Trovafloxacin mesylate tablet

Details Trovafloxacin mesylate tablet Trovafloxacin mesylate tablet

1999-01-20

2001-02-13

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S464000, C424S465000, C424S489000, C424S474000, C514S781000

Reexamination Certificate

active

06187341

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a tablet dosage form of trovafloxacin mesylate.
BACKGROUND OF THE INVENTION
Trovafloxacin is a quinolone antibiotic having the structure:
It is currently administered in the form of the mesylate salt. Trovafloxacin and its mesylate salt are disclosed and claimed in U.S. Pat. No. 5,164,402, incorporated herein by reference.
Trovafloxacin mesylate can exist in a number of polymorphic forms as disclosed in PCT/US95/07211 (which designates, inter alia, the United States), which has been published as WO 96/39406, and which is herein incorporated by reference. The polymorphs are also disclosed in the
Analyst,
June 1997, V. 122, pp. 549-552 as Polymorph I, Polymorph II, and the mesylate monohydrate. Polymorph II, in particular, is an anhydrate which is stated to be hydrophobically stable such that formulation problems of the active ingredient during tabletting or encapsulation operations are alleviated. Polymorph I, also an anhydrate, is disadvantageous in that it is reported to be substantially hygroscopic such that it picks up water from the atmosphere to form a monohydrate, a third form of trovafloxacin. Reference to polymorphs in this application utilizes the same nomenclature designations as in the
Analyst
article for the sake of continuity.
When formulating a compound into a tablet (or other) dosage form, one typically seeks, inter alia, a formulation which is storage stable at temperatures and relative humidity levels above those typically encountered. One may additionally seek other desirable properties in a formulation such as fast dissolution so that the tablet quickly dissolves and the medicine is available for absorption, and also properties such as good compressibility and high ductility, and ease of formulatability in general. Accordingly, good storage stability and fast dissolution were, inter alia, features that were sought as desirable characteristics for the instant invention.
Surprisingly, only a single diluent or filler among many tested provided good storage stability and dissolution in conjunction with good manufacturability.
SUMMARY OF THE INVENTION
This invention relates to a tablet having good storage stability and exhibiting many formulation advantages. In the discussion which follows and elsewhere herein, designation of amounts in “% ” means % by weight based on the weight of an uncoated tablet.
This invention provides a tablet comprising the Polymorph II form of trovafloxacin mesylate, a lubricant, and at least 5% of microcrystalline cellulose (MC). The uncoated tablet preferably comprises at least 20% of microcrystalline cellulose, more preferably at least 30%. “Microcrystalline cellulose” is used for its conventional, art-recognized meaning, i.e., partially depolymerized cellulose obtained from &agr;-cellulose. It is noted that Polymorph II is characterized by the following X-ray powder diffraction pattern (reproduced from WO 96/39406):
Polymorph II (B 2) Anhydrous
Peak no.
1
2
3
4
5
6
7
8
20 (°) Cu
 4.5
 7.7
9.1
13.6
15.0
18.2
18.6
22.8
d space
19.5
11.5
9.7
 6.5
 5.9
 4.9
 4.8
 3.9
Necessary ingredients in the tablet core thus include lubricant, trovafloxacin mesylate, and MC. If the MC is present in an amount below about 10%, then it is preferred that a disintegrant also be present in an amount at least equal to the weight % amount of MC that would be needed to bring the actual amount of MC up to 10%. For example, if the tablet contains 8% MC, it is preferred that the tablet additionally contain at least 2% of a disintegrant. If the MC is present in an amount of at least 10%, then no other excipients in addition to the lubricant, such as the disintegrating agent, are needed, although the addition of such may improve dissolution specifications.
In addition to trovafloxacin mesylate, lubricant, and MC, other common excipients can also be employed in the compositions of this invention. As mentioned above, a disintegrant is desirable when the amount of MC is less than 10%, but can also be useful when the amount of MC exceeds 10%. Other excipients in addition to disintegrants, including binders, lubricants, flavorings, colors, and glidants may also be useful. Some excipients can serve multiple functions, for example as both binder and disintegrant.
The tablet is desirably coated with a conventional film coating which imparts toughness, ease of swallowing, and an elegant appearance to the final product. Film coatings made entirely or partially from hydroxypropylcellulose (HPC) are preferred, although film coating polymers having equivalent toughness can be used as well. The film former used to form the film coat can also contain hydroxypropyl-methylcellulose (HPMC). Use of a film coating is preferred because it improves light stability of the dosage form.
The invention is surprising because microcrystalline cellulose is one among many conventional diluents employed in the pharmaceutical arts, a diluent being an inert excipient which has no function other than to add mass to a solid dosage form. Other common diluents include, for example, calcium salts such as calcium phosphate dibasic, calcium sulfate, and calcium carbonate and sugars such as lactose, sucrose, dextrose, maltodextrin, and mannitol. Yet it has been determined that the combination of microcrystalline cellulose with Polymorph II of trovafloxacin mesylate produces a tablet which is highly storage stable in the sense that the uncoated tablet retains its chemical stability such that there is little if any degradation of trovafloxacin mesylate or excipients upon extended storage. Other diluents such as calcium phosphate were found to suppress the dissolution profile after storage, and diluents such as sugars were found to result in degradation of the trovafioxacin mesylate after storage. Polymorph I was found to convert to the mesylate monohydrate form during storage.
Compositions (i.e., uncoated tablets) according to the invention can be dissolution tested in a USP-2 apparatus in 900 mL of aqueous KH
2
PO
4
at pH 2, concentration 50 mM, with paddles rotating at 50-100 RPM. Compositions according to the invention exhibit at least the acceptance criteria cited for Stage 1 (S
1
) testing in the USP 23 (
The United States Pharmacopeia
, edited by the United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, Md. 20852; Published by Rand McNally, Inc., 23rd Edition, Copyright 1994):
Stage
Number Tested
Acceptance Criteria
S
1
6
Each unit not less than Q + 5%
where Q in this case is 80% dissolution of trovafloxacin within 30 minutes after insertion of the uncoated tablet into the phosphate buffer.
Compositions according to the invention made using magnesium stearate as a lubricant can be stability tested in vitro by storing the tablets for 12 weeks in an open container at constant conditions of 40° C and 75% relative humidity. After the 12 week period has elapsed, each composition is tested for degradants by high performance liquid chromatography (HPLC) and/or thin layer chromatography (TLC). Compositions within the scope of the invention exhibit a degradant level less than the following
A. less than 0.5% by weight of each of the following two specific compounds, N-stearoyltrovafloxacin and N-palmitoyltrovafloxacin labeled as formulas (I) and (II):
B. less than 0.2% by weight of any other unspecified degradant, regardless of source; and
C. the total of all degradants (i.e., (A)+(B)) is less than 1.0% by weight.
When conducting the chemical stability test, sample preparation can be effected using the untabletted tablet blend. Alternatively, sample preparation can be effected using one or more tablets. An amount of blend or tablet sufficient to achieve a final concentration of 50 &mgr;g/mL of trovafloxacin is prepared using HPLC mobile phase (see below for examples) as the sample solvent. Serial dilutions with mobile phase may be necessary depending on the amount of sample used. If the tablet blend is employed, sonication is desirable to ensure complete dissolution of the sample. If o

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