Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-03-17
2001-08-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S488000, C424S489000, C424S494000, C514S772400
Reexamination Certificate
active
06270799
ABSTRACT:
The invention relates to drug formulations which comprise 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quino-lonecarboxylic acid (hereinbelow referred to as compound I) and/or pharmaceutically tolerable salts thereof and/or hydrates thereof as active compound which release the active compound they contain at a defined release rate.
The compound I has the INN (International Non-Proprietary Name) moxifloxacin.
The compound I and/or its salts and/or hydrates is a novel 8-methoxyquinolone having antibacterial action against gram-negative and gram-positive bacteria which is frequently significantly better than that of sparfloxacin and ciprofloxacin (Drugs of the Future 1997, 22 (2): 109/113). EP-A-0 305 733 and also EP-A-0 550 903 describe the preparation of the compound I and also of its pharmaceutically tolerable salts. EP-A-0 780 390 describes a specific crystal modification of the monohydrate hydrochloride of the compound I.
Tablet formulations having delayed and/or controlled release of active compound which contain quinolonecarboxylic acid antibiotics are not well known. JP-A-06 024 959 does admittedly describe an oral drug which comprises ciprofloxacin-hydrochloride, but the preparation of administration forms which release the active compound throughout the entire gastrointestinal tract is virtually impossible for cyprofloxacin-hydrochloride. The reason for this is the absorption behaviour of ciprofloxacin in the colon (S. Harder, U. Fuhr, D. Beermann, A. H. Staib, “Ciprofloxacin absorption in different regions of the human gastrointestinal tract. Investigations with the hf-capsule”, Br. J. clin. Pharmac. 30, (1990), 35-39). The data found by Staib and Fuhr for humans confirm the present data from animal experiments showing that cyprofloxacin-hydrochloride is only absorbed to a very small degree from the colon. Because of this, the great majority of the known ciprofloxacin formulations having delayed release of active compound are drug formulations which cannot be administered perorally. Thus, U.S. Pat. No. 5,473,103 describes ciprofloxacin-comprising implants. Furthermore, U.S. Pat. No. 5,520,920 describes an eye drug formulation having delayed release of active compound. Likewise, only a parenteral formulation, which completely releases the active compound in approximately 3 hours (EP-A-0 635 272), is described for the known quinolonecarboxylic acid antibiotic ofloxacin.
EP-A-0 350 733 mentions the possibility of formulating the active compounds described in this document in compositions which release, optionally delayed, the active compound only or preferably in a certain part of the intestinal tract. However, concrete formulations having delayed release of active compound of the compounds disclosed therein are not described. The concrete tablet formulation which is described in EP-A-0 350 733 for the compound of example 1 mentioned therein is a rapid-release formulation which releases the active compound usually within approximately half an hour. The pharmaceutical formulations of the hydrochloride monohydrate of the compound I described in EP-A-0 780 390 are likewise formulations having rapid release of active compound which usually lead to the release of active compound within approximately half an hour.
However, after administration of such a rapid-release tablet formulation, the concentrations of the active compound in the blood are subject to high fluctuations when the drug formulation is administered repeatedly, as is customary in therapies. After peroral administration, for example, of the above mentioned formulations having rapid release of active compound, the maximum concentrations of the active compound in the blood are reached within 4 hours. They then decrease considerably until the next administration. Thus, multiple administration of tablet formulations having rapid release of active compound result in high fluctuations of the concentration of the active compound in the blood. However, in some cases high concentrations of the active compound in the blood which occur after administration of a tablet formulation having rapid release of active compound are undesired, since, for example, side effects may also occur more frequently. Additionally, it is desirable in some cases to maintain the concentrations of the active compound in the blood at a higher level over a prolonged period.
Such a drug formulation having delayed release moreover offers a number of fundamental advantages, such as less frequent administration, which improves patient compliance. Additionally, advantages may be achieved in the case of certain infections where even longer-lasting active compound levels than with a rapid-release tablet are important. Altogether, a drug formulation having delayed release offers greater possibilities to adjust the level of active compound to match the specific infection and the sensitivity of the patient.
It was therefore the object of the present invention to develop a drug formulation of the compound I and pharmaceutically tolerable salts thereof and/or their hydrates which meets the requirements described above. Initially, therefore, the inventors intensively studied the absorption behaviour of the hydrochloride of the compound I (hereinbelow referred to as compound II) and found, very surprisingly, that, for example in contrast to the above mentioned ciprofloxacin, the compound II is also absorbed in the lower sections of the intestine (colon, rectum). Only this surprising absorption behaviour of moxifloxacin, which is different from known quinolonecarboxylic acid antibiotics, opens up any possibility of developing a retard formulation of moxifloxacin.
During further intensive investigations, it was then also surprisingly possible to develop drug formulations which release the active compound over a prolonged period in the entire gastro-intestinal tract, and finally to develop drug formulations having certain release profiles which are suitable for solving the above-described problems of the prior art.
The present invention, accordingly, provides a drug formulations having controlled release of active compound, which comprises 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolone-carboxylic acid or pharmaceutically tolerable salts and/or hydrates thereof and which has an average release between 80% in 2 hours and 80% in 16 hours and an initial release of less than 60% of the active compound in the first hour of release.
To determine the initial and average release according to the definition of the invention, the drug formulations of the present invention are tested in “Apparatus 2” of USP XXIII (The United States Pharmacopeia USP XXIII 1995, pages 1791-1792). The test medium used is 900 ml of 0.1 molar hydrochloric acid or a phosphate buffer with pH 7.4. The rotational speed of the stirrer is 50 revolutions per minute. Samples are passed through an 8 &mgr;m filter, and their active compound content is determined. The amount of active compound which is determined in this manner as being dissolved is converted into per cent by weight of the amount of active compound employed.
The drug formulation having controlled release of active compound of the present invention preferably has an average release of 80% in the period between 4 and 14 hours (80% in 4 hours and 80% in 14 hours).
In even more preferred embodiment of the drug formulation having controlled release of active compound of the present invention, the formulation has an average release of 80% in the period between 7 hours and 13 hours and an initial release of less than 50% of the active compound in the first hour of release.
The drug formulation having controlled release of active compound of the present invention can be formulated in such a manner that a relatively high initial release in the first hour of 30 to 60% of the active compound or a relatively low initial release in the first hour of 0 to 30% of the active compound are obtained.
In a preferred e
Bosche Patrick
Kettelhoit Stefan
Laich Tobias
Siefert Hans-Martin
Stass Heino
Bayer Aktiengesellscahft
Chiu Jerrie L.
Fubara Blessing
Page Thurman K.
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