EP1663226A1 - Pharmaceutical compositions of moxifloxacin and processes for their preparation - Google Patents
Pharmaceutical compositions of moxifloxacin and processes for their preparationInfo
- Publication number
- EP1663226A1 EP1663226A1 EP04769278A EP04769278A EP1663226A1 EP 1663226 A1 EP1663226 A1 EP 1663226A1 EP 04769278 A EP04769278 A EP 04769278A EP 04769278 A EP04769278 A EP 04769278A EP 1663226 A1 EP1663226 A1 EP 1663226A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- water insoluble
- substantially water
- insoluble excipient
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical group COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 title claims abstract description 20
- 229960003702 moxifloxacin Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 239000000314 lubricant Substances 0.000 claims description 19
- 239000007884 disintegrant Substances 0.000 claims description 16
- 229920000881 Modified starch Polymers 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 10
- 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 claims description 10
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 10
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 235000010980 cellulose Nutrition 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 239000003086 colorant Substances 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- -1 disintegerants Substances 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 150000004665 fatty acids Chemical class 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 235000019426 modified starch Nutrition 0.000 claims description 5
- 235000000346 sugar Nutrition 0.000 claims description 5
- 150000005846 sugar alcohols Chemical class 0.000 claims description 5
- 150000008163 sugars Chemical class 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- SKZIMSDWAIZNDD-WJMOHVQJSA-N 7-[(4as,7as)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid;hydrate;hydrochloride Chemical compound O.Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 SKZIMSDWAIZNDD-WJMOHVQJSA-N 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 claims 8
- 239000003826 tablet Substances 0.000 claims 6
- 238000009472 formulation Methods 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 4
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 4
- 229940062316 avelox Drugs 0.000 description 4
- 239000001506 calcium phosphate Substances 0.000 description 4
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 4
- 229940038472 dicalcium phosphate Drugs 0.000 description 4
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000007916 tablet composition Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010061736 Bronchitis bacterial Diseases 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002706 dry binder Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000001117 sulphuric acid Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- moxifloxacin is l-cyclopropyl-7- ([S, S]-2,8-diazabicyclo [4.3. 0] non-8-yl)-6-fluoro-l, 4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid. It is an antiinfective agent and is known from U.S. Patent No. 4,990,517.
- Moxifloxacin can be used for the treatment of various infections, like acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and community acquired pneumonia.
- U.S. Patent No. 4,990,517 discloses a pharmaceutical preparation that includes the active compound, with microcrystalline cellulose, maize starch, poly- (l-vinyl)-2- pyrrolidone (insoluble), finely divided silica and magnesium stearate.
- U.S. Patent No. 5,286,754 discloses pharmaceutical formulations of ciprofloxacin that include binder based on cellulose, disintegrant based on starch, and a disintegrant based on cellulose derivatives and/or cross-linked polyvinylpyrrolidones.
- Patent No. 6,610,327 discloses pharmaceutical preparations for oral administration that includes moxifloxacin or a salt or solvate/hydrate thereof, at least one dry binder, at least one disintegrant and at least one lubricant, characterized in that the preparation contains 2.5 % to 25% of lactose.
- the inventors have surprisingly found that bioequivalent formulations to commercially available Avelox tablet formulations can be obtained by mtragranular and extragranular distribution of substantially water insoluble pharmaceutical excipients. Summary of the Invention In one general aspect there is provided a pharmaceutical composition that includes moxifloxacin and at least one mtragranular and extragranular substantially water insoluble excipient.
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically accepted excipients.
- the other excipients may include one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants.
- the substantially insoluble excipients may include one or more of microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like.
- the binders may be one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums.
- the fillers may be one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols, and the like.
- the disintegrant may be one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium croscarmellose sodium. In particular, the disintegrant maybe croscarmellose sodium. The disintegrant maybe from 0.5 to 10% by weight of the composition. More particularly, it may be from 2 to 5% by weight of the composition.
- the lubricant or glidant may be one or more of fatty acids and their salts, colloidal silicon dioxide and talc. In particular, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide.
- the lubricant may be advantageously employed in an amount of from 0.05 to 3.0% by weight of the composition. More particularly, it may be from 0.2 to 2% by weight of the composition.
- the composition may be formulated in the form of granules filled in capsule, tablet or other suitable oral dosage form and, in particular, may be a tablet.
- the tablet formulation may further be coated.
- a process for preparing a pharmaceutical composition of moxifloxacin includes a) preparing an mtragranular portion by mixing moxifloxacin and at least one substantially water insoluble excipient; b) preparing an extragranular portion by mixing at least one substantially water insoluble excipient and other pharmaceutically accepted excipients; and c) compressing said mtragranular portion and extragranular portion to a tablet or filling said mtragranular portion and extragranular portion into a capsule.
- Embodiments of the process may include one or more of the following features.
- the mtragranular portion may further include other pharmaceutically accepted excipients.
- the other excipients may include one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants.
- the substantially insoluble excipients may include one or more of microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like.
- the binders may be one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums.
- the fillers may be one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols, and the like.
- the disintegrant may be one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium croscarmellose sodium. In particular, the disintegrant maybe croscarmellose sodium. The disintegrant maybe from 0.5 to 10% by weight of the composition. More particularly, it may be from 2 to 5% by weight of the composition.
- the lubricant or glidant may be one or more of fatty acids and their salts, colloidal silicon dioxide and talc. In particular, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide.
- the lubricant may be advantageously employed in an amount of from 0.05 to 3.0% by weight of the composition. More particularly, it may be from 0.2 to 2% by weight of the composition.
- Avelox tablet formulations can be obtained by mtragranular and extragranular distribution of substantially water insoluble pharmaceutical excipients, with or without the inclusion of lactose.
- the formulation maybe in the form of granules filled in capsule, tablet or other suitable oral dosage form.
- moxifloxacin refers its free base, salts, solvates, enantiomers or mixtures thereof.
- the salts of moxifloxacin include, for example, acid addition salts, such as salts of hydrochloric acid, sulphuric acid, acetic acid, lactic acid, etc., and also salts with bases, such as sodium hydroxide, potassium hydroxide, etc. hi particular, the acid addition salt may be moxifloxacin hydrochloride monohydrate.
- acid addition salt may be moxifloxacin hydrochloride monohydrate.
- substantially insoluble refers to the solubility less than that of lactose.
- substantially insoluble excipients include microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like.
- the mtragranular and extragranular portions may also contain other pharmaceutically acceptable excipients such as binders, disintegerants, fillers, lubricants/glidants, colorants, and the like.
- Suitable binders may include one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose, gums and the like.
- Suitable fillers may include one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols and the like.
- Suitable disintegrants include one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone, sodium croscarmellose sodium and the like. In particular, the disintegrant may be croscarmellose sodium.
- the pharmaceutical composition may contain from 0.5 to 10%, preferably from 2 to 5%, of the disintegrant.
- Suitable lubricants and glidants may include one or more of fatty acids and their salts, colloidal silicon dioxide, talc and the like.
- the lubricant is a salt of a fatty acid, for example, magnesium stearate.
- the glidant is colloidal silicon dioxide.
- the lubricant is advantageously employed in an amount of from 0.05 to 3.0%, for example, 0.2 to 2%.
- the colors maybe selected from any FDA approved colors for internal use.
- the formulation may optionally be coated.
- the dosage form may be in tablet or capsule form, however, the tablet form is particularly suitable.
- the tablet may further be coated.
- any formulation which is customary in pharmaceutical technology, such as, for example, those based on hydroxypropyl methyl cellulose (HPMC) and/or polyethylene glycol of various molecular weights may be used.
- HPMC hydroxypropyl methyl cellulose
- polyethylene glycol of various molecular weights
- the formulations prepared according to the present invention were found to be bioeqivalent to the Avelox tablet dosage form available in the US market by Bayer.
- the following data shows the phannacokinetic data of tablet formulation of present invention and Avelox tablet available in US market carried out in 12 healthy human volunteers.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to pharmaceutical compositions of moxifloxacin. The invention also relates to processes for the preparation of such compositions.
Description
PHARMACEUTICAL COMPOSITIONS OF MOXIFLOXACIN AND PROCESSES FOR THEIR PREPARATION Field of the Invention The field of the invention relates to pharmaceutical compositions of moxifloxacin. The invention also relates to processes for the preparation of such compositions. Background of the Invention Chemically, moxifloxacin is l-cyclopropyl-7- ([S, S]-2,8-diazabicyclo [4.3. 0] non-8-yl)-6-fluoro-l, 4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid. It is an antiinfective agent and is known from U.S. Patent No. 4,990,517. Moxifloxacin can be used for the treatment of various infections, like acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and community acquired pneumonia. U.S. Patent No. 4,990,517 discloses a pharmaceutical preparation that includes the active compound, with microcrystalline cellulose, maize starch, poly- (l-vinyl)-2- pyrrolidone (insoluble), finely divided silica and magnesium stearate. U.S. Patent No. 5,286,754 discloses pharmaceutical formulations of ciprofloxacin that include binder based on cellulose, disintegrant based on starch, and a disintegrant based on cellulose derivatives and/or cross-linked polyvinylpyrrolidones. U.S. Patent No. 6,610,327 discloses pharmaceutical preparations for oral administration that includes moxifloxacin or a salt or solvate/hydrate thereof, at least one dry binder, at least one disintegrant and at least one lubricant, characterized in that the preparation contains 2.5 % to 25% of lactose. As described in more detail below, the inventors have surprisingly found that bioequivalent formulations to commercially available Avelox tablet formulations can be obtained by mtragranular and extragranular distribution of substantially water insoluble pharmaceutical excipients. Summary of the Invention In one general aspect there is provided a pharmaceutical composition that includes moxifloxacin and at least one mtragranular and extragranular substantially water insoluble excipient.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically accepted excipients. The other excipients may include one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants. The substantially insoluble excipients may include one or more of microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like. The binders may be one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums. The fillers may be one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols, and the like. The disintegrant may be one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium croscarmellose sodium. In particular, the disintegrant maybe croscarmellose sodium. The disintegrant maybe from 0.5 to 10% by weight of the composition. More particularly, it may be from 2 to 5% by weight of the composition. The lubricant or glidant may be one or more of fatty acids and their salts, colloidal silicon dioxide and talc. In particular, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide. The lubricant may be advantageously employed in an amount of from 0.05 to 3.0% by weight of the composition. More particularly, it may be from 0.2 to 2% by weight of the composition. The composition may be formulated in the form of granules filled in capsule, tablet or other suitable oral dosage form and, in particular, may be a tablet. The tablet formulation may further be coated. In another general aspect there is provided a process for preparing a pharmaceutical composition of moxifloxacin. The process includes a) preparing an mtragranular portion by mixing moxifloxacin and at least one substantially water insoluble excipient; b) preparing an extragranular portion by mixing at least one substantially water insoluble excipient and other pharmaceutically accepted excipients; and c) compressing said mtragranular portion and extragranular portion to a tablet or filling said mtragranular portion and extragranular portion into a capsule.
Embodiments of the process may include one or more of the following features. For example, the mtragranular portion may further include other pharmaceutically accepted excipients. The other excipients may include one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants. The substantially insoluble excipients may include one or more of microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like. The binders may be one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums. The fillers may be one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols, and the like. The disintegrant may be one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium croscarmellose sodium. In particular, the disintegrant maybe croscarmellose sodium. The disintegrant maybe from 0.5 to 10% by weight of the composition. More particularly, it may be from 2 to 5% by weight of the composition. The lubricant or glidant may be one or more of fatty acids and their salts, colloidal silicon dioxide and talc. In particular, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide. The lubricant may be advantageously employed in an amount of from 0.05 to 3.0% by weight of the composition. More particularly, it may be from 0.2 to 2% by weight of the composition. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention The inventors have found that a bioequivalent formulation to commercially available Avelox tablet formulations can be obtained by mtragranular and extragranular distribution of substantially water insoluble pharmaceutical excipients, with or without the inclusion of lactose. The formulation maybe in the form of granules filled in capsule, tablet or other suitable oral dosage form. As used herein moxifloxacin refers its free base, salts, solvates, enantiomers or mixtures thereof. The salts of moxifloxacin include, for example, acid addition salts, such as salts of hydrochloric acid, sulphuric acid, acetic acid, lactic acid, etc., and also salts
with bases, such as sodium hydroxide, potassium hydroxide, etc. hi particular, the acid addition salt may be moxifloxacin hydrochloride monohydrate. The term "substantially insoluble" as used herein, refers to the solubility less than that of lactose. Specific examples of substantially insoluble excipients include microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like. Besides the above substantially insoluble excipients, the mtragranular and extragranular portions may also contain other pharmaceutically acceptable excipients such as binders, disintegerants, fillers, lubricants/glidants, colorants, and the like. Suitable binders may include one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose, gums and the like. Suitable fillers may include one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols and the like. Suitable disintegrants include one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone, sodium croscarmellose sodium and the like. In particular, the disintegrant may be croscarmellose sodium. The pharmaceutical composition may contain from 0.5 to 10%, preferably from 2 to 5%, of the disintegrant. Suitable lubricants and glidants may include one or more of fatty acids and their salts, colloidal silicon dioxide, talc and the like. In particular, the lubricant is a salt of a fatty acid, for example, magnesium stearate. In particular, the glidant is colloidal silicon dioxide. The lubricant is advantageously employed in an amount of from 0.05 to 3.0%, for example, 0.2 to 2%. The colors maybe selected from any FDA approved colors for internal use. The formulation may optionally be coated.
The dosage form may be in tablet or capsule form, however, the tablet form is particularly suitable. The tablet may further be coated. For coating, any formulation, which is customary in pharmaceutical technology, such as, for example, those based on hydroxypropyl methyl cellulose (HPMC) and/or polyethylene glycol of various molecular weights may be used. The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.
Example 1 :
Process: 1. All the intragranular excipients except for Polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with microcrystalline cellulose for 10- 15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry.
Example 2:
Process: 1. All the intragranular excipients except for polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with microcrystalline cellulose and colloidal silicon dioxide for 10-15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry dispersion.
Example 3:
Process: 1. All the intragranular excipients except for polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with microcrystalline cellulose and colloidal silicon dioxide for 10-15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry dispersion.
Example 4:
Process: 1. All the intragranular excipients except for polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with dicalcium phosphate and colloidal silicon dioxide for 10-15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry dispersion.
Example 5:
The process similar to above examples was followed to prepare the tablet dosage form. The dissolution profiles of above examples using USP II, 0.01 N HCL, 900ml at 50 rpm is as given below.
The formulations prepared according to the present invention were found to be bioeqivalent to the Avelox tablet dosage form available in the US market by Bayer. The following data shows the phannacokinetic data of tablet formulation of present invention and Avelox tablet available in US market carried out in 12 healthy human volunteers.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.
Claims
1. A pharmaceutical composition comprising moxifloxacin and at least one intragranular and extragranular substantially water insoluble excipient.
2. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient has solubility less than that of lactose.
3. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient comprises one or more of microcrystalline cellulose, pregelatinized starch, com starch and dicalcium phosphate dihydrate.
4. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient is microcrystalline cellulose.
5. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient is dicalcium phosphate dihydrate.
6. The pharmaceutical composition of claim 1, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipients comprise one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants.
8. The pharmaceutical composition of claim 7, wherein the binder comprises one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums.
9. The pharmaceutical composition of claim 7, wherein the disintegrant comprises one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and croscarmellose sodium.
10. The pharmaceutical composition of claim 9, wherein the disintegrant is croscarmellose sodium.
11. The pharmaceutical composition of claim 7, wherein the filler comprises one or more of cellulose derivatives, starch derivatives, sugars, and sugar alcohols.
12. The pharmaceutical composition of claim 7, wherein the lubricant or glidant comprises one or more of fatty acids and their salts, colloidal silicon dioxide and talc.
13. The pharmaceutical composition of claim 12, wherein the lubricant is magnesium stearate.
14. The pharmaceutical composition of claim 1, wherein the composition is a tablet, capsule or granules.
15. The pharmaceutical composition of claim 14, wherein the composition is a tablet.
16. The pharmaceutical composition of claim 15, wherein the tablet is coated.
17. A process for preparing a pharmaceutical composition of moxifloxacin, the process comprising: a) preparing an intragranular portion by mixing moxifloxacin and at least one substantially water insoluble excipient; b) preparing an extragranular portion by mixing at least one substantially water insoluble excipient and other pharmaceutically accepted excipients; and c) compressing said intragranular portion and extragranular portion to a tablet or filling said intragranular portion and extragranular portion into a capsule.
18. The process of claim 17, wherein the substantially water insoluble excipient has water solubility less than that of lactose.
19. The process of claim 17, wherein the substantially water insoluble excipient comprises one or more of microcrystalline cellulose, pregelatinized starch, com starch and dicalcium phosphate dihydrate.
20. The process of claim 19, wherein the substantially water insoluble excipient is microcrystalline cellulose.
21. The process of claim 19, wherein the substantially water insoluble excipient is dicalcium phosphate dihydrate.
22. The process of claim 17, wherein the moxifloxacin is moxifloxacin hydrochloride monohydrate.
23. The process of claim 17, wherein the pharmaceutically acceptable excipients comprise one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants.
24. The process of claim 23, wherein the binder comprises one or more of polyvinyl pyπolidone, hydroxypropyl cellulose and gums.
25. The process of claim 23, wherein the disintegrant comprises one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and croscarmellose sodium.
26. The process of claim 25, wherein the disintegrant is croscarmellose sodium.
27. The process of claim 23, wherein the filler comprises one or more of cellulose derivatives, starch derivatives, sugars, and sugar alcohols.
28. The process of claim 23, wherein the lubricant or glidant comprises one or more of fatty acids and their salts, colloidal silicon dioxide and talc.
29. The process of claim 28, wherein the lubricant is magnesium stearate.
30. The process of claim 28, wherein the glidant is colloidal silicon dioxide.
31. The process of claim 17, wherein the composition is a tablet.
32. The process of claim 31 further comprising coating the tablet.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1099DE2003 | 2003-09-03 | ||
| PCT/IB2004/002875 WO2005020998A1 (en) | 2003-09-03 | 2004-09-03 | Pharmaceutical compositions of moxifloxacin and processes for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1663226A1 true EP1663226A1 (en) | 2006-06-07 |
Family
ID=34259939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP04769278A Withdrawn EP1663226A1 (en) | 2003-09-03 | 2004-09-03 | Pharmaceutical compositions of moxifloxacin and processes for their preparation |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1663226A1 (en) |
| WO (1) | WO2005020998A1 (en) |
| ZA (1) | ZA200602497B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015545A1 (en) * | 2004-08-11 | 2006-02-16 | Shenzhen Tys R & D Co., Ltd. | Gelatin capsule of moxifloxacin and method for its prepartion |
| CN100363001C (en) * | 2005-09-21 | 2008-01-23 | 深圳市天一时科技开发有限公司 | A kind of moxifloxacin capsule and preparation method thereof |
| WO2007033522A1 (en) * | 2005-09-21 | 2007-03-29 | Shenzhen Tys R & D Co., Ltd. | Capsule formulation containing moxifloxacin and its preparation method |
| WO2007033515A1 (en) * | 2005-09-21 | 2007-03-29 | Shenzhen Tys R & D Co., Ltd. | Oral formulation containing moxifloxacin and its preparation method |
| WO2009135646A2 (en) * | 2008-05-05 | 2009-11-12 | Farmaprojects, Sa | Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale |
| EA028676B1 (en) | 2008-12-08 | 2017-12-29 | Рациофарм Гмбх | Compacted moxifloxacin |
| CN102247313A (en) * | 2010-06-11 | 2011-11-23 | 北京润德康医药技术有限公司 | Oral-administration slow release solid preparation by taking Moxifloxacin as active ingredient |
| BRPI1106900A2 (en) | 2011-12-26 | 2013-11-05 | Ems Sa | SOLID PHARMACEUTICAL COMPOSITION UNDERSTANDING ANTIBOTH FAMILY OF QUINOLONES AND THE PROCESS OF OBTAINING THEM |
| GR1008169B (en) * | 2013-03-19 | 2014-04-08 | "Φαρματεν Α.Β.Ε.Ε.", | Pharmaceutical composition comprising a fluoroquinolone antibacterial agent and method for the preparation thereof |
| CN104622821B (en) * | 2013-11-13 | 2018-04-10 | 武汉先路医药科技有限公司 | Solve the problems, such as Moxifloxacin tablet formula of the dissolved corrosion by granulation time effects |
| CN106074413A (en) * | 2016-07-20 | 2016-11-09 | 南通雅本化学有限公司 | A kind of pharmaceutical composition containing Moxifloxacin |
| CN109045034B (en) * | 2018-09-29 | 2021-04-13 | 哈尔滨珍宝制药有限公司 | Moxifloxacin hydrochloride pharmaceutical composition and preparation method and application thereof |
| WO2021257461A1 (en) * | 2020-06-15 | 2021-12-23 | Mylan Laboratories Limited | Combination antibacterial composition and method for antibacterial therapy |
| WO2021257466A1 (en) * | 2020-06-15 | 2021-12-23 | The Global Alliance For Tb Drug Development, Inc. | Combination antibacterial composition and method for antibacterial therapy |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3906365A1 (en) * | 1988-07-15 | 1990-01-18 | Bayer Ag | 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES, METHOD AND SUBSTITUTED (OXA) DIAZABICYCLOOCTANES AND NONANESE AS INTERMEDIATE PRODUCTS, AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THEM |
| NZ511554A (en) * | 1998-11-10 | 2003-07-25 | Bayer Ag | Pharmaceutical preparation of moxifloxacin |
-
2004
- 2004-09-03 EP EP04769278A patent/EP1663226A1/en not_active Withdrawn
- 2004-09-03 WO PCT/IB2004/002875 patent/WO2005020998A1/en not_active Ceased
-
2006
- 2006-03-27 ZA ZA200602497A patent/ZA200602497B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005020998A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200602497B (en) | 2007-09-26 |
| WO2005020998A1 (en) | 2005-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4463875B2 (en) | Pharmaceutical composition | |
| KR101840182B1 (en) | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate | |
| EP3409272B1 (en) | Pharmaceutical composition comprising eltrombopag olamine, reducing sugar, and polymeric binder | |
| EP1663226A1 (en) | Pharmaceutical compositions of moxifloxacin and processes for their preparation | |
| CZ291999B6 (en) | Tablet for the treatment of migraine and process for preparing thereof | |
| GB2414668A (en) | Sustained release delivery system for tetracycline compounds | |
| WO2018197088A1 (en) | Pharmaceutical tablet composition comprising eltrombopag olamine | |
| EP1165065B1 (en) | Swallowable tablets with high content of n-acetylcysteine | |
| CZ124497A3 (en) | Oral preparations with prolonged release of cisaprid | |
| WO2005060941A1 (en) | Extended release antibiotic composition | |
| US20110223245A1 (en) | Controlled-release formulations of pramipexole | |
| US20080260785A1 (en) | Paroxetine compositions | |
| US20060030581A1 (en) | Mannitol formulation for integrin receptor antagonist | |
| US20110262540A1 (en) | Solid Pharmaceutical Composition Comprising Exemestane | |
| WO2022153330A1 (en) | Pharmaceutical compositions comprising acalabrutinib | |
| JP6123795B2 (en) | Controlled release pharmaceutical composition | |
| WO2011086577A2 (en) | Pharmaceutical composition of moxifloxacin and its pharmaceutically acceptable salts | |
| JPH092953A (en) | Balofloxacin pharmaceutical preparation | |
| JP2020090484A (en) | Medicine tablet comprising erlotinib as active principle | |
| AU2005235237A1 (en) | Clarithromycin extended release formulation | |
| EP2233131A1 (en) | Pharmaceutical composition containing levodopa, entacapone and carbidopa | |
| WO2023232215A1 (en) | Improved pharmaceutical composition containing tadalafil and process for the preparation thereof | |
| WO2017114597A1 (en) | Pharmaceutical dosage forms comprising ((cis)-n-(4-(dimethylamino)-1,4- diphenylcyclohexyl)-n-methylcinnamamide | |
| WO2009076983A2 (en) | Improved pharmaceutical composition containing non-ergoline dopamine agonist and method for the preparation thereof | |
| HK1198466B (en) | Prasugrel-containing immediate release stable oral pharmaceutical compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20060403 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR |
|
| 17Q | First examination report despatched |
Effective date: 20060911 |
|
| DAX | Request for extension of the european patent (deleted) | ||
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20070123 |