Tablet dosage form of clavulanic acid and amoxycillin...

Details Tablet dosage form of clavulanic acid and amoxycillin... Tablet dosage form of clavulanic acid and amoxycillin...

1999-06-23

2001-02-27

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S465000, C514S770000, C514S772300, C514S775000, C514S777000, C514S778000, C514S779000, C514S781000, C514S784000, C514S960000, C514S970000

Reexamination Certificate

active

06194001

ABSTRACT:

This invention relates to dosage forms for pharmaceutical preparations of antibiotics, particularly but not exclusively incorporating the active ingredients potassium clavulanate and amoxycillin trihydrate. These are referred to in this specification as “co-amoxiclav” formulations. Co-amoxiclav is the British approved name or pharmacy equivalent name for formulations containing amoxycillin trihydrate and potassium clavulanate. The invention also reiazes to dosage forms of other salts or derivatives of clavulanic acid in combination with beta-lactam antibiotics.
Use of clavulanic acid in combination with beta-lactam antibiotics was disclosed in GB 1508977. WO92/19227 discloses tablet co-amoxiclav formulations comprising compacted granulates including intra-granular and extra-granular disintegrants.
GB-A-2005538 discloses co-amoxiclav formulations containing conventional excipients. U.S. Pat. No. 4,678,812 discloses replacement of mannitol with trehalose in tablets for diagnostic applications.
Potassium clavulanate is the least hygroscopic of the pharmaceutically acceptable clavulanic acid salts. Nevertheless it is extremely hygroscopic and liable to hydrolysis so that co-amoxiclav formulations are prone to degradation on storage even under low humidity conditions. The presence of water of crystallisation of amoxycillin may contribute to instability of these dosage forms, accelerating the decomposition once any degradation has commenced.
According to the present invention a tablet formulation comprises as active ingredients a combination of clavulanic acid or salt thereof and amoxycillin with excipients comprising trehalose together with further excipients including one or more binders, divalents, disintegrants and lubricants.
Trehalose (&agr;-D-glucopyranosyl-&agr;-D-glucopyranoside) is a naturally occurring, non-reducing disaccharide which was initially found to be associated with the prevention of desiccation damage in certain plants and animals which can dry out without damage and can revive when rehydrated.
Trehalose used in accordance with this invention may be provided in various physical forms. The forms of trehalose include trehalose dihydrate (TD) which is crystalline, amorphous trehalose (AT) which is a vitreous form, and the anhydrous forms of trehalose, anhydrous amorphous trehalose (AAT) and anhydrous crystalline trehalose (ACT). Powdered anhydrous trehalose may contain AAT and/or ACT. The term “trehalose” used in this specification refers to any physical form of trehalose including anhydrous, partially hydrated, fully hydrated and mixtures and solutions thereof. The term “anhydrous trehalose” refers to any physical form of trehalose containing less than 2% water. The anhydrous forms of trehalose may contain from 0 to 2% water and still retain superior properties in tabletLing. Amorphous trehalose (AT) contains about 2 to 9% water and trehalose dihydrate (TD) contains about 9 to 10% water. The manufacture and use of anhydrous trehalose from TD is disclosed in our copending application PCT/GB97/00367, the disclosure of which is incorporated into this specification by reference.
The use of trehalose, particularly amorphous anhydrous trehalose in co-amoxiclav solid dosage forms confers several advantages. Increased stability of the active ingredients, particularly potassium clavulanate is obtained. Furthermore the anhydrous trehalose protects the active ingredients from ambient humidity and any residual humidity in the formulation after manufacture. The protection from humidity offered by anhydrous trehalose (AAT or ACT) may be due to absorption of water to produce TD. This sequestration of water molecules from the active ingredients may decrease the exposure of the latter to moisture resulting in prolonged shelf life, particularly when a container is opened periodically for dispensing of some of the contents. AAT and ACT have the particular advantage that moisture is absorbed even at low relative humidities
Preferably the clavulanic acid salt is potassium clavulanate.
Particularly the amoxycillin is present as amoxycillin trihydrate.
Tablets of this invention may contain the active ingredients in any convenient amounts and weight ratios. For example the weight ratio may be equivalent to amoxycillin/clavulanic acid in the range 12:1 to 1:1, preferably around 4:1 to 2:1, The proportion of active ingredients in the tablets may be between the broad range of 20 to 90 preferably about 30%. The total amount of the active ingredients may be selected to give conventional dosages including higher amounts for twice daily administration as disclosed in WO95/28927. Proportions and amounts used in this specification are by weight unless indicated otherwise.
The amount of anhydrous trehalose (AAT or ACT) may be 5 to 50% , preferably 7 to 15% more preferably about 10%.
In preferred embodiments of the invention the active ingredients, especially antibiotics, preferably clavulanate, are combined with the trehalose as a preliminary step before blending with the other components for tabletting. Dry compaction by slugging with anhydrous trehalose (AAT or ACT) may be employed, (preferably in 5 to 20% of a silica binder, conveniently Gasil 200 DF from Crosfield Ltd) using 50 to 500 &mgr;m, preferably 50 to 150 &mgr;m sieved fractions.
The flow of the blend for direct compression can be improved by selection of particle size of anhydrous trehalose (AAT or ACT) from the 125 to 500 &mgr;m, preferably 125 to 250 &mgr;m sieved fractions.
In preferred embodiments of the invention an additional excipient may be employed as a desiccant to enhance the protection for the active ingredients at higher relative humidities. A preferred additional excipient is silica gel. A low percentage may be employed, for example up to 4%, preferably below 2.5% more preferably 2.4%.
Preferred formulations incorporate one or more disintegrants. Intra-granular or extra-granular disintegrants may be employed. Suitable disintegrants include starches such as maize starch and rice starch, cross-linked N-vinyl-2-pyrrolidone (CLPVP), sodium starch glycolate, croscarmellose sodium, microcrystalline or microfine cellulose, low-substituted hydroxypropyl cellulose (ie cellulose partially substituted with 2-hydroxypropyl groups, eg less than 25% substituted, preferably 7 to 16% substituted), cross-linked sodium carboxymethyl cellulose, swellable ion exchange resins, alginates, formaldehyde-casein and combinations thereof. A preferred disintegrant is CLPVP for example as marketed under the trade names POLYPLASDONE XL and POLYPLASDONE XL-10. A preferred croscarmellose sodium is marketed under the trade name Ac-Di-Sol. A preferred sodium starch glycolate is marketed under the trade names EXPLOTAB and EXPLOTAB CLV.
The proportion of disintegrant in a tablet may be 0.1% to 30%, preferably 5 to 10%. A mixture of disintegrants may be employed. An example of a suitable disintegrant combination is a combination of micro-crystalline cellulose with sodium starch glycolate, croscarmellose sodium or CLPVP.
A lubricant may be employed. Any convenient lubricant may be used for example selected from talc, calcium stearate, stearic acid, hydrogenated vegetable oil, Lutrol and polyethylene glycol. However use of magnesium stearate is preferred. Alternatively a water soluble lubricant such as sodium stearyl fumarate (eg as sold under the trade name Pruv) may be preferred. The amount of lubricant may be optional but an amount of 0.1 to 2%, preferably 0.5% of magnesium stearate or 0.2% preferably 0.1 to 1% or 0.8% sodium stearyl fumarate may be employed.
Any of the commonly used direct compression binders may be employed including starch, cellulose derivatives (eg microcrystalline cellulose) dicalcium phosphate, calcium carbonate, magnesium carbonate and sugars such as sucrose, glucose, dextrose and lactose. Other suitable binders which may be used include Ludipress (a commercial tabletting mixture of lactose and PVP), Kollidon (polyvinyl pyrrolidone (PVP)) and hydroxyethyl starch.
Any suitable filler with a low moisture content may be employed. Use

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