Title of Invention	PHARMACEUTICAL MOXIFLOXACIN PREPARATION
Abstract	The invention relates to a pharmaceutical preparation for oral administration, containing moxifloxacin, its salt and/or hydrate as well as lactose. The invention also relates to a method for producing said preparation and to its use for combating bacterial infections in man or animals.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "PHARMACEUTICAL MOXIFLOXACIN PREPARATION" BAYER HEALTHCARE AG, a body corporate organized under the laws of Germany of 51368 Leverkusen, Germany, The following specification particularly describes the invention and the manner in which it is to be performed: Le A 33 327 R/Kr/NT/09.11.1998 Foreign Countries - 1 - Pharmaceutical preparation of moxifloxacin The present invention relates to a pharmaceutical preparation for oral administration which comprises moxifloxacin, its salt and/or hydrate and lactose, to a process for its 5 preparation, and to the use of this preparation for controlling bacterial infections in humans or animals. Moxifloxacin (INN – International Nonproprietary Name) is an antibiotic having the following formula: 10 I-cycIopropyl-7-([S,S]-2,8-diazabicyclo[4.3;0]non-8-yI)-6-fluoro-l,4-dihydro-S-methoxy-4-oxo-3-quinolonecarboxylic acid 15 It is a highly effective antiinfective agent and was described for the first time in EP-A-0 350 733. EP-A-0 350 733 describes a pharmaceutical preparation which comprises the active compound, microcrystalline cellulose, maize starch, poly-(l-vinyI)-2-pyrroIidone (insoluble), finely divided silica and magnesium stearate. 20 Furthermore, EP-A-0 230 881 describes pharmaceutical preparations of ciprofloxacin, which is likewise an antibiotic from the class of the quinolonecarboxylic acids. The formulation of ciprofloxacin described in this publication corresponds to the formulation described in EP-A-350 733. However, if [his prior-art formulation is applied to moxifloxacin, it is unexpectedly found that 25 tablets manufactured using this formulation have a hardness or breaking load which in some cases, for example in the case of tablet formulations for blister packs, can be improved, and which also offers scope for improvements with respect to its release properties. It was therefore the object of the present application to provide a pharmaceutical formulation which can be used to prepare tablets having sufficient 30 hardness or breaking load, and which at the same time have excellent release properties. Le A 33 327 -2- Surprisingly, we have found that the object described above can be achieved by a pharmaceutical formulation which comprises a certain amount of lactose. The present invention accordingly provides pharmaceutical preparations for oral 5 administration which comprise moxifloxacin, at least one dry binder, at least one disintegrant and optionally a lubricant, characterized in that the preparation comprises from 2.5% to 25% of lactose (air percentages are % by weight based on the weight of the pharmaceutical preparations). 10 Furthermore, the present invention provides a process for preparing tablets which comprise such preparations. The pharmaceutical preparation according to the invention is a preparation for oral administration. Salts of moxifloxacin include, for example, acid addition salts, such as salts of hydrochloric acid, sulphuric acid, acetic acid, lactic acid, etc., and also salts with bases, such as sodium hydroxide, potassium hydroxide, etc., and/or hydrates thereof,, such as, for example, the moxifloxacin hydrochloride, which is particularly preferred according to the invention, or a monohydrate thereof. The formulation according to the invention preferably comprises from 50.to S5%, particularly preferably from 60 to 80%, of moxifloxacin or salts and/or hydrates thereof. 25 Based on the individual dose, the pharmaceutical preparation comprises generally from 50 to 800 mg of moxifloxacin, preferably from 100 to 600 mg, particularly preferably from 200 to 400 mg (in each case based on the betaine form). 30 Surprisingly, the use of lactose in the range of amounts according to the invention confers to the tablet which is prepared from the pharmaceutical preparation according to the invention an excellent hardness and breaking load, and simultaneously excellent release properties. A further advantage of the pharmaceutical preparation of the present invention consists in the-fact that it is accessible in a simple manner by 35 granulation, it being possible to use both micronized and non-micronized active compound, giving, in both cases, bioequivalent formulations. Le A 33 327 -3- The pharmaceutical preparation comprises, as components which are essential for achieving the object according to the invention, from 2.5 to 25% of lactose, preferably from 5 to 20% of lactose and particularly preferably from 7.5 to 16% of lactose. According to the invention, preference is given here to customary lactose 5 monohydrate types. The pharmaceutical preparation according to the invention comprises at least one dry binder, selected, for example, from the group consisting of: microcrystalline cellulose, fibre cellulose, calcium phosphates and mannitol. Particular preference 10 according to the invention is given to using microcrystalline cellulose. This is commercially available, for example under the name Avicel®. The pharmaceutical preparation advantageously comprises from 5 to 30%, preferably from 6.9 to 30%f particularly preferably from 12 to 25%, of the dry binder. 15 The pharmaceutical preparation according to the invention comprises at least one disintegrant, selected, for example, from the group consisting of starch, pregelatinized starch, starch glycolates, crosslinked polyvinylpyrrolidone and sodium carboxymethylcellulose (= croscarmellose sodium). Particular preference according to. the invention is given to using croscarmellose sodium. The pharmaceutical 20 preparation advantageously comprises from 1 to 10%, preferably from 1.5 to 8%, particularly preferably from 2 to 6%, of the disintegrant. The pharmaceutical preparation of the invention comprises at least one lubricant, selected from the group of the fatty acids and their salts. Particular preference 25 "according to the invention is given to using magnesium stearate. The lubricant is advantageously employed in an amount of from 0.3 to 2.0%, particularly preferably from 0.4 to 1.5% and most preferably from 0.5 to 1.1%. A particularly preferred pharmaceutical preparation of the invention comprises: 30 from 60 to 70% of moxifloxacin or salts and/or hydrates thereof, from 7.5 to 16% of lactose, . from 2 to 6% of croscarmellose sodium, from 0.5 to 1.1% of magnesium stearate and 35 up to 30% of microcrystalline cellulose. Le A 33 327 -4- The pharmaceutical preparation of the invention can advantageously be prepared by a process in which moxifloxacin, its salt and/or hydrate, at least one dry binder and lactose are granulated using water, the granules are subsequently mixed with at least one disintegrant and at least one lubricant and, if appropriate, tableted and coated. 5 For the granulation, processes according to the principle of high-speed mixer granulation are used. The granulation can be carried out using water, without addition of an adhesive. 10 The pharmaceutical preparation of the present invention is particularly preferably employed in the form of a tablet formulation which may optionally be coated (as already mentioned above, the percentages by weight in the present patent application are based on the total weight of the pharmaceutical preparation without the weight of the Optional coating). For coating, it is possible to use coating formulations which are 15 customary in pharmaceutical technology, such as, for example, those based on hydroxypropylmethylcellulose (HPMC) and/or polyethylene glycol of various molecular weights. Furthermore, the coating may comprise customary pigments, such as, for example, titanium dioxide or red iron oxide. 20 The pharmaceutical preparation according to the invention is preferably used for the treatment or the prevention of bacterial infections in humans or animals. U A 33 327 -5- Examples Example 1 5 Tablet comprising 50 mg of moxifloxacin as micronized active compound, active compound content approximately 66% (based on the uncoated tablet): moxifloxacin hydrochloride, micronized 54.6 mg microcrystalline cellulose 17.0 mg 10 lactose 8.5 mg croscarmellose sodium 2.0 mg masnesium stearate 0.6 mg HPMC coating 3.2 mg 15 Example 2 Tablet comprising 50 mg of moxifloxacin as micronized active compound, active compound content approximately 80% (based on the uncoated tablet): 20 moxifloxacin hydrochloride, micronized 54.6 mg microcrystalline c&Ilulose 7.1 mg lactose 3.55 mg croscarmellose sodium 2.7 mg magnesium stearate 0.4 mg 25 Example 3 Tablet comprising 50 mg of moxifloxacin as micronized active compound, active compound content approximately 65% (based on the uncoated tablet): 30 35 moxifloxacin hydrochloride, micronized 54.6 mg microcrystalline cellulose 12.8 mg lactose 12.8,mg croscarmellose sodium 3.4 mg magnesium stearate 0.5 mg Le A 33 327 -6-Example 4 Tablet comprising 200 mg of moxifloxacin as micronized active compound: 5 moxifloxacin hydrochloride, micronized 218.4 mg microcrystalline cellulose 68.0 mg lactose 34.0 mg croscarmellose sodium 8.0 mg magnesium stearate 2.4 mg 10 HPMC coating 9.0 mg Example 5 Tablet comprising 400 mg of moxifloxacin as micronized active compound: 15 moxifloxacin hydrochloride, micronized 436.8 mg microcrystalline cellulose 136.0 mg lactose 68.0 mg croscarmellose sodium 16.0 mg magnesium stearate 4.8 mg HPMC coating Example 6 14.0 mg 25 Tablet comprising 400 mg of moxifloxacin as non-micronized active compound: moxifloxacin hydrochloride, 436.8 mg microcrystalline cellulose 136.0 mg lactose 68.0 mg 30 croscarmellose sodium 32.0 mg magnesium stearate 6.0 mg HPMC coating 21.0 mg Figure I shows the comparison of the breaking strength of tablets according to 35 Example 6 and the formulation according to EP-A-0 350 733 (page 53). Le A 33 327 -7- Figure 2 shows the comparison of the release of moxifloxacin HCI from tablets according to Example 6 and the formulation according to EP-A-0 350 733. The tablets were in each case' prepared on a laboratory scale using comparable 5 granulation and tabletting conditions. Figure 1 shows clearly the improved tablet hardness of the formulation according to the invention. Nevertheless, the active compound is released more quickly, as shown in Figure 2. 10 Figure 3 shows the comparison of the blood concentration curves of tablets according to Example 5 and 6. If tablets according to Example 5 (micronized moxifloxacin HCI) are compared to 15 tablets according to Example 6 (non-micronized moxifloxacin HCI) with respect to their bioequivalence, a further unexpected advantage of the formulation according to the invention becomes evident, which consists in the fact that, inspite of the distinctly different dimensions of the active compound particles, both formulations give identical blood concentrations over time. Thus, a micronization step in the 20 formulation of the invention is not necessary, resulting in cost advantages. Le A 33 327 -8-Patent Claims 1. Pharmaceutical preparation for oral administration which comprises 5 moxifloxacin or a salt and/or hydrate thereof, at least one dry binder, at least one disintegrant, and at least one lubricant, characterized in that the preparation comprises from 2.5% to 25% of lactose. 10 2. Pharmaceutical preparation for oral administration according to Claim I, characterized in that the preparation comprises from 50 to. 800 mg of moxifloxacin or its salts and/or hydrates, based on an individual dosage. 15 3. Pharmaceutical preparation for oral administration according to Claim 1 or 2, characterized in that the dry binder is microcrystalline cellulose. 4. Pharmaceutical preparation for oral administration according to any of Claims 1 to 3, characterized in that the disintegrant is croscarmellose sodium. 20 5. Pharmaceutical preparation for oral administration according to any of Claims 1 to 4, characterized in that the lubricant is magnesium stearate. 6. Pharmaceutical preparation for oral administration according to any of Claims 25 1 to 5, characterized in that it comprises: from 60 to 76% of moxifloxacin or a salt and/or hydrate thereof, from 7.5 to 16% of lactose, from 2 to 6% of croscarmellose sodium, from 0.5 to 1.1% of magnesium stearate, 30 and up to 30% of microcrystalline cellulose. 7. Tablet preparation for oral administration which comprises a core of the pharmaceutical preparation according to any of Claims 1 to 6 and a film coating. 35 8 Pharmaceutical preparation for oral administration according to any of Claims 1 to 7, characterized in that it comprises moxifloxacin hydrochloride. 9. Pharmaceutical preparation for oral administration as claimed in any of claims 1 to 8, for controlling bacterial infections in humans or animals. 10. Process for preparing the pharmaceutical preparation for oral administration as claimed in any of claims 1 to 8, characterized in that 50 to 85% of moxifloxacin or salts and/or hydrate thereof, 2.5 to 25% of lactose, 5 to 30% of the dry binder, 1 to 10% of the disintegrant and 0.3 to 2.0% of the lubricant are granulated using water, the granules are subsequently mixed with at least one disintegrant and at least one lubricant and, if appropriate, tabletted and coated. Dated this 6th day of June, 2005. (JAYANTA PAL) OF REMFRY AND SAGAR ATTORNEY FOR THE APPLICANTS 9 Le A 33 327 - 10- Pharmaceutical preparation of moxifloxacin Abstract 5 The present invention relates to a pharmaceutical preparation for oral administration which comprises moxifloxacin, its salt and/or hydrate and lactose, to a process for its preparation, and to the use of this preparation for controlling bacterial infections in humans and animals.

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562-mumnp-2005-description(granted)-(5-3-2008).pdf

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562-mumnp-2005-pct-search report.pdf

562-mumnp-2005-petition under rule 137(31-7-2007).pdf

562-mumnp-2005-power of authority(13-7-2009).pdf

562-mumnp-2005-power of authority(30-7-2007).pdf

562-mumnp-2005-power of authority(6-6-2005).pdf

562-mumnp-2005-wo international publication report(6-6-2005).pdf

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