AU2008229994B2 - 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
AU2008229994B2
AU2008229994B2 AU2008229994A AU2008229994A AU2008229994B2 AU 2008229994 B2 AU2008229994 B2 AU 2008229994B2 AU 2008229994 A AU2008229994 A AU 2008229994A AU 2008229994 A AU2008229994 A AU 2008229994A AU 2008229994 B2 AU2008229994 B2 AU 2008229994B2
Authority
AU
Australia
Prior art keywords
preparation
preparation according
acid
antibiotic
mixture
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
Application number
AU2008229994A
Other versions
AU2008229994A1 (en
Inventor
Peter Deuringer
Jan-Olav Henck
Hitoshi Ichihashi
Venkata-Rangarao Kanikanti
Yoshifumi Katakawa
Takaaki Nishioka
Roland Rupp
Heino Stass
Chika Taniguchi
Wolfgang Weber
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 Intellectual Property GmbH
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 Intellectual Property GmbH filed Critical Bayer Intellectual Property GmbH
Priority to AU2008229994A priority Critical patent/AU2008229994B2/en
Publication of AU2008229994A1 publication Critical patent/AU2008229994A1/en
Assigned to BAYER SCHERING PHARMA AKTIENGESELLSCHAFT reassignment BAYER SCHERING PHARMA AKTIENGESELLSCHAFT Request for Assignment Assignors: BAYER HEALTHCARE AG
Application granted granted Critical
Publication of AU2008229994B2 publication Critical patent/AU2008229994B2/en
Assigned to BAYER INTELLECTUAL PROPERTY GMBH reassignment BAYER INTELLECTUAL PROPERTY GMBH Request for Assignment Assignors: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT
Anticipated expiration legal-status Critical
Expired legal-status Critical Current

Links

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
    • 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
    • A61K31/495—Heterocyclic 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
    • 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
    • A61K31/495—Heterocyclic 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • 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
    • A61K9/2072—Pills, 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered 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
    • 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
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)

Description

A ustralian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Sustained-Release Preparations Of Quinolone Antibiotics And Method For Preparation Thereof The following statement is a full description of this invention, including the best method of performing it known to me: P/00/0II Coc I Sustained-Release Preparations Of Quinolone Antibiotics And Method For Preparation Thereof The present invention relates to solid, orally administrable matrix preparations of 5 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. 10 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 15 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 20 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. 25 For the production of preparations having controlled release of active compound, in pnnciple various techniques are known. Thus it is often desired to leave the preparation for a relatively long penod 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 30 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 35 a) increase the density of the preparation (EP-A 265 061), -2 b) use special additives such as ammonium myristate which, as is known, slow the further transport of preparations in the gastrointestinal tract (R. Gr6ning; G. Heung, Int. J. Pharm. 56, 111 (1989)), 5 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 10 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 15 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 hydrophilic/hydrophobic. At present, matrix tablets are very 20 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. 25 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 30 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. 35 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 C\NRPortb1\DCC\JXJ\3402742I DOC-18/01/2011 -3 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, 5 35-39, (1990)). 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. 10 The present invention seeks to provide delayed-release preparations of quinolone antibiotics which guarantee an adequate therapeutic action on administration once daily. The invention therefore relates to an orally administrable antibiotic matrix preparation comprising quinolone active compound, characterized in that it releases 80% of the active 15 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 I 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. 20 A first aspect of the invention provides an orally administrable preparation comprising a quinolone antibiotic, wherein the preparation comprises 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. 25 A second aspect of the invention provides an orally administrable preparation comprising a quinolone antibiotic, wherein the preparation comprises a mixture of a) water-swellable polymer and b) a mixture of at least two derivatives of the quinolone antibiotic.
C:NRPonbI\DCC\JXJ\3402742 1 DOC-1g/0112011 - 3a A third aspect of the invention provides a process for the production of a preparation according to the first or second aspect, comprising: mixing one part of the antibiotic with disintergrant, granulating and mixing with glidant and lubricant (IR part); 5 mixing a second part of the antibiotic with acid and hydroxypropylmethylcellulose, granulating and mixing with glidant and lubricant (CR part); tableting the IR part and the CR part to provide a combination tablet; and coating the resulting tablets. 10 A fourth aspect of the invention provides a preparation obtained by the process of the third aspect. 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 15 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. 20 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. 25 According to a preferred embodiment, the preparation according to the invention contains as active compound a combination, preferably a mixture, of two different -4 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. 5 A preferred embodiment relates to preparations which as active compound contains 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 10 solubility is significantly decreased, however, at the pH of the intestinal tract (2 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 I to 4.5). An equivalent effect can also be achieved by using mixtures of other 15 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. 20 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, nice and potato starch, carboxymethyl starches, sodium 25 starch glycolates), cellulose ethers such as alkylcelluloses, hydroxyalkylcelluloses, carboxyalkylcelluloses and their alkali metal salts (methyl-, hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and sodium carboxymethylcelluloses, crosslinked carboxnymethylcelluloses), dextrins, dextran, pectins, polyoses, gum arabic, tragacanth, carrageenan, galactommanans such as guar gum, algin, alginic acid and 30 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 35 polymers form gels in the presence of water, they can also be called "get-forming polymers".
-5 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 5 viscosity" in the context of the present invention means an (apparent) viscosity 6f 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 0 C. 10 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. 15 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 0 C). 20 The content of the hydrophilic polymer, preferably of the HPMC, can vary within wide limits. Preferably, however, I 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 25 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 30 which is more accessible for absorption. For this purpose, preferred organic acids have 2 to 10 C atoms and I 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, 35 organic acid, the preparations according to the invention can alsi'r contain disintegrants, e.g. crosslinked polyvinylpyrrolidone such as *Kollidon CL, glidants, e.g. colloidal silica such as ®Aerosil, hydrogenated vegetable oils, stearic acid, talc or -6 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. 5 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 former, e.g. HPMC, plasticizers, e.g. polyethylene glycol, and light-scattering and light-absorbing 10 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 15 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 20 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 25 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 30 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 35 rapid-release part and a delayed-release part, e.g. in the form of a two-layer/ablet.
-7 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 5 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 10 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. 15 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. 20 The delayed-release preparations according to the invention expediently contain 500 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. 25 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 part 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 30 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 35 (ready-to-compress) CR granules. The (ready-to-compress) CR granules aid 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.
-8 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 5 Example I Amount in mg Substances employed 366.70 Ciprofloxacin hydrochloride 41.70 Ciprofloxacin betaine 46.700 Kollidon CL** 4.30 Aerosil 200*** 4.70 Magnesium stearate 464.10 Subtotal IR part -302.70 Ciprofloxacin hydrochloride 464.30 Ciprofloxacin betaine 125.40 Succinic acid 103.10 Hydroxypropylmethylcellulose 50 cP* 5.20 Aerosil 200*** 9.30 Magnesium stearate 1 010.00 Subtotal CR part 18.00 Hydroxypropylmethylcellulose 15 cP* 6.00 Titanium dioxide 6.00 Polyethylene glycol 400**** 30.00 Coating sub-total 23 x 9.5 mm Oblong tablet * Viscosity, in each case measured as a 2% strength by weight aqueous solution at 20 0 C 10 ** Crosslinked polyvinylpyrrolidone *** Colloidal silica, specific surface area 200 m 2 /g **** The numerical information relates to the average molecular weight -9 Example 2 Amount in mg Substances employed 183.40 Ciprofloxacin hydrochloride 20.90 Ciprofloxacin betaine 22.30 Kollidon CL 2.30 Magnesium stearate 1.10 Aerosil 200 230.00 Subtotal IR part 151.40 Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine 64.00 Succinic acid 52.30 Hydroxypropylmethylcellulose 15 cP 7.60 Magnesium stearate 2.60 Aerosil 200 510.00 Subtotal CR part 12.00 Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 400 4.00 Titanium dioxide 20.00 Coating sub-total 19 x 8 mm Oblong tablet - 10 Example 3 Amount in mg Substances employed 183.40 Ciprofloxacin hydrochloride 20.90 Ciprofloxacin betaine 22.30 Kollidon CL 2.30 Magnesium stearate 1.10 Aerosil 200 230.00 Subtotal IR part 151.40 Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine 65.10 Succinic acid 73.00 Hydroxypropylmethylcellulose 15 cP 10.70 Magnesium stearate 2.70 Aerosil 200 535.00 Subtotal CR part 12.00 Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 3350 4.00 Titanium dioxide 20.00 Coating sub-total 19 x 8 mm Oblong tablet - 11 Example 4 Amount in mg Substances employed 183.40 Ciprofloxacin hydrochloride 20.90 Ciprofloxacin betaine 22.30 Kollidon CL 2.30 Magnesium stearate 1.10 Aerosil 200 230.00 Subtotal IR part 151.40 Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine 64.00 Succinic acid 72.00 Hydroxypropylmethylcellulose 50 cP 7.90 Magnesium stearate 2.60 Aerosil 200 530.00 Subtotal CR part 12.00 Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 400 4.00 Titanium dioxide 20.00 Coating sub-total 19 x 8 mm Oblong tablet - 12 Example 5 Amount in mg Substances employed 262.00 Ciprofloxacin hydrochloride 29.80 Ciprofloxacin betaine 8.90 Succinic acid 42.20 Kollidon CL 1.80 Aerosil 200 5.30 Magnesium stearate 350.00 Subtotal JR part 116.40 Ciprofloxacin hydrochloride 178.50 Ciprofloxacin betaine 134.00 Succinic acid 87.80 HydroxypropylmetlylcelIulose 15 cP 2.70 Aerosil 200 10.60 Magnesium stearate 530.00 Subtotal CR part 12.00 Hydrox ro ImethyIcellulose 15 cP 4.00 Polyethylene glycol 400 4.00 Titanium dioxide 20.00 Coating sub-total 19 x 8 mm Oblong tablet - 13 Example 6 Amount in mg Substances employed 183.40 Ciprofloxacin hydrochloride 20.90 Ciprofloxacin betaine 6.20 Succinic acid 24.70 Kollidon CL 1.20 Aerosil 200 3.60 Magnesium stearate 240.00 Subtotal IR part 151.40 Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine 174.00 Succinic acid 95.70 Hydroxypropylmethylcellulose 15 cP 3.40 Aerosil 200 13.40 Magnesium stearate 670.00 Subtotal CR part 12.00 Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 400 4.00 Titanium dioxide 20.00 Coating sub-total 19 x 8 mm Oblong tablet - 14 Example 7 Amount in mg Substances employed 366.70 Ciprofloxacin hydrochloride 41.70 Ciprofloxacin betaine 46.60 Kollidon CL 4.70 Magnesium stearate 2.30 Aerosil 200 462.00 Subtotal IR part 302.70 Ciprofloxacin hydrochloride 464.30 Ciprofloxacin betaine 125.30 Succinic acid 103.00 Hydroxypropylmethylcellulose 15 cP 20.50 Magnesium stearate 5.20 Aerosil 200 1 021.00 Subtotal CR part 18.00 Hydroxypropylmethylcellulose 15 cP 6.00 Polyethylene glycol 3350 6.00 Titanium dioxide 30.00 Coating sub-total 23 x 9.5 mm Oblong tablet - 15 Comparative Example A Amount in mg Substances employed 357.00 Ciprofloxacin betaine 58.00 Kollidon CL 6.00 Magnesium stearate 4.00 Aerosil 200 425.00 Subtotal IR part 833.00 Ciprofloxacin betaine 108.00 Succinic acid 108.00 Hydroxypropylmethylcellulose 50 cP 16.00 Magnesium stearate 10.00 Aerosil 200 1 075.00 Subtotal CR part 18.00 Hydroxypropylmethylcellulose 15 cP 6.00 Polyethylene glycol 400 6.00 Titanium dioxide 30.00 Coating sub-total 23 x 9.5 mm Oblong tablet - 16 Comparative Example B Amount in mg Substances employed 357.00 Ciprofloxacin betaine 58.00 Kollidon CL 6.00 Magnesium stearate 4.00 Aerosil 200 425.00 Subtotal IR part 833.00 Ciprofloxacin betaine 108.00 Succinic acid 108.00 Hydroxypropylmethylcellulose 3 cP 16.00 Magnesium stearate 10.00 Aerosil 200 1 075.00 Subtotal CR part 18.00 Hydroxypropylmethylcellulose 15 cP 6.00 Polyethylene glycol 400 6.00 Titanium dioxide 30.00 Coating sub-total 23 x 9.5 mm Oblong tablet In 0.IN HCl solution or acetate buffer at pH 4.5, the preparations according to the 5 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. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.
P:\WPDOCS\CRN\A.MM\Spe\l267883t di.isional doc-29/05/06 - 17 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general 5 knowledge in the field of endeavour to which this specification relates.

Claims (33)

1. Orally administrable preparation comprising a quinolone antibiotic, wherein the 5 preparation comprises 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 10 b) a mixture of at least two derivatives of the quinolone antibiotic.
2. Orally administrable preparation comprising a quinolone antibiotic, wherein the preparation comprises a mixture of 15 a) water-swellable polymer and b) a mixture of at least two derivatives of the quinolone antibiotic.
3. Preparation according to Claim 2, wherein the polymer has a viscosity of 5 to 400 20 cP, measured as a 2% strength by weight aqueous solution at 20'C.
4. Preparation according to any one of Claims 1 to 3, wherein the preparation comprises, as a mixture of two derivatives of the quinolone antibiotic, a mixture of a salt with the free base. 25
5. Preparation according to any one of Claims I to 4, wherein the preparation comprises, as a mixture of two derivatives of the quinolone antibiotic, a mixture of two salts. 30
6. Preparation according to any one of Claims I to 5, wherein the quinolone antibiotic is ciprofloxacin. C:\NRPorbI\DCCJXJu3402742 iDOC-18/01/2011 - 19
7. Preparation according to any one of Claims I to 6, wherein the two derivatives are ciprofloxacin hydrochloride and ciprofloxacin betaine.
8. Preparation according claim 7, wherein the ciprofloxacin hydrochloride and 5 ciprofloxacin betaine are in a weight ratio of 1:20 to 20:1.
9. Preparation according to any one of Claims I to 8, wherein the polymer is selected from the group consisting of polysaccharides, cellulose ethers and their alkali metal salts, dextrins, dextran, pectins, polyoses, gum arabic, tragacanth, carrageenan, 10 galactomannans, algin, alginic acid, alginates, polypeptides, proteins, chitin derivatives, fully synthetic polymers and mixtures thereof.
10. Preparation according to any one of Claims I to 9, wherein the polymer is has a viscosity of at most 75 cP, measured as a 2% strength by weight aqueous solution 15 at 2 0 0C.
11. Preparation according to any one of Claims I to 10, wherein the polymer is hydroxypropylmethylcellulose. 20
12. Preparation according to Claim 11, wherein the hydroxypropylmethylcellulose has a viscosity of at most 50 cP, measured as a 2% strength by weight aqueous solution at 20*C.
13. Preparation according to any one of Claims 1 to 12, wherein the preparation 25 additionally comprises at least one adjuvant selected from the group consisting of an organic acid, disintegrant, glidant and lubricant.
14. Preparation according to any one of Claims 1 to 13, wherein the preparation is a combination preparation comprising a rapid-release (IR) part and a delayed release 30 (CR) part.
15. Preparation according to Claim 14, wherein the IR part comprises the quinolone C NRPotbIl\DCC\JXJ\3402742_.DOC-1/01/2011 - 20 antibiotic, disintegrant, glidant and lubricant and/or the CR part comprises the quinolone antibiotic, polymer, an organic acid, glidant and lubricant.
16. Preparation according to Claim 14 or Claim 15, wherein the IR part and/or the CR 5 part comprise a mixture of two derivatives of the quinolone antibiotic.
17. Preparation according to any one of Claims 14 to 16, wherein the IR part comprises an organic acid. 10
18. Preparation according to any one of Claims 14 to 17, wherein the preparation is in the form of a two-layer tablet.
19. Preparation according to any one of the Claims 1 to 18, wherein the preparation comprises an organic acid having 2 to 10 carbon atoms and I to 4 carboxyl groups. 15
20. Preparation according to Claim 19, wherein the organic acid is selected from the group consisting of acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid and citric acid. 20
21. Preparation according to any one of the Claims I to 20, wherein the preparation comprises crosslinked polyvinylpyrrolidone as disintegrant.
22. Preparation according to any one of Claims I to 21, wherein the preparation comprises a glidant selected from the group consisting of colloidal silica, 25 hydrogenated vegetable oils, stearic acid, talc and mixtures thereof.
23. Preparation according to any one of Claims 1 to 22, wherein the preparation comprises magnesium stearate as lubricant. 30
24. Preparation according to any one of Claims 1 to 23, wherein the preparation comprises 2 to 20 parts by weight of active compound mixture per part by weight of polymer. C-\NRPonbl\DCOJXJu402742 LDOC- 18/01/2011 -21
25. Preparation according to any one of Claims 1 to 24, wherein the preparation comprises 2 to 20 parts by weight of active compound mixture per part by weight of hydroxypropylmethylcellulose. 5
26. Preparation according to any one of Claims 1 to 25, wherein the preparation comprises 500 to 1000 mg of the betaine derivative of the quinolone antibiotic, per single unit dose form. 10
27. Preparation according to any one of claims I to 26, wherein the preparation releases 80% of the antibiotic 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 0 C in the course of I to 4 hours. 15
28. Process for the production of a preparation according to any one of Claims I to 27, comprising: mixing one part of the antibiotic with disintergrant, granulating and mixing with glidant and lubricant (IR part); mixing a second part of the antibiotic with acid and hydroxypropylmethylcellulose, 20 granulating and mixing with glidant and lubricant (CR part); tableting the IR part and the CR part to provide a combination tablet; and coating the resulting tablets.
29. Process according to claim 28, wherein one part of the antibiotic is mixed with 25 disintegrant, granulated and mixed with glidant and lubricant (IR part), and another part of the antibiotic is mixed with acid and hydroxypropylmethylcellulose, granulated and mixed with lubricant and glidant (CR part), and wherein the IR part and CR part are tabletted to give combination tablets and the resulting tablets are coated. 30
30. Process according to Claim 28 or Claim 29, wherein the IR part and the CR part are tabletted to give a two-layer tablet C\NRPorbl\DCC\JX\3402742 I.DOC.i/0i/201l - 22
31. Process according to any one of Claims 28 to 30, wherein the acid is admixed to the [R part. 5
32. Preparation obtained by the process of any one of Claims 28 to 31.
33. Orally administrable preparation according to claim I to claim 2 or a process for the production of a preparation according to claim 28, substantially as hereinbefore described with reference to the Examples but excluding the comparative Examples.
AU2008229994A 2000-06-26 2008-10-17 Sustained-Release Preparations Of Quinolone Antibiotics And Method For Preparation Thereof Expired AU2008229994B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2008229994A AU2008229994B2 (en) 2000-06-26 2008-10-17 Sustained-Release Preparations Of Quinolone Antibiotics And Method For Preparation Thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10031043 2000-06-26
AU2006202275A AU2006202275A1 (en) 2000-06-26 2006-05-29 Sustained-release preparations of quinolone antibiotics and method for preparation thereof
AU2008229994A AU2008229994B2 (en) 2000-06-26 2008-10-17 Sustained-Release Preparations Of Quinolone Antibiotics And Method For Preparation Thereof

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
AU2006202275A Division AU2006202275A1 (en) 2000-06-26 2006-05-29 Sustained-release preparations of quinolone antibiotics and method for preparation thereof

Publications (2)

Publication Number Publication Date
AU2008229994A1 AU2008229994A1 (en) 2008-11-13
AU2008229994B2 true AU2008229994B2 (en) 2011-02-10

Family

ID=36616702

Family Applications (2)

Application Number Title Priority Date Filing Date
AU2006202275A Abandoned AU2006202275A1 (en) 2000-06-26 2006-05-29 Sustained-release preparations of quinolone antibiotics and method for preparation thereof
AU2008229994A Expired AU2008229994B2 (en) 2000-06-26 2008-10-17 Sustained-Release Preparations Of Quinolone Antibiotics And Method For Preparation Thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
AU2006202275A Abandoned AU2006202275A1 (en) 2000-06-26 2006-05-29 Sustained-release preparations of quinolone antibiotics and method for preparation thereof

Country Status (1)

Country Link
AU (2) AU2006202275A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015198A1 (en) * 1998-09-14 2000-03-23 Ranbaxy Laboratories Limited Orally administered controlled drug delivery system providing temporal and spatial control

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015198A1 (en) * 1998-09-14 2000-03-23 Ranbaxy Laboratories Limited Orally administered controlled drug delivery system providing temporal and spatial control

Also Published As

Publication number Publication date
AU2006202275A1 (en) 2006-06-22
AU2008229994A1 (en) 2008-11-13

Similar Documents

Publication Publication Date Title
US7780986B2 (en) Method of preparing sustained-release preparations of quinolone antibiotics
CA2285266C (en) Extended release formulations of erythromycin derivatives
AU1203601A (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
AU2003270948B2 (en) Extended Release Formulations of Erythromycin Derivatives
CA2358395C (en) Extended release formulations of erythromycin derivatives
AU2007201031A1 (en) Extended release formulations of erythromycin derivatives
CA2465698A1 (en) Extended release formulations of erythromycin derivatives

Legal Events

Date Code Title Description
PC1 Assignment before grant (sect. 113)

Owner name: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT

Free format text: FORMER APPLICANT(S): BAYER HEALTHCARE AG

FGA Letters patent sealed or granted (standard patent)
PC Assignment registered

Owner name: BAYER INTELLECTUAL PROPERTY GMBH

Free format text: FORMER OWNER WAS: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT

MK14 Patent ceased section 143(a) (annual fees not paid) or expired