CA2414271C - Sustained-release preparations of quinolone antibiotics and method for preparation thereof - Google Patents

Sustained-release preparations of quinolone antibiotics and method for preparation thereof Download PDF

Info

Publication number
CA2414271C
CA2414271C CA002414271A CA2414271A CA2414271C CA 2414271 C CA2414271 C CA 2414271C CA 002414271 A CA002414271 A CA 002414271A CA 2414271 A CA2414271 A CA 2414271A CA 2414271 C CA2414271 C CA 2414271C
Authority
CA
Canada
Prior art keywords
preparation according
active compound
preparation
polymer
glidant
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.)
Expired - Lifetime
Application number
CA002414271A
Other languages
French (fr)
Other versions
CA2414271A1 (en
Inventor
Venkata-Rangarao Kanikanti
Roland Rupp
Wolfgang Weber
Peter Deuringer
Jan-Olav Henck
Heino Stass
Takaaki Nishioka
Yoshifumi Katakawa
Chika Taniguchi
Hitoshi Ichihashi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Healthcare AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of CA2414271A1 publication Critical patent/CA2414271A1/en
Application granted granted Critical
Publication of CA2414271C publication Critical patent/CA2414271C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

The present invention relates to an orally administrable preparation comprising a quinolone antibiotic which releases the active compound with a delay.

Description

Le A 34 260-Foreign countries Pv/Ke/NT
. CA 02414271 2002-12-23 Delayed-release preparations of Quinolone antibiotics and processes for their preparation The present invention relates to solid, orally administrable matrix preparations of quinolone antibiotics having delayed release and to a process for their preparation.
Active compounds from the quinolones class have been employed for a long time as broad-spectrum antibiotics, and numerous administration forms are obtainable on the market, such as tablets, infusion solutions, eye drops etc.
For many medicaments - as also for the quinolones class - formulations are desirable which after administration once daily guarantee a controlled, long-lasting and uniform release of the active compound. In this way, the desired active compound concentration in the plasma (below: "plasma level") and the therapeutic action can be maintained over a relatively long period without large variations.
Formulations which release the active compound in this manner over a relatively long period are designated as delayed-release or controlled-release (CR) preparations.
It is very difficult, however, to develop orally administrable quinolone preparations which, in spite of administration only once daily, guarantee an adequately high antibiotic action; the patient must therefore take at least two doses daily.
It is desirable, however, to reduce the frequency of taking of such quinolone antibiotics to once daily.
For the production of preparations having controlled release of active compound, in principle various techniques are known. Thus it is often desired to leave the preparation for a relatively long period in the stomach in order to make possible the rapid and complete absorption of the active compound to be delayed in the absorption window (i.e. in the section of the gastrointestinal tract in which absorption takes place). The residence time in the stomach, however, depends strongly on the nature and nutritive value of the food in the stomach (S.S. Davis in G. Hardy et al., Drug Delivery to the Gastrointestinal Tract, Ellis Holwood Ltd., Chichester, England 1989). In order to prolong the residence time in the stomach, various attempts have been investigated which either a) increase the density of the preparation (EP-A 265 061), Le A 34 260-Foreign countries , ~ CA 02414271 2002-12-23 b) use special additives such as ammonium myristate which, as is known, slow the further transport of preparations in the gastrointestinal tract (R. Groping;
G. Heung, Int. J. Pharm. 56, 111 (1989)), S c) employ preparations swelling in the stomach (balloon tablets) (Agyilirah et al., Int. J. Pharm. 75, 241 (1991)), d) employ preparations having a large spatial expansion (EP-A 235 718) or e) employ bioadhesive preparations which preferably should adhere to the mucous membranes of the gastrointestinal tract (R. Khosla, S.S. Davis, J. Pharm.
Pharmacol. 39, 47 (1987)).
Another delayed-release technique makes use of a matrix of hydrophilic polymers and, if appropriate, pharmaceutical excipients in which the active compound is embedded. In an aqueous environment, the polymer swells to give a gel, which then either slowly erodes (together with the poorly soluble active compound) or diffuses through the (readily soluble) active compound. The polymer can by hydrophilic, hydrophobic or mixed hydrophiliclhydrophobic. At present, matrix tablets are very popular, since they are comparatively inexpensive and highly tolerable and can be produced in conventional equipment.
Another method consists in the use of buffered or pH-sensitive coatings which allow controlled release in certain sections of the gastrointestinal tract.
A technically complicated method consists in the use of osmotic systems (OROS) which function according to the following principle: water penetrates slowly into the tablet through a water-permeable membrane and leads to swelling of a water-swellable ingredient there; the pressure resulting due to the increase in volume drives the active compound out of the tablets through an opening intended for this purpose.
All these techniques have disadvantages, in particular expensive and complicated production methods, inter- and intraindividual variability or dependence of the desired action on the posture.
In the production of delayed-release preparations, care also has to be taken in each case of where the absorption of the active compound can take place: the smaller the 30725-197(S) absorption window, the more difficult the production of delayed-release preparations turns out to be. Quinolones such as ciprofloxacin, for example, are mainly absorbed in the upper part of the small intestine (duodenum); absorption in the lower part of the small intestine and in the large intestine is significantly lower (S_ Harder et al., Br. J. Clin. Pharmacol. 30, 35-39, (I990)). Therefore the active compound must be released in order to achieve maximum bioavailability before the preparation leaves this absorption window. Moreover, the strong influence of the pH of the surrounding medium on the solubility of quinolone active compounds has to be taken into account; it decreases with increasing pH.
The invention therefore relates to an orally administrable antibiotic matrix preparation comprising quinolone active compound, characterized in that it releases 80% of the active compound both in 0.1 N hydrochloric acid and in acetate buffer at pH 4.5 in the USP XXIV paddle test at 50 revolutions per minute/37°C in the course of 1 to 4 hours. In order to prevent floating up of the tablet during the test, it can be placed in a wire cage, as is described, for example, in the Japanese Pharmacopoeia.
The term "quinolone active compound" in the context of the present invention denotes the class consisting of the substances having a quinolone parent structure which can be used as antiinfectives, in particular the quinolonecarboxylic acids.
Preferred quinolone active compounds include ciprofloxacin, olamufloxacin, clinafloxacin, trovafloxacin, cadrofloxacin, alatrofloxacin mesylate, gatifloxacin, rufloxacin, sparfloxacin, levofloxacin, irloxacin, grepafloxacin, moxifloxacin, prulifloxacin, pazufloxacin, gemifloxacin, sitafloxacin, tosulfloxacin, amifloxacin, ~ lomefloxacin, R-lomefloxacin and nitrosoxacin-A. The most preferred quinolone active compound is ciprofloxacin and its hydrates.
The term "quinolone active compound" in the context of the present invention also includes quinolone derivatives which only release the active compound in the body ('prodrugs'), e.g. esters of a quinolonecarboxylic acid.
According to a preferred embodiment, the preparation according to the invention contains as active compound a combination, preferably a mixture, of two different Le A 34 260-Forei Qn countries quinolone derivatives. An example of such an embodiment according to the invention would be a preparation which as active compound contains a mixture of two different quinolone salts.
A preferred embodiment relates to preparations which as active compound contain the mixture of a free quinolone base and its salt. Mixtures of ciprofloxacin hydrochloride and ciprofloxacin betaine are particularly preferred.
Ciprofloxacin hydrochloride is highly soluble, for example, at low pH values;
the solubility is significantly decreased, however, at the pH of the intestinal tract (>_ 6.5).
However, it has turned out that mixtures of ciprofloxacin hydrochloride and free ciprofloxacin base (betaine) in a weight ratio of 1:20 to 20:1, in particular 1:10 to 10:1, are released from the preparation largely independently of pH (in the pH
range from 1 to 4.5). An equivalent effect can also be achieved by using mixtures of other derivatives, e.g. salts, bases or prodrugs of the active compound. Mixtures of stereoisomers in the context of the invention do not come, however, under the term "combination of two different quinolone derivatives", but rather mixtures of hydrate and anhydrate.
A particular embodiment of the preparations according to the invention relates to matrix tablets. Preferred matrix tablets contain a delayed-release part (CR
part) and a rapid-release part (IR part). Suitable release-delaying polymers for the matrix are water-swellable polymers, e.g. polysaccharides such as starches and starch derivatives (maize, wheat, rice and potato starch, carboxymethyl starches, sodium starch glycolates), cellulose ethers such as alkylcelluloses, hydroxyalkylcelluloses, carboxyalkylcelluloses and their alkali metal salts (methyl-, hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and sodium carboxymethylcelluloses, crosslinked carboxymethylcelluloses), dextrins, dextran, pectins, polyoses, gum arabic, tragacanth, carrageenan, galactommanans such as guar gum, algin, alginic acid and alginates, polypeptides and proteins such as gelatin and casein, furthermore chitin derivatives such as chitosan, fully synthetic polymers such as (meth)acrylic acid copolymers (methyl methacrylate, hydroxymethyl methacrylate copolymers, polyvinyl alcohol, uncrosslinked polyvinylpyrrolidone and vinylpyrrolidone copolymers, and mixtures of the compounds mentioned. Since the water-swellable polymers form gels in the presence of water, they can also be called "gel-forming polymers".

Le A 34 260-Foreign countries Highly viscous polymers are often used for delayed-release preparations. In the present invention, it has been found, however, that low-viscosity polymers positively effect the release behaviour of the preparations. In principle, all hydrophilic polymers of low viscosity can be used for the purpose of delaying release. The term "low-s viscosity" in the context of the present invention means an (apparent) viscosity of 5 to 400 mPa~s (cP), preferably of at most 75 cP, in particular of at most 50 cP, measured using a rotary viscometer as a 2% strength by weight aqueous solution at 20°C.
Hydroxypropylmethylcellulose (HPMC) is particularly preferred. HPMC of USP
XXIV Specification 2910, i.e. having a methoxy content of 28 to 30% by weight and a hydroxypropoxy content of 7 to 12% by weight, e.g. Metolose~ 60 SH
(Shinetsu, Japan) is especially preferred. The desired degree of delay of the preparation can be adjusted by choice of viscosity and amount of HPMC.
Preferred HPMC has a viscosity of 5 to 400 cP, preferably of at most 75 cP, in particular of at most 50 cP (in each case measured using a rotary viscometer as a 2%
strength by weight aqueous solution at 20°C).
The content of the hydrophilic polymer, preferably of the HPMC, can vary within wide limits. Preferably, however, 1 part by weight of hydrophilic polymer per 2 to 20, preferably per 5 to 15, parts by weight of active compound is employed.
In order to guarantee the release of the active compound from the dose form even in the small intestine and to keep the pH of the external layer and the environment of the preparation in the acidic range and thereby to prevent as largely as possible the risk of the precipitation of the active compound in the higher pH of the intestinal fluid, an organic acid can be incorporated into the preparation (if present, preferably in the delayed-release part); in this way, the active compound is prepared in a form which is more accessible for absorption. For this purpose, preferred organic acids have 2 to 10 C atoms and 1 to 4 carboxyl groups, for example acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid and citric acid.
Besides active compound, hydrophilic release-delaying polymer and, if appropriate, organic acid, the preparations according to the invention can also contain disinte rg ants, e.g. crosslinked polyvinylpyrrolidone such as °Kollidon CL, lidants, e.g. colloidal silica such as ~Aerosil, hydrogenated vegetable oils, stearic acid, talc or Le A 34 260-Foreign countries mixtures thereof, lubricants, e.g. magnesium stearate, and also, if appropriate, other excipients. Both glidants and lubricants are preferably incorporated into the granules before the tabletting phase.
The tablets can then be coated in order, if appropriate, to mask a bitter taste of the active compound, to protect the active compound from the effect of light and/or in order to make the tablets aesthetically more pleasing. The coating can be carried out, for example, by spraying on an aqueous suspension of: film formers, e.g. HPMC, plasticizers, e.g. polyethylene glycol, and light-scattering and light-absorbing pigments, e.g. titanium dioxide. To dry off the water, hot air can be directed at the tablet bed during the coating.
Delayed-release preparations can be prepared using the components described.
Besides the delayed-release part (CR part), a rapid-release part (IR part) can also be employed in order to obtain a rapid influx and a higher plasma level. Rapid-release (IR) preparations are understood in the context of the present invention as meaning those which release the active compound according to USP XXIV paddle method as rapidly as desired, preferably within 3 minutes to less than 60 minutes. The rapid release can be controlled within certain limits by variation of the composition, e.g. by variation of the disintegrant content, or by the production parameters. Rapid-release parts of the preparation according to the invention do not unconditionally have to contain two different quinolone derivatives.
It is thus possible to produce combination preparations which in a single-unit dose form contain preparations having different release profiles: thus preparations having a different release profile can be used in order to control the plasma level exactly timewise. "Combination preparations" within the meaning of the invention are understood as meaning not only single-unit dose forms ('fixed combinations') and combination packs, which separately of one another each contain a preparation having a different release profile (kit of parts), but also IR or CR parts which are administered simultaneously or at different times, provided they are employed for the treatment or prophylaxis of the same disease.
The present invention thus also relates to a combination preparation which has a rapid-release part and a delayed-release part, e.g. in the form of a two-layer tablet.

Le A 34 260-Foreign countries -The rapid-release part can contain quinolone active compound (e.g.
ciprofloxacin hydrochloride and ciprofloxacin betaine), disintegrant (e.g. crosslinked polyvinylpyrrolidone such as Kollidon~ CL), glidants (colloidal silica, e.g.
Aerosil~) and lubricants (e.g. magnesium stearate) and, if appropriate, organic acid or other excipients. The delayed-release parts can contain active compound (ciprofloxacin hydrochloride and ciprofloxacin betaine), the release-delaying polymer (e.g.
HPMC
of low viscosity), organic acid (e.g. succinic acid), a glidant (e.g.
colloidal silica) and a lubricant (e.g. magnesium stearate) and, if appropriate, further excipients.
The starting materials for the rapid-release and the delayed-release part can be granulated before tabletting (e.g. using wet or dry granulation techniques). The granules can be mixed with glidants and lubricants, and the compressible (ready-to-compress) granules of the two layers can be tabletted (e.g. with the use of conventional two-layer tabletting machines) to give two-layer tablets. Some of the glidant could also be granulated.
Since the addition of an organic acid increases the release rate of the active compound, in particular of ciprofloxacin hydrochloride and betaine, it may also be recommended to admix organic acid to the IR part.
The delayed-release preparations according to the invention expediently contain S00 to 1 000 mg of active compound, calculated as betaine, per single-unit dose form.
"Single-unit dose forms" are understood as meaning those preparations which are administered as an individual dose, e.g. tablets, coated tablets or capsules.
For the production of delayed-release preparations according to the invention having an IR and CR part, it is possible to use, for example, the following process:
for the production of the IR pan the active compound (preferably as a mixture of two derivatives) is mixed with disintegrant, in particular Kollidon CL, and granulated and mixed with glidant, in particular aerosol, and lubricant, in particular magnesium stearate, in order to obtain compactable (ready-to-compress) IR granules.
For the delayed-release part, the active compound (as a mixture of two derivatives) is mixed with acid, e.g. succinic acid, and gel-forming polymer, in particular HPMC, and granulated. These CR granules are mixed with glidant, in particular Aerosil~, and lubricant, in particular magnesium stearate, in order to obtain compressible (ready-to-compress) CR granules. The (ready-to-compress) CR granules and the IR
granules are tabletted using a conventional two-layer tabletting machine to give a two-layer tablet. The tablet obtained can then be coated.

Le A 34 260-Foreig_,n countries _g_ The following working examples are intended to explain the subject of the invention with the aid of two-layer tablets, but without restricting it thereto.
Examples Example 1 Amount in Substances em to ed m 366.70 Ci rofloxacin h drochloride 41.70 Ci rofloxacin betaine 46.700 Kollidon CL**

4.30 Aerosi1200***

4.70 Ma esium stearate 464.10 SubtotallR an 302.70 Ci rofloxacin h drochloride 464.30 Ci rofloxacin betaine 125.40 Succinic acid 103.10 H drox ro Imeth lcellulose 50 cP*

5.20 Aerosi1200***

9.30 Ma nesium stearate 1 010.00 Subtotal CR an 18.00 H drox ro lmeth (cellulose 15 cP*

6.00 Titanium dioxide 6.00 Pol eth lene 1 co1400****

30.00 Coatin sub-total 23 x 9.5 Oblon tablet mm * Viscosity, in each case measured as a 2% strength by weight aqueous solution at 20°C
** Crosslinked polyvinylpyrrolidone *** Colloidal silica, specific surface area 200 m2/g **** The numerical information relates to the average molecular weight Le A 34 260-Foreign countries _g_ Example 2 Amount in Substances em to ed m 183.40 Ci rofloxacin h drochloride 20.90 Ci rofloxacin betaine 22.30 Kollidon CL

2.30 Ma esium stearate 1.10 Aerosi1200 230.00 SubtotallR art 151.40 Ci rofloxacin h drochloride 232.10 Ci rofloxacin betaine 64.00 Succinic acid 52.30 H drox ro lmeth lcellulose 15 cP
7.60 Ma esium stearate 2.60 Aerosi1200 510.00 Subtotal CR art 12.00 H drox ro lmeth (cellulose 15 cP

4.00 Pol eth lene 1 co1400 4.00 Titanium dioxide 20.00 Coatin sub-total 19 x 8 mm Oblon tablet Le A 34 260-Foreign countries Example 3 Amount in Substances employed m 183.40 Ci rofloxacin h drochloride 20.90 Ci rofloxacin betaine 22.30 Kollidon CL

2.30 Ma esium stearate 1.10 Aerosi1200 230.00 SubtotallR art 151.40 Ci rofloxacin h drochloride 232.10 Ci rofloxacin betaine 65.10 Succinic acid 73.00 H drox ro lmeth lcellulose 15 cP

10.70 Ma nesium stearate 2.70 Aerosi1200 535.00 Subtotal CR art 12.00 H drox ro lmeth lcellulose 15 cP

4.00 Pol eth lene 1 col 3350 4.00 Titanium dioxide 20.00 Coatin sub-total 19 x 8 mm Oblon tablet Le A 34 260-Foreign countries Example 4 Amount in Substances em to ed m 183.40 Ci rofloxacin h drochloride 20.90 Ci rofloxacin betaine 22.30 Kollidon CL

2.30 Ma nesium stearate 1.10 Aerosi1200 230.00 SubtotallR an 151.40 Ci rofloxacin h drochloride 232.10 Ci rofloxacin betaine 64.00 Succinic acid 72.00 H drox ro Imeth lcellulose 50 cP

7.90 Ma nesium stearate 2.60 Aerosi1200 530.00 Subtotal CR an 12.00 H drox ro lmeth lcellulose 15 cP

4.00 Pol eth lene I co1400 4.00 Titanium dioxide 20.00 Coatin sub-total 19 x 8 mm Oblon tablet Le A 34 260-Foreign countries Example 5 Amount in Substances employed m 262.00 Ci rofloxacin h drochloride 29.80 Ci rofloxacin betaine 8.90 Succinic acid 42.20 Kollidon CL

1.80 Aerosi1200 5.30 Ma esium stearate 350.00 SubtotallR art 116.40 Ci rofloxacin h drochloride 178.50 Ci rofloxacin betaine 134.00 Succinic acid 87.80 H drox ro lmeth lcellulose 15 cP

2.70 Aerosi1200 10.60 Ma nesium stearate 530.00 Subtotal CR an 12.00 H drox ro lmeth lcellulose 15 cP

4.00 Pol eth lene of col 400 4.00 Titanium dioxide 20.00 Coatin sub-total 19 x 8 mm Oblon tablet Le A 34 260-Foreign countries Example 6 Amount in Substances em to ed m 183.40 Ci rofloxacin h drochloride 20.90 Ci rofloxacin betaine 6.20 Succinic acid 24.70 Kollidon CL

1.20 Aerosi1200 3.60 Ma nesium stearate 240.00 SubtotallR art 151.40 Ci rofloxacin h drochloride 232.10 Ci rofloxacin betaine 174.00 Succinic acid 95.70 H drox ro lmeth lcellulose 15 cP

3.40 Aerosi1200 13.40 Ma nesium stearate 670.00 Subtotal CR art 12.00 H drox ro lmeth lcellulose 15 cP

4.00 Pol eth lene 1 co1400 4.00 Titanium dioxide 20.00 Coatin sub-total 19 x 8 mm Oblon tablet Le A 34 260-Foreign countries Example 7 Amount in Substances em to ed m _ 366.70 Ci rofloxacin h drochloride 41.70 Ci rofloxacin betaine 46.60 Kollidon CL

4.70 Ma nesium stearate 2.30 Aerosi1200 462.00 SubtotallR an 302.70 Ci rofloxacin h drochloride 464.30 Ci rofloxacin betaine 125.30 Succinic acid 103.00 H drox ro lmeth (cellulose 15 cP

20.50 Ma nesium stearate 5.20 Aerosi1200 1 021.00 Subtotal CR an 18.00 H drox ro lmeth (cellulose 15 cP

6.00 Pol eth lene 1 col 3350 6.00 Titanium dioxide 30.00 Coatin sub-total 23 x 9.5 Oblong tablet mm ~

Le A 34 260-Foreign countries Comparative Example A
Amount in Substances em to ed m 357.00 Ci rofloxacin betaine 58.00 Kollidon CL

6.00 Ma esium stearate 4.00 Aerosi1200 425.00 SubtotallR art 833.00 Ci rofloxacin betaine 108.00 Succinic acid 108.00 H drox ro lmeth (cellulose 50 cP

16.00 Ma esium stearate 10.00 Aerosi1200 1 075.00 Subtotal CR art 18.00 H drox ro (meth lcellulose 15 cP

6.00 Pol eth lene 1 co1400 6.00 Titanium dioxide 30.00 Coatin sub-total 23 x 9.5 Oblon tablet mm Le A 34 260-Foreign countries Comparative Example B
Amount in Substances employed m 357.00 Ci rofloxacin betaine 58.00 Kollidon CL

6.00 Ma esium stearate 4.00 Aerosi1200 425.00 SubtotallR an 833.00 Ci rofloxacin betaine 108.00 Succinic acid 108.00 H drox ro lmeth lcellulose 3 cP

16.00 Ma nesium stearate 10.00 Aerosi1200 1 075.00 Subtotal CR art 18.00 H drox ro Imeth lcellulose 15 cP

6.00 Pol eth lene 1 co1400 6.00 Titanium dioxide 30.00 Coatin sub-total 23 x 9.5 Oblon tablet mm In O.1N HCI solution or acetate buffer at pH 4.5, the preparations according to the invention of Examples 1 to 7 show largely pH-independent release in conventional release apparatuses (USP paddle test), while the preparations of Comparative Examples A and B show strong pH dependence.

Claims (34)

CLAIMS:
1. An orally administrable antibiotic matrix preparation comprising a quinolone active compound and an excipient, wherein the preparation releases 80% of the active compound both in 0.1 N hydrochloric acid and in acetate buffer at pH 4.5 in the USP XXIV paddle test at 50 revolutions per minute/37°C in the course of 1 to 4 hours.
2. The preparation according to claim 1, comprising an excipient selected from the group consisting of a hydrophilic release-delaying polymer, an organic acid, a disintegrant, a glidant and a lubricant.
3. An orally administrable preparation comprising a quinolone antibiotic, containing a mixture of:

a) gel-forming polymer of a viscosity of 5 to 400 cP, measured as a 2% strength by weight aqueous solution at 20°C; and b) a mixture of at least two derivatives of the quinolone antibiotic.
4. An orally administrable preparation comprising a quinolone antibiotic, containing a mixture of:

a) water-swellable polymer; and b) a mixture of at least two derivatives of the quinolone antibiotic.
5. The preparation according to claim 3 or 4, further comprising an excipient selected from the group consisting of an organic acid, a disintegrant, a glidant and a lubricant.
6. The preparation according to any one of claims 1 to 5, wherein the preparation is a combination preparation comprising a rapid-release (IR) part and a delayed release (CR) part.
7. The preparation according to claim 6, wherein the IR part comprises a quinolone antibiotic active compound, a disintegrant, a glidant and a lubricant.
8. The preparation according to claim 6 or 7, wherein the CR part comprises a quinolone antibiotic active compound, a polymer, an organic acid, a glidant and a lubricant.
9. The preparation according to claim 6, wherein the IR part comprises a quinolone antibiotic active compound, a disintegrant, a glidant and a lubricant, and the CR part comprises a quinolone antibiotic active compound, a polymer, an organic acid, a glidant and a lubricant.
10. The preparation according to any one of claims 6 to 9, wherein the IR part and CR part each comprises a mixture of two derivatives of the quinolone antibiotic.
11. The preparation according to any one of claims 6 to 10, wherein the IR part further comprises an organic acid.
12. The preparation according to any one of claims 6 to 11, in the form of a two-layer tablet.
13. The preparation according to any one of claims 3 to 5 and 7, comprising, as a mixture of two derivatives of the quinolone antibiotic, a mixture of a salt with the free base.
14. The preparation according to any one of claims 3 to 5 and 7, comprising, as a mixture of two derivatives of the quinolone antibiotic, a mixture of two salts.
15. The preparation according to any one of claims 3 to 5, 7, 13 and 14, wherein the quinolone antibiotic is ciprofloxacin.
16. The preparation according to claim 13, wherein the two derivatives are ciprofloxacin hydrochloride and ciprofloxacin betaine.
17. The preparation according to claim 16, comprising ciprofloxacin hydrochloride and ciprofloxacin betaine in a weight ratio of 1:20 to 20:1.
18. The preparation according to claim 17, comprising ciprofloxacin hydrochloride and ciprofloxacin betaine in a weight ratio of 1:10 to 10:1.
19. The preparation according to any one of claims 3 to and 13 to 18, wherein the polymer is selected from the group consisting of a polysaccharide, a cellulose ether and an alkali metal salt thereof, a dextrine, dextran, a pectin, a polyose, gum arabic, tragacanth, carrageenan, galactomannans, a polypeptide, a protein, a chitin derivative, a fully synthetic polymer and a mixture thereof.
20. The preparation according to any one of claims 2, 5, 8, 9 and 11, wherein the organic acid is an organic acid having 2 to 10 C atoms and 1 to 4 carboxyl groups.
21. The preparation according to claim 20, wherein the organic acid is selected from the group consisting of acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid and citric acid.
22. The preparation according to any one of claims 2, 5, 7 and 9, wherein the disintegrant is a crosslinked polyvinylpyrrolidone.
23. The preparation according to any one of claims 2, 5, 7 to 9 and 22, wherein the glidant is selected from the group consisting of colloidal silica, a hydrogenated vegetable oil, stearic acid, talc and a mixture thereof.
24. The preparation according to any one of claims 2, 5, 7, 9 and 22, wherein the lubricant is magnesium stearate.
25. The preparation according to any one of claims 3 to 5 and 13 to 19, wherein the polymer has a viscosity of at most 75 cP, measured as a 2% by weight strength aqueous solution at 20°C.
26. The preparation according to claim 25, wherein the polymer has a viscosity of at most 50 cP, measured as a 2%
by weight strength aqueous solution at 20°C.
27. The preparation according to claim 25 or 26, wherein the polymer is hydroxypropylmethylcellulose.
28. The preparation according to any one of claims 2 to 5, 8, 9, 13 to 19 and 25 to 27, comprising 2 to 20 parts by weight of active compound per part by weight of polymer.
29. The preparation according to claim 28, comprising to 15 parts by weight of active compound per part by weight of polymer.
30. The preparation according to any one of claims 1 to 29, comprising 500 to 1,000 mg of active compound, calculated as betaine, per single-unit dose form.
31. A process for the production of a preparation according to any one of claims 6 to 10, comprising:

mixing a first part of the active compound with a disintegrant, granulated and mixed with a glidant and a lubricant (IR part);
mixing a second part of the active compound with an organic acid and a polymer, granulated and mixed with a glidant and a lubricant (CR part); and tabletting the IR part and the CR part to give combination tablets and, optionally, the resulting tablets are coated.
32. A process for the production of the preparation according to any one of claims 6 to 10, comprising:
mixing a first part of the active compound with a disintegrant, granulated and mixed with a glidant and a lubricant (IR part);
mixing a second part of the active compound with an organic acid and hydroxypropylmethylcellulose, granulated and mixed with a glidant and a lubricant (CR part); and tabletting the IR part and CR part to give combination tablets and the resulting tablets are coated.
33. The process according to claim 31 or 32, wherein the IR part and CR part are tabletted to give a two-layer tablet.
34. The process according to claim 31, 32 or 33, wherein an organic acid is additionally admixed with the IR
part.
CA002414271A 2000-06-26 2001-06-13 Sustained-release preparations of quinolone antibiotics and method for preparation thereof Expired - Lifetime CA2414271C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10031043.5 2000-06-26
DE10031043A DE10031043A1 (en) 2000-06-26 2000-06-26 Retarded preparations of quinolone antibiotics and process for their preparation
PCT/EP2001/006695 WO2002000219A1 (en) 2000-06-26 2001-06-13 Sustained-release preparations of quinolone antibiotics and method for preparation thereof

Publications (2)

Publication Number Publication Date
CA2414271A1 CA2414271A1 (en) 2002-12-23
CA2414271C true CA2414271C (en) 2005-09-27

Family

ID=7646816

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002414271A Expired - Lifetime CA2414271C (en) 2000-06-26 2001-06-13 Sustained-release preparations of quinolone antibiotics and method for preparation thereof

Country Status (41)

Country Link
US (3) US7709022B2 (en)
EP (1) EP1296685B1 (en)
JP (1) JP4958373B2 (en)
KR (1) KR100939617B1 (en)
CN (1) CN1273138C (en)
AR (1) AR029688A1 (en)
AT (1) ATE355062T1 (en)
AU (1) AU2001270573A1 (en)
BG (1) BG65914B1 (en)
BR (1) BRPI0111911B8 (en)
CA (1) CA2414271C (en)
CU (1) CU23264B7 (en)
CY (1) CY1107574T1 (en)
CZ (1) CZ301812B6 (en)
DE (2) DE10031043A1 (en)
DK (1) DK1296685T3 (en)
DO (1) DOP2001000199A (en)
EE (1) EE04992B1 (en)
ES (1) ES2282270T3 (en)
GT (1) GT200100126A (en)
HK (1) HK1058479A1 (en)
HN (1) HN2001000132A (en)
HR (1) HRP20030050B1 (en)
HU (1) HU229806B1 (en)
IL (2) IL153333A0 (en)
MA (1) MA25761A1 (en)
MX (1) MXPA02012727A (en)
MY (1) MY140994A (en)
NO (1) NO325415B1 (en)
NZ (1) NZ523352A (en)
PE (1) PE20020207A1 (en)
PL (1) PL203710B1 (en)
PT (1) PT1296685E (en)
RU (1) RU2332204C2 (en)
SI (1) SI1296685T1 (en)
SK (1) SK287384B6 (en)
SV (1) SV2002000505A (en)
TW (1) TWI279232B (en)
UA (1) UA83616C2 (en)
WO (1) WO2002000219A1 (en)
ZA (1) ZA200210350B (en)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10031043A1 (en) * 2000-06-26 2002-02-14 Bayer Ag Retarded preparations of quinolone antibiotics and process for their preparation
WO2004000924A1 (en) * 2002-06-25 2003-12-31 Micro Science Tech Co., Ltd. Polymer resin formulation having anti-microbial or anti-cogulability and preparation method thereof
ATE482706T1 (en) * 2003-02-10 2010-10-15 Bayer Schering Pharma Ag TREATMENT OF BACTERIAL DISEASES OF THE RESPIRATORY ORGANS BY LOCAL APPLICATION OF FLUOROCHINOLONES
WO2004073729A1 (en) * 2003-02-21 2004-09-02 Translational Research Ltd. Compositions for nasal administration of drug
KR100974482B1 (en) 2003-03-27 2010-08-10 가부시키가이샤 바이오악티스 Powder medicine applicator for nasal cavity
US20070092566A1 (en) * 2003-08-04 2007-04-26 Ryouichi Hoshino Oral sustained-release tablet
US7943585B2 (en) * 2003-12-22 2011-05-17 Sandoz, Inc. Extended release antibiotic composition
WO2006007323A2 (en) * 2004-06-28 2006-01-19 Alza Corporation Dosage forms for low solubility and/or low dissolution rate free acid pharmaceutical agents
WO2006060672A2 (en) * 2004-12-03 2006-06-08 Dr. Reddy's Laboratories Ltd. Modified release ciprofloxacin compositions
EP2286800A1 (en) * 2005-04-11 2011-02-23 Abbott Laboratories Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
EP1880722B1 (en) * 2006-07-19 2010-03-17 Tabuk Pharmaceutical Manufacturing Co. Pharmaceutical compositions of ciprofloxacin
CN101668544B (en) 2006-12-26 2013-04-24 株式会社新日本科学 Preparation for transnasal application
BRPI0908596A2 (en) * 2008-03-21 2015-09-15 Mylan Pharmaceuticals Inc prolonged release formulation and pharmaceutical composition
BRPI1007945C8 (en) 2009-02-13 2021-05-25 Romark Laboratories Lc pharmaceutical formulation of controlled release of nitazoxanide, tizoxanide or a combination thereof, and bilayer tablet for oral administration
US9101539B2 (en) * 2009-05-15 2015-08-11 Shin Nippon Biomedical Laboratories, Ltd. Intranasal pharmaceutical compositions with improved pharmacokinetics
US11033624B2 (en) * 2010-06-02 2021-06-15 Novaflux Inc. Medical item for prevention and treatment of ear infection
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
WO2015168642A1 (en) 2014-05-02 2015-11-05 Labib Mohamed E Drug-releasing device usable in mucosal body cavities
US11744967B2 (en) 2017-09-26 2023-09-05 Shin Nippon Biomedical Laboratories, Ltd. Intranasal delivery devices

Family Cites Families (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2951792A (en) * 1959-11-18 1960-09-06 Smith Kline French Lab Sustained release pharmaceutical tablets
FR2100858B1 (en) 1970-07-03 1975-06-06 Daiichi Seiyaku Co
US4122157A (en) 1977-03-04 1978-10-24 Richardson-Merrell Inc. Nitrofurantoin sustained release tablet
US4293539A (en) * 1979-09-12 1981-10-06 Eli Lilly And Company Controlled release formulations and method of treatment
FR2470599A1 (en) * 1979-12-07 1981-06-12 Panoz Donald IMPROVEMENTS IN PROCESSES FOR THE PREPARATION OF GALENIC SHAPES WITH DELAYED ACTION AND PROGRAMMED RELEASE AND GALENIC FORMS OF MEDICAMENTS THUS OBTAINED
DE3142854A1 (en) 1981-10-29 1983-05-11 Bayer Ag, 5090 Leverkusen 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-CHINOLINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS
US4370313A (en) * 1981-10-26 1983-01-25 Eaton Laboratories, Inc. Nitrofurantoin dosage form
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4530928A (en) * 1982-01-13 1985-07-23 Merck & Co., Inc. Quinoline carboxylic acid complexes with guanidinium carbonate
US4440740A (en) * 1982-04-26 1984-04-03 Merck & Co., Inc. α-Keto aldehydes as enhancing agents of gastro-intestinal drug absorption
US4443428A (en) * 1982-06-21 1984-04-17 Euroceltique, S.A. Extended action controlled release compositions
IT1198386B (en) 1982-07-06 1988-12-21 Lepetit Spa A PROTRACTED RELEASE PRODUCT CONTAINING SULOCTIDYL
IL70071A (en) 1982-11-01 1987-12-31 Merrell Dow Pharma Multilayered sustained release pharmaceutical tablets having non-uniform distribution of active ingredient
US4478822A (en) * 1983-05-16 1984-10-23 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
US4639458A (en) * 1985-01-22 1987-01-27 Merck & Co., Inc. Tablet and formulation
NL8500724A (en) * 1985-03-13 1986-10-01 Univ Groningen DEVICES FOR REGULAR RELEASE OF ACTIVE SUBSTANCES AND METHOD OF MANUFACTURE THEREOF
FR2585246A1 (en) * 1985-07-26 1987-01-30 Cortial PROCESS FOR OBTAINING SOLID PHARMACEUTICAL FORMS WITH PROLONGED RELEASE
US5188840A (en) * 1985-09-26 1993-02-23 Chugai Seiyaku Kabushiki Kaisha Slow-release pharmaceutical agent
US4734285A (en) * 1985-10-28 1988-03-29 The Dow Chemical Company Sustained release compositions
IT1188212B (en) * 1985-12-20 1988-01-07 Paolo Colombo SYSTEM FOR THE RELEASE SPEED OF ACTIVE SUBSTANCES
US5286754A (en) * 1986-01-21 1994-02-15 Bayer Aktiengesellschaft Pharmaceutical formulations of ciprofloxacin
DE3601566A1 (en) * 1986-01-21 1987-07-23 Bayer Ag PHARMACEUTICAL PREPARATIONS OF CIPROFLOXACIN
JPS62195323A (en) * 1986-02-24 1987-08-28 Eisai Co Ltd Gastric resident particle
EP0265061B1 (en) 1986-09-18 1992-01-08 London School of Pharmacy Innovations Ltd Pharmaceutical formulation
US4869908A (en) * 1987-01-09 1989-09-26 K.V. Pharmaceutical Co. Fibre formulations
US4786503A (en) * 1987-04-06 1988-11-22 Alza Corporation Dosage form comprising parallel lamine
US5200193A (en) * 1987-04-22 1993-04-06 Mcneilab, Inc. Pharmaceutical sustained release matrix and process
DE3720757A1 (en) * 1987-06-24 1989-01-05 Bayer Ag DHP COAT TABLET
US5472710A (en) * 1988-04-16 1995-12-05 Schwarz Pharma Ag Pharmaceutical preparation to be administered orally with controlled release of active substance and method for its manufacture
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US5007790A (en) * 1989-04-11 1991-04-16 Depomed Systems, Inc. Sustained-release oral drug dosage form
US5085865A (en) * 1989-04-12 1992-02-04 Warner-Lambert Company Sustained release pharmaceutical preparations containing an analgesic and a decongestant
DK469989D0 (en) * 1989-09-22 1989-09-22 Bukh Meditec PHARMACEUTICAL PREPARATION
IT1237904B (en) * 1989-12-14 1993-06-18 Ubaldo Conte CONTROLLED SPEED RELEASE TABS OF ACTIVE SUBSTANCES
JPH0624959A (en) * 1991-10-04 1994-02-01 Bayer Yakuhin Kk Medice release solid pharmaceutical preparation of gastric suspending type sustained
DE4200821A1 (en) * 1992-01-15 1993-07-22 Bayer Ag TASTE-MASKED PHARMACEUTICAL AGENTS
JP2958731B2 (en) * 1992-02-14 1999-10-06 日本特殊陶業株式会社 Aluminum oxide based sintered body and method for producing the same
US5582837A (en) * 1992-03-25 1996-12-10 Depomed, Inc. Alkyl-substituted cellulose-based sustained-release oral drug dosage forms
IT1255522B (en) * 1992-09-24 1995-11-09 Ubaldo Conte COMPRESSED FOR THERAPEUTIC USE SUITABLE FOR SELLING ONE OR MORE ACTIVE SUBSTANCES WITH DIFFERENT SPEEDS
IT1256393B (en) * 1992-11-17 1995-12-04 Inverni Della Beffa Spa MULTI-LAYER MATERIAL FORMS FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS
JP2686215B2 (en) 1993-04-28 1997-12-08 信越化学工業株式会社 Sustained-release tablets
IT1264696B1 (en) 1993-07-09 1996-10-04 Applied Pharma Res PHARMACEUTICAL FORMS INTENDED FOR ORAL ADMINISTRATION ABLE TO RELEASE ACTIVE SUBSTANCES AT A CONTROLLED AND DIFFERENTIATED SPEED
DE4406424A1 (en) * 1994-02-28 1995-08-31 Bayer Ag Expandable dosage forms
US5464633A (en) * 1994-05-24 1995-11-07 Jagotec Ag Pharmaceutical tablets releasing the active substance after a definite period of time
US5900425A (en) * 1995-05-02 1999-05-04 Bayer Aktiengesellschaft Pharmaceutical preparations having controlled release of active compound and processes for their preparation
CN1048628C (en) 1995-07-06 2000-01-26 东北制药总厂 Prepn of cyclopropyloxacini injecta
US5705190A (en) * 1995-12-19 1998-01-06 Abbott Laboratories Controlled release formulation for poorly soluble basic drugs
IT1282650B1 (en) * 1996-02-19 1998-03-31 Jagotec Ag PHARMACEUTICAL TABLET, CHARACTERIZED BY A HIGH INCREASE IN VOLUME IN CONTACT WITH BIOLOGICAL LIQUIDS
US5972389A (en) * 1996-09-19 1999-10-26 Depomed, Inc. Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter
US5891474A (en) * 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
ATE302597T1 (en) * 1997-06-06 2005-09-15 Depomed Inc STOMACH-RESIDENT ORAL DOSAGE FORMS OF WATER-SOLUBLE DRUGS WITH CONTROLLED RELEASE
IN186245B (en) * 1997-09-19 2001-07-14 Ranbaxy Lab Ltd
US6270799B1 (en) 1997-09-25 2001-08-07 Bayer Aktiengesellscahft Medicament formulation with a controlled release of an active agent
PA8466701A1 (en) * 1998-01-21 2000-09-29 Pfizer Prod Inc TROVAFLOXACINO MESYLATE TABLET
HUP0103632A3 (en) 1998-09-14 2005-06-28 Ranbaxy Lab Ltd Orally administered controlled drug delivery system providing temporal and spatial control
AU781718B2 (en) 1999-11-02 2005-06-09 Depomed, Inc. Pharmacological inducement of the fed mode for enhanced drug administration to the stomach
WO2001056544A2 (en) 2000-02-04 2001-08-09 Depomed, Inc. Shell-and-core dosage form approaching zero-order drug release
US6488962B1 (en) 2000-06-20 2002-12-03 Depomed, Inc. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms
DE10031043A1 (en) * 2000-06-26 2002-02-14 Bayer Ag Retarded preparations of quinolone antibiotics and process for their preparation
US6780057B2 (en) * 2001-12-21 2004-08-24 Intel Corporation Coaxial dual pin sockets for high speed I/O applications

Also Published As

Publication number Publication date
IL153333A (en) 2010-05-31
HU229806B1 (en) 2014-07-28
MY140994A (en) 2010-02-12
EE04992B1 (en) 2008-04-15
US20070237824A1 (en) 2007-10-11
AR029688A1 (en) 2003-07-10
HRP20030050B1 (en) 2011-07-31
HN2001000132A (en) 2001-09-11
KR20030023883A (en) 2003-03-20
CN1438889A (en) 2003-08-27
PL203710B1 (en) 2009-11-30
SI1296685T1 (en) 2007-06-30
CY1107574T1 (en) 2013-03-13
CU23264B7 (en) 2008-03-14
PT1296685E (en) 2007-05-31
EE200200707A (en) 2004-08-16
MA25761A1 (en) 2003-04-01
BRPI0111911B1 (en) 2015-08-25
BRPI0111911B8 (en) 2021-05-25
EP1296685B1 (en) 2007-02-28
CZ301812B6 (en) 2010-06-30
AU2001270573A1 (en) 2002-01-08
IL153333A0 (en) 2003-07-06
NO20026160D0 (en) 2002-12-20
DOP2001000199A (en) 2002-05-15
NO325415B1 (en) 2008-04-21
UA83616C2 (en) 2008-08-11
US7709022B2 (en) 2010-05-04
HUP0300953A3 (en) 2009-04-28
DE10031043A1 (en) 2002-02-14
NZ523352A (en) 2004-08-27
ES2282270T3 (en) 2007-10-16
PL360632A1 (en) 2004-09-20
HRP20030050A2 (en) 2004-06-30
ATE355062T1 (en) 2006-03-15
BG107372A (en) 2003-09-30
US8187632B2 (en) 2012-05-29
EP1296685A1 (en) 2003-04-02
HUP0300953A2 (en) 2003-08-28
CN1273138C (en) 2006-09-06
SV2002000505A (en) 2002-12-02
DE50112123D1 (en) 2007-04-12
CA2414271A1 (en) 2002-12-23
CZ20024216A3 (en) 2003-04-16
US20070065509A1 (en) 2007-03-22
JP2004504278A (en) 2004-02-12
SK287384B6 (en) 2010-08-09
HK1058479A1 (en) 2004-05-21
US20040024018A1 (en) 2004-02-05
US7780986B2 (en) 2010-08-24
KR100939617B1 (en) 2010-02-01
GT200100126A (en) 2002-01-31
BR0111911A (en) 2003-05-13
SK18212002A3 (en) 2003-04-01
PE20020207A1 (en) 2002-04-27
DK1296685T3 (en) 2007-05-07
TWI279232B (en) 2007-04-21
MXPA02012727A (en) 2003-05-14
NO20026160L (en) 2002-12-20
ZA200210350B (en) 2004-02-10
BG65914B1 (en) 2010-05-31
WO2002000219A1 (en) 2002-01-03
RU2332204C2 (en) 2008-08-27
JP4958373B2 (en) 2012-06-20

Similar Documents

Publication Publication Date Title
US7780986B2 (en) Method of preparing sustained-release preparations of quinolone antibiotics
AU737324B2 (en) Extended release formulations of erythromycin derivatives
CA2387621A1 (en) Extended release formulations of erythromycin derivatives
AU2008229994B2 (en) Sustained-Release Preparations Of Quinolone Antibiotics And Method For Preparation Thereof
AU773863B2 (en) Extended release formulations of erythromycin derivatives
CA2325541C (en) Extended release formulations of erythromycin derivatives
CA2358395C (en) Extended release formulations of erythromycin derivatives
WO2008050188A2 (en) Sustained release pharmaceutical compositions of alfuzosin and process for preparation thereof
AU2007201031A1 (en) Extended release formulations of erythromycin derivatives
CA2465698A1 (en) Extended release formulations of erythromycin derivatives

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20210614