned first and containing said additive dissolved in water. solution at a concentration of 0.5% ~ 10% (based on weight / weight); and a step to dry washed precipitate, and obtain yellow powder composition consisting essentially of particles, which are formed of a homogeneous mixture of amorphous substance of pivoxil Cefditoren with additive with high molecular content, soluble in water mentioned above present in a proportion of 1% ~ 3% based on weight of substance pivoxil Cefditoren. For process of preparing powder composition of second aspect of this invention, e is provided, according to a fourth aspect of this invention, a process for preparation of a yellow powder composition, consisting essentially of particles, which comprise mixtures of a crystallographically stable, amorphous and water soluble substance of pivoxil Cefditoren with additive or additives with high molecular content, soluble in water and whose particles have a uniform internal texture within each particle, characterized in that process comprises a step of dissolving a orthorhombic substance of pivoxil Cefditoren in an aqueous acidic solution which contains a first additive with high molecular content, soluble in water made of a cellulose derivative solubilized in water, as chosen from hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate , hydroxypropylcellulose, methylcellulose and a sa alkali metal or pharmaceutically acceptable alkaline earth metal salt of carboxymethylcellulose, or pluran, carrageenan, polyvinylpyrrolidone or an ester of glycol polypropylene glycol acid as dissolved in a concentration of 0.05% ~ 1% (based on weight / weight) and whose solution Acidic acid also contains hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid in a concentration of 0.1N ~ 12N of acid, so that amount of pivoxil Cefditoren dissolved in aqueous acidic solution is in a range from 10 to 130 times, based on total weight of first additive with high molecular content, soluble in water contained in aqueous acidic solution, and so that an acidic aqueous solution containing pivoxil Cefditoren, first additive with high content, is prepared molecular content, soluble in water and acid dissolved in it; a step to subsequently neutralize prepared acidic aqueous solution, by slowly adding to it an aqueous solution or solutions of potassium or sodium hydroxide or sodium or potassium hydrogen carbonate, or sodium or potassium carbonate, alone or in combination or adding slowly to this an aqueous solution of ammonium hydroxide, keeping aqueous acidic solution at a temperature of 10 ° C or lower under agitation, and with amount of basic sodium or potassium compound or ammonium hydroxide to add it to aqueous acidic solution that is adjusted so that reaction solution, after neutralization, shows a pH value of 6.5 ~
7. 1; a step to contain during the neutralization reaction, the agitation of the aqueous solution containing pivoxil Cefditoren at a temperature of 10 ° C or lower, to cause the joint precipitation of pivoxil
Cefditoren and the first additive with high molecular content, soluble in water, simultaneously from the aqueous solution; a step for collecting by filtration or centrifugation, the precipitate deposited from the mixture of the resulting neutralization reaction; a step for washing the precipitate collected with an aqueous solution, which contains a second additive with high molecular content, soluble in water made of a substance different from the first additive with high molecular content, soluble in water mentioned above, contained in the aqueous solution acidic containing pivoxil Cefditoren, and whose aqueous solution contains the second additive with high molecular content, dissolved in it at a concentration of 0.5% ~ 10% (based on weight / weight), while allowing at least a part of the Second additive with high molecular content, soluble in water used here in the aqueous washing solution, during the washing operation, to transfer from the aqueous washing solution of the second additive with high molecular content, soluble in water to the surfaces of the particles of the precipitate; and a step to subsequently dry the washed precipitate and obtain a yellow colored powder composition, consisting essentially of such particles, which contain pivoxil Cefditoren and from which the central or neutral part of each particle is formed, only of a homogeneous mixture of the crystallographically stable, amorphous, water-soluble substance of pivoxil Cefditoren with the first additive with high molecular content, soluble in water present in a proportion of 0.5% ~ 5% based on the weight of the substance pivoxil Cefditoren and of which forms the surface layer of each particle from a homogeneous mixture of the crystallographically stable, amorphous and water-soluble substance of pivoxil Cefditoren with the first additive with high molecular content, soluble in water and also with the second additive with high molecular content, soluble in water. The process of the fourth aspect of this invention can be carried out in the same way as the process of the third aspect of this invention. It is preferably carried out by process of the fourth aspect of this invention, by means of a process comprising a step to dissolve the orthorhombic crystalline substance of pivoxil Cefditoren in an aqueous acidic solution, which contains an additive with high molecular content, soluble in water, as chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone as dissolved at a concentration of 0.05% ~ 1% (on a weight / weight basis) and whose aqueous acidic solution also contains hydrochloric acid or phosphoric acid at a concentration of 0.5N ~ 2. ON of the acid, so that the amount of pivoxil Cefditore dissolved in the aqueous acidic solution is in a range of 10 to 100 times based on the total weight of the first additive with high molecular content, soluble in water contained in the Acidic aqueous solution, so that an acidic aqueous solution containing pivoxil Cefditoren, the additive is prepared with high molecular content, soluble in water and the acid dissolved in it; a step to subsequently neutralize the prepared acidic aqueous solution containing pivoxil Cefditoren, by slowly adding to it an aqueous solution of sodium hydroxide ÍN ~ 2N or / and an aqueous solution of sodium hydrogen carbonate ÍN ~ 2N or by slowly adding to it an aqueous solution of aqueous 1N ~ 2N ammonium hydroxide, keeping the aqueous acidic solution at a temperature of 5 ° C or lower under agitation, until the acidic aqueous solution is neutralized to a pH value of 6.5 ~ 7.0; a step to continue the agitation of the neutralization reaction mixture, at a temperature of 5 ° C or lower during the neutralization reaction, to cause the co-precipitation of the pivoxil Cefditoren and the first additive with high molecular content, soluble in water , simultaneously from the aqueous solution; a step for collecting the precipitate deposited from the resulting neutralization reaction mixture; a step for washing the precipitate collected with the aqueous solution, which is contained as the "second additive with high molecular content, soluble in water made of a substance different from the first additive with high molecular content, soluble in water mentioned above, so that an additive with a high molecular content, soluble in water, of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone is chosen, and whose aqueous solution contains the second additive with high molecular content dissolved in it at a concentration of 0.5% ~ 10% (based on to weight / weight) while allowing at least a part of the second additive with high molecular content, soluble in water used here in the aqueous wash solution, during the operation, transfer from the aqueous solution of the second additive with high molecular content , soluble in water to the surfaces of the particles of the precipitate, a step to subsequently dry the precipitate washing, to obtain the yellow powder composition consisting essentially of the particles from which the central or neutral part of each particle is formed, only of a homogeneous mixture of the amorphous substance of the pivoxil Cefditoren with the first additive with high content molecular, soluble in water, and from which the surface layer of each particle of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren is formed with the first additive with high molecular content, soluble in water and also with the second additive with high molecular content, soluble in water. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a pattern of a powder X-ray diffraction graph that is obtained by measuring in a powder X-ray diffractometer, the powder composition, which consists essentially of particles formed from a powder. homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylmethylcellulose, which was produced in Example 6 of this invention which is provided below.
Fig. 2a shows an infrared absorption spectrum (as measured by the compressed KBr method) of the pivoxil component Cefditoren contained in the particles, which are formed essentially from the homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylmethylcellulose , and which are produced in Example 6 of this invention which is provided below. Fig. 2b shows an infrared absorption spectrum (as measured by the compressed KBr method) of the crystalline substance of pivoxil Cefditoren (which is the orthorhombic crystalline substance, as obtained in Example 1 of the PCT International Open Placement Publication No. W098 / 12200). The arrows provided in these graphs of the infrared absorption spectrum indicate the maximum absorption points at the wave number of 1750"1. Best Way to Develop the Invention Now, this invention is illustrated concretely with reference to the typical examples of the same, but not limited to, these Examples The crystalline substance of the pivoxil Cefditoren that is used in Example 1 ~ 14, given below, is the orthorhombic crystalline substance of pivoxil Cefditoren (mp 215 ° C, a purity about 97%) which is obtained in Example 1 of PCT International Open Laid Publication No. W098 / 12200. The following Examples 1-3 illustrate the preparation of the yellow powder composition, according to the first aspect of This invention, and Examples 4-14 illustrate the preparation of the yellow powder composition, according to the second aspect of this invention. Crystalline (20 g) of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(Z) -2- (4-methylthiazol-5-yl) ethenyl ] -3-cephem-4-pivaloyloxy ethyl ester of carboxylic acid, ie pivoxil Cefditoren, was dissolved in an acidic aqueous solution (140 ml) containing hydroxypropylcellulose (200 mg), as dissolved in it and hydrochloric acid at a concentration of IN of HCl, taking a time of 11 minutes for the dissolution of the pivoxil Cefditoren in it. During the dissolution operation, the aqueous solution was maintained at a temperature of 5 ° C or lower. Then, an acidic aqueous solution (pH 0.6) was prepared in which the pivoxil Cefditoren had completely dissolved. This acidic aqueous solution containing pivoxil Cefditoren, (at a pH of 7.0) was then neutralized by a slow addition of an aqueous ammonia IN (approximately 138 ml) to it over a period of 60 minutes at a time. temperature of 5 ° C or lower. Then the deposition of the precipitate occurred. The mixture of the resulting neutralization reaction containing the precipitate, as deposited, was stirred overnight at a temperature of 5 ° C or lower. The deposited precipitate was collected by filtration from the reaction mixture, and then washed thoroughly with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (60 ml). The precipitate that was washed dried under reduced pressure. Then, 19.6 g of a yellow powder (the composition of this invention) was obtained, which consists essentially of numerous fine particles, each of which was formed from a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylcellulose. When the observation was made, under an electron microscope (amplification: x 10000), of the surface of the fine particles present in the resulting yellow colored powder, it was then demonstrated that the surface of these fine particles had a simple and uniform phase or texture . The content of the hydroxypropylcellulose within the fine particles present in the resulting yellow colored powder, was calculated, from an analysis, by means of gas chromatography, to be 1% (by weight) based on the pivoxil component. Cefditoren. Furthermore, when analyzing said fine particles in the aforementioned X-ray powder diffraction apparatus, it was discovered that no maximum point appeared in the diffraction angle, in the pattern of the resulting X-ray diffraction graph, and therefore, the component of the pivoxil Cefditoren present in these fine particles was in the form of an amorphous substance . Example 2 The crystalline substance of the pivoxil Cefditoren (5g) was dissolved in an aqueous acidic solution (35 ml) containing hydroxypropylmethylcellulose (50 mg), as dissolved therein and 1N HCl, at a temperature of 5 ° C or lower, and taking a time of 10 minutes for the dissolution of pivoxil Cefditoren. Then, an aqueous acidic solution (pH 1.32) was prepared in which the pivoxil Cefditoren had completely dissolved. The resulting aqueous solution containing pivoxil Cefditoren (to a pH of 6.9) was then neutralized by a slow dropwise addition of an aqueous ammonia IN (approximately 33 ml) at that for the time period of 30 minutes at a temperature of 5 ° C or lower. Then the deposition of the precipitate occurred. The resulting neutralization reaction mixture was stirred overnight at a temperature of 5 ° C or lower. The deposited precipitate was collected by means of filtration, and then thoroughly washed with an aqueous solution (15 ml) of 0.5% (by weight) of hydroxypropylmethylcellulose. The precipitate that was washed dried under reduced pressure. Then, 4.9 g of a yellow powder (the composition of this invention) was obtained, consisting essentially of fine particles, each of which is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylmethylcellulose.
The content of the hydroxypropylmethylcellulose within the fine particles, present in the resulting yellow colored powder, was calculated to be 1% (by weight), based on the component of the pivoxil Cefditoren. Furthermore, when analyzing such fine particles in the aforementioned powder X-ray diffraction apparatus, it was found that the component of the pivoxil Cefditoren present in these fine particles was in the form of the amorphous substance. Example 3 The crystalline substance of pivoxil Cefditoren (5 g) was dissolved in an aqueous acidic solution (35 ml) containing polyvinylpyrrolidone (50 mg), as dissolved therein and HCl, at a concentration of IN, at a temperature of 5 mg. ° C or lower and taking a time of 10 minutes for the dissolution of pivoxil Cefditoren. Then, an aqueous acidic solution (pH 0.4) was prepared in which the pivoxil Cefditoren was completely dissolved. Subsequently, this aqueous solution was neutralized by a slow addition drop or drop of an aqueous ammonia IN (approximately 34 ml) to it for 30 minutes, at a temperature of 5 ° C or lower. During the neutralization reaction, the precipitate was deposited. The mixture of the resulting neutralization reaction (pH: 6.8) containing the precipitate, as formed, was stirred at a temperature of 5 ° C or lower overnight. The deposited precipitate was collected by filtration, and then thoroughly washed with an aqueous solution (15 ml) of 0.5% (by weight) of polyvinylpyrrolidone. The precipitate that was washed dried at a reduced pressure.
Then, 4.9 g of a yellow powder consisting essentially of numerous fine particles was obtained, each of which was formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with pilivinylpyrrolidone. The content of the polyvinylpyrrolidone within the fine particles present in the resulting yellow powder was calculated to be 1% (by weight) based on the component of the pivoxil Cefditoren. When analyzing said fine particles in the aforementioned powder X-ray diffraction analyzer, it was discovered that the component of the pivoxil Cefditoren that existed in these fine particles was in the form of an amorphous substance. EXAMPLE 4 The crystalline substance of pivoxil Cefditoren (10 g) was dissolved in an aqueous acidic solution (100 ml) containing approximately 1 g of hydroxypropylmethylcellulose, as it was dissolved therein (at a concentration of 1%) and HCl at a concentration of IN, at a temperature of 10 ° C or lower. Then, an aqueous acidic solution was prepared in which the pivoxil Cefditoren was completely dissolved. This obtained acidic aqueous solution was neutralized by means of a slow dropwise addition of an aqueous solution of 1N sodium hydroxide (100 ml), while maintaining the temperature at 5 ° C or lower. During the neutralization reaction, the precipitate was slowly deposited from the aqueous solution. The mixture of the resulting neutralization reaction containing the precipitate was stirred overnight at a temperature of 5 ° C or lower. Subsequently, the neutralization reaction mixture was filtered and the precipitate that was collected was placed in a filtration apparatus, which operated under a reduced pressure. An aqueous solution of 1% hydroxypropylcellulose was added to the filtration apparatus, then the precipitate was also washed under pushing pressure. The precipitate that was washed, dried under reduced pressure, and then 9.6 g of a yellow powder was obtained consisting essentially of numerous fine particles, each of which was formed from a mixture including pivoxil Cefditoren and hydroxypropylmethylcellulose. The fine particles present in the resulting yellow colored powder were examined by means of a powder X-ray diffraction analyzer (Geigerflex 2027, developed by Rigaku Denki KK), to obtain a graph of the powder X-ray diffraction of said particles. fine particles. The result of the analysis of the X-ray diffraction pattern for dust, indicated that no maximum point was observed in the diffraction angle in the graph, and that the component of the pivoxil Cefditoren, present in the fine particles, was found in the form of an amorphous substance.
The total content of the hydroxypropylmethylcellulose plus hydroxypropylcellulose within the fine particles present in the resulting yellow colored powder was calculated to be 2% (by weight) based on the component of the pivoxil Cefditoren. In addition, the aqueous solution of the hydroxypropyl cellulose, which had been used for the washing operation of the precipitate that was collected from the aforementioned neutralization reaction mixture, was fully recovered after the washing operation. A measurement of the total residual amount of hydroxypropylcellulose remaining in the aqueous solution of hydroxypropylcellulose that had been used in the washing operation was made and then recovered as indicated above. It was observed that the total residual amount that was measured of hydroxypropylcellulose present in the aqueous solution that was recovered after the washing step was significantly lower than the initial total amount of hydroxypropylcellulose, which was initially contained in the aqueous solution of hydroxypropylcellulose, such and how it was loaded in the wash step. Based on this observed fact, it was deduced that during the wash operation of the precipitate, an amount of the hydroxypropylcellulose component present, such as the solute in the aqueous wash solution, had been transferred into the precipitate, at least within the surface of the precipitate, from the aqueous washing solution of hydroxypropylcellulose, which was used just in the washing step. In addition, - when an examination was carried out, under an electron microscope (amplification x 10000), with respect to several of the fine particles, as they were chosen from the resulting yellow colored powder as above, it was demonstrated that the surface of these fine particles had a simple and uniform texture or tissue, and furthermore that on the surface of the fine particles, substantially no presence of separate grains independently of pivoxil Cefditoren, or any presence of separate grains independently of either hydroxypropylmethylcellulose or hydroxypropylcellulose was observed. Example 5 The crystalline substance of pivoxil Cefditoren (50 g), was dissolved in an acidic aqueous solution (350 ml) containing hydroxypropylmethylcellulose (500 mg), as dissolved and HCl at a concentration of IN, at a temperature of 5 ° C. , and taking the time during a period of 45 minutes for the dissolution of pivoxil Cefditoren. The resulting aqueous solution was filtered through a millipore membrane filter (1 μm), to remove insoluble solids from the solution. Then, an aqueous acidic solution containing pivoxil Cefditoren and hydroxypropylmethylcellulose completely dissolved therein, as well as hydrochloric acid was prepared. The resulting acidic aqueous solution which was obtained was neutralized to a pH of 3.3, by means of a slow dropwise addition of an aqueous solution of sodium hydroxide (315 ml), and then to a pH of 7.0 by means of a Slow addition of an aqueous solution of sodium hydrogen carbonate IN (43.5 ml), while the temperature of the solution of the resulting reaction was maintained at 5 ° C or lower. The total period of time taken for the dropwise addition of the aqueous solutions of the inorganic bases was 1.5 hours for completion. During the neutralization reaction, the precipitate deposited slowly. The solution of the resulting neutralization reaction containing the precipitate as formed was subsequently stirred overnight at a temperature of 5 ° C or lower, and then the reaction solution was again adjusted to its pH of 7.0 by means of of a dropwise addition of an aqueous solution of sodium hydrogen carbonate IN. The mixture of the neutralization reaction which was obtained as mentioned above, was filtered to recover the precipitate thereof. The resulting precipitate was thoroughly washed with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (150 ml). The precipitate that was washed, was subsequently dried under reduced pressure. Therefore, 48.5 g. * Of a yellow powder (the composition of this invention) consisting essentially of numerous fine particles) was obtained, each of which was formed of a homogeneous mixture comprising the substance pivoxil Cefditoren and hydroxypropylcellulose. The total content of hydroxypropylmethylcellulose, plus hydroxypropylcellulose contained in the fine particles present in the resulting yellow powder, was calculated to make 1.1% (by weight) based on the component of the pivoxil Cefditoren. The fine particles present in the resulting yellow colored powder were placed in a powder X-ray diffraction analyzer for examination. The result of the analysis of the pattern of the X-ray diffraction graph that was obtained, indicated that no maximum point was observed in the diffraction angle in the graph, and therefore that the component pivoxil Cefditoren contained in the fine particles, it was present in the form of an amorphous substance. Further, when an electron microscope examination was performed, with respect to various fine particles obtained, it was shown that the surface of the particles had a simple uniform texture, and that substantially no separate grain was seen separately on the surface of the particles. the fine particles. It is considered that the fine particles present in the yellow powder, as observed in this Example, had such a structure that the central or neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose, while the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren, hydroxypropylmethylcellulose and hydroxypropylcellulose. Comparative Example 1 The procedure of Example 5 was repeated in the same manner as in Example 5, except that the use of hydroxypropylmethylcellulose and hydroxypropylcellulose was completely omitted. In other words, the crystalline substance of the pivoxil Cefditoren (5 g) was dissolved in water (50 ml) containing 1N HCl, taking a period of 23 minutes for the dissolution of pivoxil Cefditoren, while maintaining the temperature of the solution at 5 ° C. ° C or lower. After the end of the dissolution of the pivoxyl Cefditoren in the acidic water, a 1N aqueous solution of sodium hydroxide (40 ml) was slowly added dropwise to the acidic aqueous solution resulting from the pivoxil Cefditoren, to neutralize the subsequent solution. at a pH of 2.1. Then, an aqueous solution of 1N sodium hydrogen carbonate (10 ml) was added dropwise to the aqueous solution of pivoxil Cefditoren to further neutralize the solution. During the neutralization step, the reaction solution was maintained at a temperature of 5 ° C or lower. The total time taken for the completion of the addition of these aqueous solutions of inorganic bases was 27 minutes. The mixture of the resulting neutralization reaction containing the precipitate as formed (pH 6.2) was stirred for 1.5 hour at a temperature of 5 ° C or lower, and then further neutralized to a pH of 7.0 through a drop addition. dropwise of an aqueous solution of sodium hydrogen carbonate IN. During the last step of the neutralization reaction, the precipitate of pivoxil Cefditoren was deposited from the aqueous solution. The mixture of the neutralization reaction that was obtained was stirred at a temperature of 5 ° C or lower during the night. The obtained neutralization reaction mixture containing the precipitate was filtered to recover the deposited precipitate. The precipitate that was collected was washed thoroughly with water (25 ml) while cooling to 5 ° C. The precipitate that was washed was subsequently dried to obtain a fine powder (4.4 g) which was formed of a crystalline substance of pivoxil Cefditoren. Fine particles present in fine dust, were examined by means of the powder X-ray diffraction analyzer, to indicate that a maximum point appeared at the diffraction point in the pattern of the resulting X-ray diffraction graph. It was then deduced that the component of pivoxyl Cefditoren contained in the fine powder was present in the form of a crystalline substance. Example 6 The crystalline substance of pivoxil Cefditoren (50 g) was dissolved for 45 minutes in an aqueous acidic solution (350 ml) containing hydroxypropylmethylcellulose (500 mg) as dissolved in it and HCl at a concentration of 1N, at a temperature of 5 ° C or lower. The resulting aqueous solution containing pivoxil Cefditoren was filtered through a millipore membrane filter (1 μm) to remove the insoluble solids therefrom. Then, an aqueous acidic solution was prepared in which the pivoxil Cefditoren, hydroxypropylmethylcellulose and hydrochloric acid were completely dissolved. The acidic aqueous solution obtained was neutralized to a pH of 7.0 by means of a slow dropwise addition of an aqueous ammonia IN, that is an aqueous solution of ammonium hydroxide IN (331 ml) while the solution was maintained Acidic aqueous at a temperature of 5 ° C or lower. The total time taken for the completion of the dropwise addition of the aqueous ammonia was 1.5 hours. During this neutralization reaction, the precipitate was deposited slowly. The mixture of the resulting neutralization reaction containing the precipitate as formed was subsequently stirred overnight at a temperature of 5 ° C or lower. Then, the pH of the reaction mixture was again adjusted to a pH of 7.0 by means of a dropwise addition of an aqueous ammonia IN. The mixture of the neutralization reaction obtained according to the aforementioned was filtered to recover the precipitate thereof. The resulting precipitate was thoroughly washed with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (150 ml). The precipitate that was washed, was subsequently dried under a reduced pressure. Then 48.8 g of a yellow powder was obtained (the composition of this invention) consisting essentially of numerous fine particles, wherein each of them is substantially formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose. The fine particles present in the yellow powder were analyzed by means of a high performance liquid chromatography, to detect that the fine particles had a content of 96% (by weight) of the component pivoxil Cefditoren based on the weight of the fine particles. In addition, the total content of hydroxypropylmethylcellulose plus hydroxypropylcellulose within the fine particles was calculated to be 1.3% (by weight) based on the weight of the pivoxil component Cefditoren. The fine particles present in the resulting yellow colored powder were placed and examined by means of the powder X-ray diffraction analyzer (Geigerflex 2027, developed by Rigaku Denki KK) to provide an X-ray diffraction graph for dust of said particles. thin The result of the analysis of the pattern of the X-ray diffraction graph revealed that no maximum point was observed in the diffraction angle in the graph and therefore that the component pivoxil Cefditoren contained in the fine particles, was present in the form of amorphous substance. In addition, the examination carried out under an electron microscope with respect to various fine particles, showed that the surface of the fine particles had a simple and uniform texture and that in addition any separately separated grain was substantially absent on the surface of the fine particles. . It is considered that the fine particles present in the yellow powder as observed in this Example have such structure that the central or neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose, while the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose and hydroxypropylcellulose a diffraction graph of X-ray diffraction for powder, which was provided when measuring the particles fine particles of the yellow powder, as produced in this Example, in the powder X-ray diffraction analyzer (Geigerflex 2027, developed by Rigaku Denki KK) is shown in Fig. 1 of the accompanying drawings. An infrared absorption spectrum (measured by the compressed KBr method) of the amorphous substance of the pivoxil Cefditoren present in the fine particles just mentioned above was measured by placing the fine particles in an infrared spectrometer. The graph of the infrared absorption spectrum that was then obtained is shown in Fig. 2a of the accompanying drawings. The infrared absorption spectrum for the crystalline substance of pivoxil Cefditoren which is used in this Example as the starting material was measured in a similar way, and the measured graph of this is also shown in Fig. 2b of the accompanying drawings. Comparative Example 2 The procedure of Example 6 was repeated substantially in the same manner as in Example 6, except that the use of hydroxypropylmethylcellulose and hydroxypropylcellulose was omitted. That is, pivoxil Cefditoren in the form of crystalline substance (20 g) was dissolved for 3 hours in a volume of water (190 ml) containing HCl at a concentration of IN, at a temperature of 5 ° C or lower. After the end of the dissolution of the pivoxil Cefditoren in the acidified water, the resulting aqueous solution was filtered through a millipore filter of membranes (1.0 μm). The resulting acidic aqueous solution containing the pivoxil Cefditoren, was neutralized to a pH of 6.03 by means of a slow dropwise addition of an aqueous ammonia IN (192 ml) while maintaining the acidic solution at a temperature of 5 ° C. or lower. The mixture of the resulting neutralization reaction containing the precipitate as formed (pH 6.03) was stirred overnight at a temperature of 5 ° C or lower, and then added again dropwise of IN aqueous ammonia to adjust the pH of the reaction mixture at pH 5.8. During this step of the neutralization reaction, the precipitate of pivoxil Cefditoren was deposited from the aqueous solution. The obtained neutralization reaction mixture was stirred at a temperature of 5 ° C or lower overnight. The mixture of the resulting neutralization reaction containing the precipitate was filtered to recover the deposited precipitate. The collected precipitate was washed with cold water at 5 ° C (60 ml). The precipitate that was washed was subsequently dried to obtain a fine powder (19.4 g) which was formed of a crystalline substance of pivoxil Cefditoren. The resultant fine powder that was obtained was examined through a powder X-ray diffraction analyzer to indicate that a maximum point appeared in the diffraction angle, in the pattern of the X-ray diffraction graph obtained. It is further confirmed that the component of the pivoxil Cefditoren contained in the resulting fine particles was in the form of a crystalline substance. Example 7 The crystalline substance of pivoxil Cefditoren (5 g) was dissolved for 16 minutes in an aqueous acidic solution (35 ml) containing hydroxypropylmethylcellulose (50 mg) as dissolved therein and HCl at a concentration of 1N, at a temperature of 5 ° C or lower. Then, an aqueous acidic solution (pH 0.8) was prepared in which the pivoxil Cefditoren, hydroxypropylmethylcellulose and hydroxypropylcellulose were completely dissolved. The resulting acidic aqueous solution was neutralized to a pH of 6.7 by a slow dropwise addition of the aqueous ammonia IN (approximately 34 ml) while the aqueous acidic solution was maintained at a temperature of 5 ° C or lower. The time it took to finish the dropwise addition of the aqueous ammonia was 33 minutes. During the neutralization reaction, the precipitate was deposited slowly. The mixture of the resulting neutralization reaction containing the precipitate as formed was stirred overnight at a temperature of 5 ° C or lower. The mixture of the neutralization reaction that was obtained was filtered to collect the precipitate. The resulting precipitate was thoroughly washed with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (75 ml). The precipitate that was washed, was subsequently dried under a reduced pressure. Therefore, 4.8 g of a yellow powder (the composition of this invention) was obtained which consists essentially of numerous fine particles, each of which was substantially formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose. The total content of hydroxypropylmethylcellulose and hydroxypropylcellulose contained in the fine particles present in the resulting yellow colored powder was calculated to be 1.1% (by weight) based on the weight of the pivoxil component Cefjditoren. The fine particles that were obtained were placed and examined by the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph indicated that no maximum point was observed in the diffraction angle, and therefore that the component of the pivoxil Cefditoren contained in the fine particles was present in the form of amorphous substance. In addition, a verification was made under an electron microscope with respect to various of the fine particles, to demonstrate that the surface of the fine particles had a simple or uniform phase or texture. It is considered that the fine particles present in the yellow powder, as observed in this Example, have such structure that the central and neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose, while the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of the pivoxil Cefditoren, hydroxypropylmethylcellulose and hydroxypropylcellulose. EXAMPLE 8 The crystalline substance of the pivoxil Cefditoren (5 g) was dissolved for 10 minutes in an aqueous acidic solution (35 ml) containing hydroxypropylmethylcellulose (100 mg) as dissolved in it and HCl at a concentration of IN, at a temperature of 5 ° C or lower. Then, an aqueous acidic solution (pH 07) was prepared in which the pivoxil Cefditoren, hydroxypropylmethylcellulose and hydrochloric acid were completely dissolved. The acidic aqueous solution obtained was neutralized to a pH of 7.0 by means of a slow dropwise addition of an aqueous ammonia IN (approximately 34 ml) while maintaining the aqueous acidic solution at a temperature of 5 ° C or lower. The time taken to complete the dropwise addition of the aqueous ammonia was 30 minutes. During the neutralization reaction, the precipitate deposited slowly. The solution of the obtained neutralization reaction, which contained the precipitate, was stirred at a temperature of 5 ° C or lower overnight. The mixture of the neutralization reaction that was obtained was filtered according to what was indicated in the top part, to collect the precipitate. The resulting precipitate was thoroughly washed with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (15 ml). The precipitate that was washed, was subsequently dried under a reduced pressure. Therefore, 5 g of a yellow powder (the composition of this invention) consisting essentially of numerous fine particles, each of which was formed substantially of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose, was obtained. The total content of hydroxypropylmethylcellulose plus hydroxypropylcellulose within the fine particles present in the resulting yellow powder, was calculated to be 2.0% (by weight) based on the weight of the pivoxil Cefditoren component. The fine particles that were obtained were placed and examined by the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph, indicated that no maximum point appeared in the diffraction angle, and that therefore the component of the pivoxil Cefditoren contained in the particles, was present as a substance amorphous It is considered that the fine particles present in the yellow powder, as shown in this example, have such structure that the central and neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose, but the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of the pivoxil Cefditoren, hydroxypropylmethylcellulose and hydroxypropylcellulose. Example 9 The crystalline substance of the pivoxil Cefditoren (5g) was dissolved for 10 minutes in an aqueous acidic solution (35 ml) containing hydroxypropylmethylcellulose (40 mg) as dissolved therein and HCl at a concentration of IN, at a temperature of 5 ml. ° C or lower. Then, an aqueous acidic solution (pH 0.4) was prepared in which the pivoxil Cefditoren, hydroxypropylmethylcellulose and hydrochloric acid were completely dissolved. The resulting acidic aqueous solution which was obtained was neutralized to a pH of 6.9 by means of a slow dropwise addition of an aqueous ammonia IN (approximately 34 ml), while maintaining the aqueous acidic solution at a temperature of 5 °. C or lower. The time it took to finish the dropwise addition of the aqueous ammonia was 30 minutes. During the neutralization reaction, the precipitate deposited slowly. The solution of the resulting neutralization reaction containing the precipitate was stirred overnight at a temperature of 5 ° C or lower. The obtained neutralization reaction mixture was filtered as indicated above, to collect the precipitate. The resulting precipitate was thoroughly washed with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (15 ml). The precipitate that was washed, was subsequently dried under a reduced pressure. Therefore, 5 g of a yellow powder (the composition of this invention) consisting essentially of numerous fine particles was obtained, each of which was formed substantially from a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose. The total content of hydroxypropylmethylcellulose and hydroxypropylcellulose within the fine particles present in the resulting yellow colored powder was calculated to be 1.1% (by weight) based on the weight of the pivoxil component Cefditoren. The fine particles that were obtained were placed and examined in the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph indicated that no maximum point appeared in the diffraction angle, and therefore that the component of the pivoxil Cefditoren contained in the fine particles was present in the form of amorphous substance. It is considered that the fine particles present in the yellow powder, as shown in this Example, have such a structure that the neutral and center part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose , but the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren, hydroxypropylmethylcellulose and hydroxypropylcellulose. Example 10 The crystalline substance of pivoxil Cefditoren (5 g) was dissolved for 10 minutes in an aqueous acidic solution (35 ml) containing hydroxypropylcellulose (50 mg)., as dissolved and HCl at an IN concentration at a temperature of 5 ° C or lower. Then, an aqueous acidic solution (pH 0.7) was prepared in which the pivoxil Cefditoren, hydroxypropylcellulose and hydrochloric acid were completely dissolved. The resultant acidic aqueous solution which was obtained here was neutralized to a pH of 6.7 by means of a slow dropwise action of an aqueous ammonia IN (approximately 34 ml), while the aqueous acidic solution was maintained at a temperature of 5 ml. ° C or lower. The time taken for the completion of the dropwise addition of aqueous ammonia was 36 minutes. During the neutralization reaction, the precipitate deposited slowly. The solution of the resulting neutralization reaction containing the precipitate as formed was stirred overnight at a temperature of 5 ° C or lower. The neutralization reaction mixture obtained as specified above was filtered to collect the precipitate. The resulting precipitate was thoroughly washed with an aqueous solution of 0.5% (by weight) of hydroxypropylmethylcellulose (15 ml). The precipitate that was washed, was subsequently dried under a reduced pressure.
Then 5 g of a yellow powder (the composition of this invention) was obtained, consisting essentially of numerous fine particles, each of which was substantially formed of a homogeneous mixture comprising the amorphous substance of the pivoxil Cefditoren and hydroxypropylcellulose. The total content of hydroxypropylcellulose and hydroxypropylmethylcellulose within the fine particles present in the resulting yellow colored powder was calculated to be 1% (by weight) based on the weight of the pivoxil component Cefditoren. The fine particles that were obtained were placed and examined in the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph, indicated that no maximum point appeared in the diffraction angle of the graph, and therefore, that the component of the pivoxil Cefditoren contained in the fine particles, was present in the form of amorphous substance. It is considered that the fine particles present in the yellow powder as indicated in this Example, have such structure, that the central and neutral part of being fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylcellulose , but the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren, hydroxypropylcellulose and hydroxypropylmethylcellulose. EXAMPLE 11 The crystalline substance of the pivoxil Cefditoren (5 g) was dissolved for 10 minutes in an aqueous acidic solution (35 ml) containing hydroxypropylcellulose (50 mg) as dissolved therein and HCl at a concentration of IN, at a temperature of 5 ° C or lower. Then, an acidic aqueous mixture (pH 0.3) was prepared in which the pivoxil Cefditoren, hydroxypropylcellulose and hydrochloric acid were completely dissolved. The resultant acidic aqueous solution obtained here was neutralized to a pH of 6.9, by means of a slow dropwise addition of an aqueous ammonia IN (approximately 34.5 ml) while the aqueous acidic solution was maintained at a temperature of 5 ml. ° C or lower. The time taken for the completion of the dropwise addition of the aqueous ammonia was 43 minutes. During the neutralization reaction, the precipitate deposited slowly. The solution of the resulting neutralization reaction containing the precipitate as formed was stirred at a temperature of 5 ° C or lower overnight. The mixture of the neutralization reaction obtained as indicated above was filtered to collect the precipitate. The resulting precipitate was thoroughly washed with an aqueous solution of 0.5% (by weight) methylcellulose (15 ml). The precipitate that was washed, was subsequently dried under a reduced pressure. Then 4.9 g of a yellow powder (the composition of this invention) was obtained which consists essentially of numerous fine particles, each of which was formed substantially of a homogeneous mixture, comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylcellulose. The total content of the hydroxypropylmethylcellulose and methylcellulose within the fine particles present in the resulting yellow colored powder was calculated to be 1% (by weight) based on the weight of the pivoxil component Cefditoren.
Then the fine particles that were obtained were placed and examined in the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph, indicated that no maximum point appeared in the diffraction angle in said graph, and therefore that the component of the pivoxil Cefditoren contained in the fine particles was present. in the form of the amorphous substance. It is considered that the fine particles contained in the yellow powder, as indicated in this Example, have such structure that the central and neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylcellulose, but the surface layer of the fine particles is formed of a homogeneous mixture consisting of the amorphous substance of pivoxil Cefditoren, hydroxypropylcellulose and methylcellulose. Example 12 The crystalline substance (5 g) was dissolved for 10 minutes in an aqueous acidic solution (35 ml) containing hydroxypropylmethylcellulose (50 mg), as dissolved and 1N-HCl at a temperature of 5 ° C or lower. Then, an aqueous acidic solution (pH 1.1) was prepared in which the pivoxil Cefditoren, hydroxypropylmethylcellulose and hydrochloric acid were completely dissolved. The resulting acidic aqueous solution which was obtained here was neutralized to a pH of 7.0 by means of a slow dropwise addition of an aqueous ammonia IN (approximately 34 ml), while the aqueous acidic solution was maintained at a temperature of 5 ml. ° C or lower. The time taken for the completion of the dropwise addition of the aqueous ammonia was 50 minutes. During the neutralization reaction, the precipitate deposited slowly. The solution of the resulting neutralization reaction containing the precipitate as formed was stirred at a temperature of 5 ° C or lower overnight. The obtained neutralization reaction mixture was filtered, as indicated above, to collect the precipitate. The precipitate that was washed, was subsequently dried under a reduced pressure. Then 4.9 g of a yellow powder (the composition of this invention) was obtained which consists essentially of numerous fine particles, each of which was formed substantially of a homogeneous mixture comprising the amorphous substance of the pivoxil Cefditoren hydroxypropylmethylcellulose. The total content of the hydroxypropylmethylcellulose and hydroxypropylcellulose within the fine particles present in the resulting yellow colored powder was calculated to be 1.1% (by weight) based on the weight of the pivoxil component Cefditoren. The fine particles that were obtained were placed and examined by the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph indicated that no maximum point was observed in the diffraction angle in the graph, and therefore that the component of the pivoxil Cefditoren contained in the fine particles was present in the form of an amorphous substance. It is considered that the fine particles contained in the yellow powder, as observed in this Example, have such structure that the central and neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of the pivoxil Cefditoren and hydroxypropylmethylcellulose, while the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren, hydroxypropylmethylcellulose and hydroxypropylcellulose. Example 13 The crystalline substance of pivoxil Cefditoren (5 g) was dissolved for 16 minutes in an aqueous acidic solution (35 ml) containing methyl cellulose (50 mg), as dissolved and HCl at a concentration of IN, at a temperature of 5 mg. ° C or lower. Then, an aqueous acidic solution (pH 0.4) was prepared in which the pivoxil Cefditoren, methylcellulose and hydrochloric acid were completely dissolved. The resulting acidic aqueous solution which was obtained was neutralized to a pH of 6.7 by means of a slow dropwise action of an aqueous ammonia IN (approximately 34 ml), while the aqueous acidic solution was maintained at a temperature of 5 °. C or lower. The time taken for the completion of the dropwise addition of the aqueous ammonia was 40 minutes. During the neutralization reaction, the precipitate deposited slowly. The solution of the resulting neutralization reaction containing the precipitate, as formed, was stirred at a temperature of 5 ° C or lower overnight.
The obtained neutralization reaction mixture was filtered, as indicated above, to collect the precipitate. The resulting precipitate was washed thoroughly with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (15 ml). The precipitate that was washed, was subsequently dried under a reduced pressure. Then 4.9 g of a yellow powder (the composition of this invention) consisting essentially of numerous fine particles, each of which was formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and methylcellulose, was obtained. The total content of methylcellulose and hydroxypropylcellulose within the fine particles present in the resulting yellow colored powder was calculated to be 2% (by weight) based on the weight of the pivoxil component Cefditoren. The fine particles that were obtained were placed and examined in the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph indicated that no maximum point was observed in the diffraction angle in the graph, and therefore that the component of the pivoxil Cefditoren contained in the fine particles was present in the form of an amorphous substance. It is considered that the fine particles present in the yellow powder, as observed in this Example, have such a structure that the central and neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and methylcellulose , but the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren, methylcellulose and hydroxypropylcellulose. Example 14 The crystalline substance of the pivoxil Cefditoren (5 g) was dissolved for 10 minutes in an acidic aqueous solution (35 ml) containing methyl cellulose (50 mg), as dissolved and HCl at an IN concentration, at a temperature of 5 ml. ° C or lower. Then, an aqueous acidic solution (pH 0.3) was prepared in which the pivoxil Cefditoren, methylcellulose and hydrochloric acid were completely dissolved. The resulting acidic aqueous solution which was obtained was neutralized to a pH of 6.7 by means of a slow dropwise addition of an aqueous ammonia IN (approximately 34.5 ml), while the aqueous acidic solution was maintained at a temperature of 5 °. C or lower. The time taken for the completion of the dropwise addition of the aqueous ammonia was 23 minutes. During the neutralization reaction, the precipitate deposited slowly. The solution of the resulting neutralization reaction containing the precipitate, as formed, was stirred at a temperature of 5 ° C or lower overnight. The obtained neutralization reaction mixture was filtered, as indicated above, to collect the precipitate. The resulting precipitate was washed thoroughly with an aqueous solution of 0.5% (by weight) of hydroxypropylcellulose (15 ml). The precipitate that was washed, was subsequently dried under a reduced pressure. Then 4.9 g of a yellow powder (the composition of this invention) consisting essentially of numerous fine particles, each of which was formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and methylcellulose, was obtained. The total content of methylcellulose and hydroxypropylmethylcellulose within the fine particles present in the resulting yellow colored powder was calculated to be 1.1% (by weight) based on the weight of the pivoxil component Cefditoren. The fine particles that were obtained were placed and examined in the powder X-ray diffraction analyzer. The result of the analysis of the pattern of the resulting X-ray diffraction graph indicated that no maximum point was observed in the diffraction angle in the graph, and therefore that the component of the pivoxil Cefditoren contained in the fine particles, was present in the form of an amorphous substance. It is considered that the fine particles present in the yellow powder, as observed in this Example, have such a structure that the central and neutral part of these fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and methylcellulose , but the surface layer of the fine particles is formed of a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren, methylcellulose and hydroxypropylmethylcellulose. Test Example 1 A gram of the yellow powder (the composition of this invention), which was obtained in Example 6 above, and which consisted essentially of the particles, as formed, was then taken as a sample. substantially a homogeneous mixture comprising the amorphous substance of pivoxil Cefditoren and hydroxypropylmethylcellulose, and in which the surface layer of said particles additionally contained hydroxypropylcellulose. The sample that was taken was placed in 250 ml of acidic water (pH 1.2), which contained approximately IN HCl at 37 ° C and was stirred at 37 ° C for 2 hours. The resulting acidic aqueous solution was passed through a millipore filter of membranes (1 μm) to remove the insoluble solids therefrom. The obtained clear aqueous solution, which contained pivoxil Cefditoren and the aforementioned water-soluble cellulose derivatives, as dissolved therein, was measured with respect to the concentration of pivoxil Cefditoren. By means of this measurement test, it was observed that the amorphous substance of the pivoxil Cefditoren contained in the yellow powder has a solubility of at least 4 mg / ml in the acidic water at 37 ° C. On the other hand, a test similar to that given above was performed to measure the solubility of the crystalline substance of pivoxil Cefditoren (the orthorhombic crystalline substance of pivoxil Cefditoren, as obtained in Example 1 of the PCT International Placement Publication Open No. W098 / 12200), which was used as starting material. It was found that this crystalline substance of pivoxil Cefditoren has a solubility of only 0.4 mg / ml in the aforementioned acidic water at 37 ° C. Test Example 2 Five grams of the yellow powder composition, as obtained in Example 6, were placed in a sealed container and then stored therein at 40 ° C under an atmosphere of dry air for 4 months. After storage, the was removed. yellow powder composition of the container, and was measured for its X-ray diffraction in the powder X-ray diffraction analyzer, same as that used in Example 6. An analysis of the pattern of the resulting X-ray diffraction graph, He indicated that no maximum point appeared in the diffraction angle in the graph. Subsequently it was discovered that the pivoxil Cefditoren contained in the fine particles present in the aforementioned yellow powder, even after storage at 40 ° C for 4 months, could remain in the form of the amorphous substance and therefore has a stability crystallographic Industrial Applicability The yellow powder composition, which consists essentially of the particles that are formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with an additive with high molecular content, soluble in water, for example, is now provided, according to with this invention, a cellulose derivative solubilized in water, and such a composition is administered orally and is very useful as an orally administrable antibacterial agent, which has a broad antibacterial spectrum. The component of the pivoxil Cefditoren contained in this composition, has a high solubility in acidified water HCl, having a pH value of about 1.2 and therefore, the composition of this invention, can present a high therapeutic efficacy when administered orally.
Claims (11)
- CLAIMS 1. A yellow powder composition, orally administrable, consisting essentially of solid particles, which are formed from a homogeneous mixture of a substance of pivoxil Cefditoren crystallographically stable, amorphous and soluble in water, with an additive with high content molecular, soluble in water having a uniform internal texture within each particle, characterized in that such a yellow colored powder composition, consists essentially of the solid particles, which are formed from a mixture of (i) the substance of pivoxil Cefditoren crystallographically stable, amorphous and soluble in water, ie 7- [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [(Z) -2- (4-methylthiazole- 5-yl) ethenyl] -3-cephem-4-pivaloyloxymethyl ester of carboxylic acid, with (ii) the additive with high molecular content, soluble in water, which is a pharmaceutically acceptable cellulose derivative, solubilized in water, as chose d and hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose and an alkaline metal salt or pharmaceutically acceptable alkaline earth metal salt of carboxymethylcellulose, or pluran, carrageenan, polyvinylpyrrolidone or an ester of glycol polypropylene glycolic acid, which additive with high molecular content, soluble in water ( ii) content in the aforementioned solid particles is present in said particles, in a proportion of 0.5% -5% based on the weight of the substance of pivoxil Cefditoren, that said particles are fused at a temperature of 120 ° C or higher, but they do not show any defined melting point, that the amorphous substance of the pivoxil Cefditoren (1) contained in said particles, does not show any maximum point of the diffraction angle in a graph of X-ray diffraction for powder of such particles, but presents in its infrared absorption spectrum (as measured by the bromide method of compressed potassium) a substantially higher maximum absorption point at a wave number of 1750"1, as compared to the well defined maximum absorption point presented by the orthorhombic crystalline substance of pivoxil Cefditoren at a wave number of 1750" 1 in the infrared absorption spectrum, and that the amorphous substance of pivoxil Cefditoren (i) contained in such particles, can be dissolved in acidified water containing hydrochloric acid (pH 1.2) at a solubility of at least 4 mg / ml pivoxil Cefditoren, at 37 ° C and has such a crystallographic stability, that the amorphous substance of pivoxil Cefditoren does not involve crystallization when stored at 40 ° C for 4 months in a sealed container under drying conditions.
- 2. A composition as set forth in claim 1, which consists essentially of particles, each of which is formed of a homogeneous mixture of a crivographically stable, amorphous and water-soluble pivoxil Cefditoren substance with hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose or polyvinylpyrrolidone mixed as the additive with high molecular content, soluble in water, which is present in an amount of 1% -3% based on the weight of the pivoxil Cefditoren.
- 3. A yellow powder composition, orally administrable, consisting essentially of particles, wherein each of them contains mixtures of a substance of pivoxil Cefditoren crystallographically stable, amorphous and soluble in water with additive or additives with high molecular content, soluble in water, and whose particles have a uniform internal texture within each particle, characterized in that the yellow powder composition consists essentially of the particles, each of which consists essentially of a mixture of (i) the substance of pivoxil Cefditoren crystallographically stable, amorphous and soluble in water, that is to say 7- [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [(Z) -2- (4- methylthiazol-5-yl) ethenyl] -3-cephem-4-pivaloyloxymethyl ester of carboxylic acid, with (ii) a first additive with high molecular content, soluble in water, which is either a pharmaceutically stable cellulose derivative, solubilized in water, as chosen from hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, methylcellulose and an alkali metal salt or pharmaceutically acceptable alkaline earth metal salt of carboxymethylcellulose, or pluran, carrageenan, polyvinylpyrrolidone or an ester of alginic acid of polypropylene glycol, which the central and neutral part of the respective particles which lies under the surface layer of the respective particles, is form only a homogeneous mixture of (1) the amorphous substance of pivoxil Cefditoren with (ii) the first additive with high molecular content, soluble in water mentioned above, but the surface layer of said particles is formed of a homogeneous mixture of (i) the amorphous substance of pivoxil Cefditoren with (ii) the first additive with high molecular content, soluble in water, and also with (iii) a second additive with high molecular content, soluble in water, which is additionally incorporated, which is made of a substance different from the first additive with high molecular content, soluble in water aforementioned, present together in the central or neutral part of such particles which are under the particle surface layer, and whose second additive with high molecular content, soluble in water is selected from hydroxypropylmethylcellulose hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone, which both the first additive with high molecular content, soluble in water (ii) and the second additive with high molecular content, soluble in water (iii) are present in a total proportion of them of 0.5% - 5% based on the weight of the substance of pivoxil Cefditoren contained in such particles, that said particles are fused at a temperature of 120 ° C or higher, but does not show any n defined melting point, that the amorphous substance of pivoxil Cefditoren (i) contained in the particles, does not show any maximum point of the diffraction angle in a graph of X-ray diffraction for dust of said particles, but presents in its spectrum of infrared absorption (as measured by means of the compressed potassium bromide method), a maximum point of maximum absorption, and a wave number of 1750 cm "1 as compared to the well defined maximum point of absorption of the substance orthorhombic crystal of pivoxil Cefditoren at a number of 1750 cm "1 in the infrared absorption spectrum, and that the amorphous substance of pivoxil Cefditoren (i) contained in said particles, can be dissolved in acidified water containing hydrochloric acid (pH 1.2) at a solubility of at least 4 mg / ml of pivoxil Cefditoren at 37 ° C and has a crystallographic stability such that the amorphous substance of pivoxil Cefditoren, did not imply to crystallization when stored at 40 ° for 4 months in a sealed container under dry conditions.
- 4. A composition as set forth in Claim 3, wherein the central or neutral part of the respective particles, which lies under the surface layer of the respective particles, is formed of a homogeneous mixture of the amorphous substance of pivoxil. Cefditoren with hydroxypropylmethylcellulose, but the surface layer of such particles, is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylmethylcellulose and also with hydroxypropylcellulose or methylcellulose. A composition as set forth in Claim 3, wherein the central or neutral part of the respective particles, which lies beneath the surface layer of the respective particles, is formed of a homogeneous mixture of the amorphous substance of pivoxil. Cefditoren with hydroxypropylcellulose, but the surface layer of said particles is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with hydroxypropylcellulose and also with hydroxypropylmethylcellulose or methylcellulose. 6. A composition as set forth in Claim 3, wherein the central or neutral part of the respective particles, which lies under the surface layer of the particles, is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with methylcellulose, but the surface layer of the particles is formed from a homogeneous mixture of the amorphous substance. of pivoxil Cefditoren with methylcellulose and also with hydroxypropylmethylcellulose or hydroxypropylcellulose. A composition as set forth in Claim 3, wherein the central or neutral part of the respective particles, which lies under the surface layer of the particles, is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with polyvinylpyrrolidone, but the surface layer of the particles is formed of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with polyvinylpyrrolidone and also with hydroxypropylmethylcellulose or hydroxypropylcellulose or methylcellulose. 8. A process for the preparation of a yellow powder composition, consisting essentially of particles, each of which is formed of a homogeneous mixture of a crystallographically stable, amorphous and water soluble pivoxil Cefditoren substance with an additive with high molecular content, soluble in water, and whose particles have a uniform internal texture within each particle characterized in that the process comprises a step to dissolve an orthorhombic crystalline substance of pivoxil Cefditoren, ie 7 - [(Z) -2 - (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [/ Z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4-pivaloyloxymethyl ester of carboxylic acid, in an aqueous acidic solution, which contains an additive with high molecular content, soluble in water made either of a cellulose derivative solubilized in water, as chosen from hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, Tilcellulose and an alkaline metal salt or pharmaceutically acceptable alkaline earth metal salt of carboxymethylcellulose or pluran, carrageenan, polyvinylpyrrolidone or an ester of alginic acid or polypropylene glycol, as dissolved at a concentration of 0.05% to 1% (based on weight / weight) , and whose aqueous acidic solution also contains hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid at a concentration of 0. IN - 12N of the acid, so that the amount of pivoxil Cefditoren dissolved in the aqueous solution Acidic is in the range of 10 to 100 times, based on the total weight of said additive with high molecular content, soluble in water contained in the aqueous acidic solution, and so that an aqueous acidic solution containing pivoxil Cefditoren is prepared, the additive with high molecular content, soluble in water and the acid dissolved in it, a step to subsequently neutralize the solution acidic aqueous solution which was prepared by slowly adding to it a solution or aqueous solutions of sodium or potassium hydroxide, sodium or potassium hydrogen carbonate, or sodium or potassium carbonate, simple or combined, or an aqueous solution of ammonium hydroxide, maintaining the aqueous acidic solution at a temperature of 10 ° C or lower under agitation, and with the amount of the basic sodium or potassium compound or ammonium hydroxide to be added to the aqueous acidic solution, which is adjusted in such a way that the solution of the reaction after neutralization, shows a pH value of 6.5 -7.1, and a step to continue during the neutralization reaction the agitation of the aqueous solution containing pivoxil Cefditoren at a temperature of 10 ° C or lower, to cause the combined precipitation of pivoxil Cefditoren and the additive with high molecular content, soluble in water simultaneously from the aqueous solution, a step for recol ect by means of filtration or centrifugation, the precipitate that was deposited from the neutralization reaction mixture, a step for washing the collected precipitate with an aqueous solution of a high molecular content, water soluble additive made of the same substance as the additive with high molecular content, soluble in water mentioned above and containing said dissolved additive in the solution, at a concentration of 0.5% 10% (based on weight / weight), while allowing at least a part of the additive with high molecular content, soluble in water used here in the aqueous wash solution, during the washing operation for transferring the aqueous wash solution of the high molecular content, water-soluble additive to the surfaces of the precipitate particles, and a step to then dry the precipitate that was washed, to thereby obtain a powder composition of yellow color, consisting essentially of the particles, each of which is formed of a homogeneous mixture of the crystallographically stable pivoxil substance Cefditoren, amorphous and soluble in water with the additive with high molecular content, soluble in water mentioned above, present in a proportion of 0.5% 5% based on the weight of the substance of pivoxil Cefditoren. 9. A process as set forth in Claim 8, which process comprises a step for dissolving the orthorhombic substance of pivoxil Cefditoren in an aqueous acidic solution, which contains an additive with high molecular content, soluble in water as chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone, as they were dissolved in a concentration of 0.05% to 1% (based on weight / weight) and whose aqueous acidic solution also contains hydrochloric acid or phosphoric acid at a concentration of 0.5N 2.0N of acid, so that the amount of the pivoxil Cefditoren dissolved in the aqueous acidic solution, is in a range of 10 to 100 times based on the total weight of the additive with high molecular content, soluble in water contained in the aqueous acidic solution, and in such a way that an acidic aqueous solution containing pivoxil Cefditoren, the additive with high molecular content, soluble in water and the acid is prepared or dissolved in it, a step to subsequently neutralize the acidic aqueous solution containing pivoxil Cefditoren, by slowly adding thereto an aqueous solution of sodium hydroxide IN-2N or / and an aqueous solution of sodium hydrogencarbonate IN-2N, or by slowly adding to it an aqueous solution of ammonium hydroxide IN-2N, keeping the acidic aqueous solution at a temperature of 5 ° C or lower with stirring, until the aqueous acidic solution is neutralized to a pH value of 6.5 ~ 7.0, a step to continue during the neutralization reaction the agitation of the resulting neutralization reaction mixture at a temperature of 5 ° C or lower, to cause a joint precipitation of the pivoxil Cefditoren and the additive with high molecular content, soluble in water simultaneously from said aqueous solution, a step to collect the precipitate deposited from the resulting neutralization reaction mixture, a or to wash the collected precipitate with an aqueous solution of an additive with high molecular content, soluble in water made of the same substance as the additive with high molecular content, soluble in water that was mentioned first and containing said additive dissolved in the solution, at a concentration of 0.5% -105 (based on weight / weight), and a step to then dry the washed precipitate, and thereby obtain the yellow colored powder compound consisting essentially of the particles, each of which a homogeneous mixture of the amorphous substance of pivoxil Cefditoren is formed with the additive with high molecular content, soluble in water mentioned above, present in a part of 1% -3% based on the weight of the substance of pivoxil Cefditoren. 10. A process for the preparation of a yellow powder composition, consisting essentially of particles, each of which comprises mixtures of a crystallographically stable, amorphous and water soluble pivoxil Cefditoren substance, with an additive or additives with high molecular content, soluble in water, and whose particles have a uniform internal texture within each particle that characterized in that the process comprises a step to dissolve an orthorhombic crystalline substance of pivoxil Cefditoren, in an aqueous acidic solution, which contains a first additive with high molecular content, soluble in water made from either a cellulose derivative solubilized in water , as chosen from hydroxypropylmethylcellulose, phthalate I from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and an alkali metal salt or pharmaceutically acceptable alkaline earth metal salt of carboxymethylcellulose, or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of glycol polypropylene, as dissolved in a 0.05% concentration - 1 % (based on weight / weight), and whose aqueous acidic solution also contains hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid or butyric acid at a concentration of 0. IN - 12N of the acid, so that the amount of pivoxil Cefditoren dissolved in the aqueous acidic solution is in the range of 10 to 100 times, based on the total weight of the first additive with high molecular content, soluble in water, contained in the aqueous acidic solution, and in a way that it is prepared an aqueous acidic solution containing pivoxil Cefditoren, the additive with high molecular content, soluble in water and the acid dissolved in it, a step to subsequently neutralize the aqueous acidic solution that was prepared, slowly adding to it a solution or aqueous solutions of hydroxide of sodium or potassium, sodium or potassium hydrogen carbonate, or sodium or potassium carbonate, simple or combined, or by slowly adding to it a solution n aqueous ammonium hydroxide solution, keeping the aqueous acidic solution at a temperature of 10 ° C or lower under agitation, and with the amount of the basic sodium or potassium compound, or ammonium hydroxide to be added to the aqueous acidic solution it is adjusted in such a way that the solution of the reaction after neutralization shows a pH value of 6.5-7.1, and a step to continue during the neutralization reaction the stirring of the aqueous solution containing pivoxil Cefditoren at a temperature of 10. ° C or lower, to cause the joint precipitation of pivoxil Cefditoren and the first additive with high molecular content, soluble in water simultaneously from the aqueous solution, a step to collect by means of filtration or centrifugation, the precipitate that was deposited, from the mixture of the neutralization reaction, a step to wash the collected precipitate with an aqueous solution containing a second additive with high Molecular, water-soluble content made from the same substance as the additive with high molecular content, soluble in water that was mentioned first contained in the aqueous acidic solution containing pivoxil Cefditoren and whose aqueous solution contains the second additive with high molecular content, soluble in water dissolved in it, at a concentration of 0.5% 10% (based on weight / weight), while allowing at least a part of the second additive with high molecular content, soluble in water used here in the aqueous solution of washing, during the washing operation to transfer from the aqueous washing solution of the second additive with high molecular content, soluble in water to the surfaces of the particles of the precipitate, and a step to then dry the precipitate that was washed, to obtain a yellow powder composition, consisting essentially of the particles, each of which contains pivoxil Cefditoren and of which, it is formed the central and neutral part of each particle, only from a homogeneous mixture of the substance of pivoxil Cefditoren crystallographically stable, amorphous and soluble in water with the first additive with high molecular content, soluble in water present in a proportion of 0.5% - 5% based on the weight of the substance of pivoxil Cefditoren, and from which the surface layer is formed of each particle, from a homogeneous mixture of the substance pivoxil Cefditoren crystallographically stable, amorphous and soluble in water with the first additive with high molecular content, soluble in water and also with the second additive with high molecular content, soluble in water. 11. A process as set forth in Claim 10, which process comprises a step for dissolving the orthorhombic substance of pivoxil Cefditoren in an aqueous acidic solution, which contains an additive with high molecular content, soluble in water as chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone, as dissolved at a concentration of 0.05 - 1% (based on weight / weight) and whose aqueous acidic solution also contains hydrochloric acid or phosphoric acid at a concentration of 0.5N - 2. ON of the acid, so that the amount of pivoxil Cefditoren dissolved in the aqueous acidic solution is in a range of 10 to 100 times, based on the total weight of the first additive with high molecular content, soluble in water contained in the aqueous acidic solution, and in a manner that an aqueous acidic solution containing pivoxil Cefditoren, the additive with high molecular content, soluble in water and the dissolved in it, a step to subsequently neutralize the aqueous acidic solution that was prepared and containing pivoxil Cefditoren, by slowly adding to it an aqueous solution of sodium hydroxide IN-2N or / and an aqueous solution of sodium hydrogen carbonate or potassium IN - 2N, or by slowly adding to it an aqueous solution of ammonium hydroxide IN - 2N, keeping the aqueous acidic solution at a temperature of 5 ° C or lower under agitation, until the aqueous acidic solution is neutralized to a value pH of 6.5 -7.0, one step to continue stirring the neutralization reaction mixture at a temperature of 5 ° C or lower during the neutralization reaction, to cause the co-precipitation of the pivoxil Cefditoren and the first additive with high content molecular, soluble in water simultaneously from the aqueous solution, a step to collect the deposited precipitate from the neutralization reaction mixture resulting ion, a step for washing the collected precipitate, with an aqueous solution containing, as the second additive with high molecular content, soluble in water made of a substance different from the first additive with high molecular content, soluble in water mentioned above, a additive with high molecular content, soluble in water as chosen from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone and whose aqueous solution contains the second additive with high molecular content dissolved in it, at a concentration of 0.5% - 10% (based on weight / weight), while allowing at least a part of the second additive with high molecular content, soluble in water used in the aqueous washing solution, during the washing operation, to transfer from the aqueous solution of the second additive with high content molecular, soluble in water to the surfaces of the particles of the precipitate, and a step to then dry the prec cleaned, and thus obtain the yellow powder composition, consisting essentially of such particles of which the central or neutral part of each particle is formed only of a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with the first additive with high content molecular, soluble in water and from which the surface layer of each particle is formed, from a homogeneous mixture of the amorphous substance of pivoxil Cefditoren with the first additive with high molecular content, soluble in water and also with the second additive with high molecular content, soluble in water.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10/1920 | 1998-01-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00006722A true MXPA00006722A (en) | 2002-02-26 |
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