Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-04
2001-01-23
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S210030
Reexamination Certificate
active
06177421
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions containing antibiotics and &bgr;-lactam inhibitors, and more particularly, to improved tablet formulations of amoxicillin and clavulanate having a low moisture content and excellent dissolution rates and bioavailabilities. The invention also relates to a novel method for making same.
BACKGROUND OF THE INVENTION
&bgr;-lactames are enzymes which open the &bgr;-lactam ring of such antibiotics as penicillins and cephalosporins to yield products which are devoid of antibacterial activity. Clavulanic acid or 3-(&bgr;-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo [3,2,0]heptane-2-carboxylic acid, including its pharmaceutically acceptable salts and esters, has now been well-recognized as a medium potency antibiotic which inhibits the production of &bgr;-lactam enzymes, thereby enhancing the efficacy of &bgr;-lactam antibiotics.
In particular, the combination of clavulanic acid and amoxycillin has been shown to be particularly effective against &bgr;-lactams. The latter antibiotic is usually combined in a relatively large weight excess with the clavulanic acid to yield various pharmaceutical compositions. Dry, unit-dose compressed tablets for oral administration are just one example.
Unfortunately, in the preparation of many of these compositions the art has necessitated the inclusion of a complex formulation of excipients, including binders, glidants, disintegrants and even desiccants, etc. to yield a pharmaceutically acceptable carrier. This is in part due to the fact that clavulanate is a highly hygroscopic material which is highly unstable in aqueous media. Methods of formulation must therefore ensure that the product can retain its potency during storage, and yet can subsequently yield satisfactory dissolution rates. One such process is disclosed in WO 92/19227 and mandates the inclusion of both an intra-cellular and an extra-cellular disintegrant. Another process which is described in U.S. Pat. No. 4,537,887 specifies the inclusion of an edible desiccant within the composition itself. Other processes warrant the inclusion of a desiccant within a container housing the amoxycillin/clavulanate combination. In this regard, U.S. Pat. Nos. 4,301,149 and 4,441,609 are particularly salient.
What is therefore needed in the art is an improved tablet composition containing a &bgr;-lactam antibiotic such as amoxicillin and a &bgr;-lactamase inhibitor such as clavulanic acid which is simpler to manufacture and is highly moisture-resistant, and yet still presents a potent combination against &bgr;-lactames.
SUMMARY OF THE INVENTION
These and other objects of the invention are provided by a dry, unit-dose pharmaceutical composition comprising at least one &bgr;-lactam antibiotic in combination with at least one &bgr;-lactamase inhibitor, together with a pharmaceutically acceptable carrier. The composition contains one or more intra-cellular disintegrants, but does not comprise an extra-granular disintegrant. The composition is compressed to a hardness level which helps to ensure storage stability and moisture resistance, but which does not negatively affect dissolution/disintegration rates.
Further included as part of the invention is a method of forming a dry, unit-dose composition in tablet form containing at least one &bgr;-lactam antibiotic together with at least one pharmaceutically acceptable form of at least one &bgr;-lactamase inhibitor. The composition is prepared using intra-granular disintegrants, but without an extra-granular disintegrant. As part of the method, the composition is compressed to an acceptable hardness. By further incorporating a satisfactory level of intra-granular disintegrants, dissolution rates for the composition are good.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
It has now been discovered that a low moisture tablet formulation of antibiotic and &bgr;-lactam inhibitor may be prepared by compressing a mixture of the two active components.
The novel composition of the invention contains as one active component at least one &bgr;-lactam antibiotic. The antibiotic is selected from the group consisting of penicillins and cephalosporins and their pharmaceutically acceptable compounds, including the salts, esters, aldehydes and ketone products thereof, as well as mixtures of any of the foregoing. Preferred is the penicillin known in the art as amoxycillin in a pharmaceutically acceptable form. Especially desirable is amoxycillin. Even more preferred are the salts and esters of amoxycillin, including amoxicillin trihydrate.
A second active component of the invention is at least one &bgr;-lactamase inhibitor. Of these, clavulanic acid or one of its pharmaceutically acceptable compounds such as the salts or esters thereof are preferred. Potassium clavulanate (C6H8NO5K) is an especially preferred compound as the active component in the final formulation.
Any effective weight composition of the foregoing antibiotic(s) and &bgr;-lactam inhibitor(s) is desirable. An especially synergistic combination, however, will typically comprise an excess of antibiotic. Thus, a weight ratio of antibiotic to inhibitor will typically be within the range of about 10:1 to 1:1, more preferably about 6:1 to 1:1, and even more desirably about 3:1 to 1:1, with respect to the free forms of the respective compounds. In one particularly preferred embodiment, there will be about 2 parts of antibiotic for every 1 part of &bgr;-lactam inhibitor. Another particularly preferred embodiment will have about 4 parts antibiotic for every 1 part of inhibitor. Together, the antibiotic and inhibitor will comprise about 10 to 99.9% by weight of the final formulation, desirably about 20 to 80%, and more preferably will be within the range of about 30% to 45% thereof. On an actual weight basis, the composition will typically contain about 100 to 2000 milligrams of antibiotic with about 50 to 1000 milligrams of inhibitor, with respect to the free forms of the respective compounds. More preferably, there will be about 100 to 500 mg. of antibiotic for every 50 to 250 mg. of inhibitor. An especially preferred formulation of the composition of the invention will contain about 250 milligrams of antibiotic and about 125 grams of inhibitor. Another especially preferred formulation will have about 500 milligrams of antibiotic together with about 125 grams of &bgr;-lactam inhibitor. The foregoing weight amounts will vary, of course, depending upon the particular dosage loading desired by the skilled artisan.
The active components heretofore described are formulated with a pharmaceutically acceptable carrier. The carrier may be formed from pharmaceutical additives known in the art, and can include for example one or more of the following: disintegrants, glidants, adsorbents, lubricants, binders, fillers, and the like. Examples of suitable disintegrants include starches, sodium starch glycolate, croscarmellose sodium, formaldehyde, cross-linked N-vinyl-2-pyrrolidone (CLPVP), as well as various cellulosic compounds and materials known in the art. Of the foregoing, CLPVP and croscarmellose sodium are particularly useful, especially in combination. These are most preferably included in the formulation before compressing into a tablet or other final form, and hence may be referred to as “intra-granular” disintegrants. It is especially preferred that the final formulation not contain any extra-granular disintegrants. As that term is used herein, “extra-granular” refers to the intermediary product stage after the active ingredients have been blended together with any additives, pressed into slugs and milled into granulates, but before they have been pressed into dosage units such as tablets or otherwise shaped into a final dosage form. Disintegrant(s) will comprise at least about 4% of the final formulation (on a total weight basis), and more preferably will make up at least about 6% thereof. In certain embodiments, there will be at least about 8% of disintegrants or more in the composition.
Suitable lubricants include the long-chain fatty acids,
Greene Siobhan
Moir Peter
Fuisz International Ltd.
Levis John F.
Schmidt Richard D.
Spivack Phyllis G.
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