Swallow tablet comprising paracetamol

Details Swallow tablet comprising paracetamol Swallow tablet comprising paracetamol

1999-09-02

2001-11-13

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S452000, C424S464000, C424S465000

Reexamination Certificate

active

06316025

ABSTRACT:

The present invention relates to pharmaceutical compositions containing N-acetyl-p-aminophenol, known by the generic names paracetamol, acetaminophen and APAP (hereinafter referred to as paracetamol). In particular, the invention relates to a fast acting paracetamol formulation in the form of a swallow tablet or capsule which has a greatly improved rate of absorption following ingestion by the patient.
Paracetamol is an analgesic and antipyretic agent which is widely used in prescription and non-prescription medicines, often in combination with other biologically active compounds. Following ingestion of paracetamol in a solid form, such as a tablet or capsule, the rate of absorption and hence the onset of pharmacological activity has been found to vary from patient to patient and can sometimes be very slow.
Many attempts have been made to improve the rate of onset of activity, for example by speeding up the disintegration of tablets by making effervescent formulations.
United Kingdom patent publication GB 2 103 087 (Bristol-Myers) describes an analgesic composition containing paracetamol that has an increased rate of absorption. GB 2 103 087 refers to a publication (J. Wojcicki et al, Zbl. Pharm., 118, (1979), Vol 2-3) describing investigations into the pharmacokinetics of paracetamol in which a single oral dose of 1000 mg of paracetamol was administered with 4000 mg of antacid in the form of calcium carbonate. According to the reference in GB 2 103 087, the combination was found to decrease the rate of absorption of paracetamol, when compared with the rate of absorption from paracetamol (1000 mg ) alone.
According to GB 2 103 087, an improved rate of absorption is achieved by co-administering a therapeutic dose comprising from about 150 mg to about 2000 mg of paracetamol with from about 60 mg to about 1200 mg of an antacid. The publication states that any antacid or combinations thereof commonly used to neutralise stomach acids may be used. GB 2 103 087 identifies antacids of special interest to be calcium carbonate, magnesium carbonate, a combination of calcium carbonate and magnesium carbonate, sodium bicarbonate and magnesium hydroxide. GB 2 103 087 exemplifies compositions comprising combinations of paracetamol with calcium carbonate, with a mixture of calcium carbonate and magnesium carbonate and with sodium bicarbonate.
The examples in GB 2 103 087 include two tablet formulations containing paracetamol and sodium bicarbonate; one such formulation comprises 325 mg of paracetamol and 225 mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is 0.69 to 1, and the second formulation comprises 500 mg of paracetamol and 225 mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is 0.4 to 1. When the various formulations exemplified in GB 2 103 087 were administered to healthy volunteers it was found that, for all the formulations tested, the actual increase in rate of absorption, was between 7 and 31% compared to conventional paracetamol tablets.
It has now been found unexpectedly that by selecting sodium bicarbonate and combining it with paracetamol in a tablet or capsule formulation such that it is present in an amount of at least 300 mg per tablet and the weight ratio of bicarbonate to paracetamol is at least 0.74 to 1, a swallow tablet or capsule can be produced which gives a statistically significant improvement in the rate of absorption over that obtained from a commercially available paracetamol tablet containing no sodium bicarbonate. This improvement is not observed when other antacids, eg. calcium carbonate, are combined with paracetamol in a solid dosage form at equivalent levels. More surprisingly, the rate of absorption following oral administration of such a solid dosage form comprising paracetamol and sodium bicarbonate also shows an improvement over that obtained following oral administration of an aqueous solution of a commercially available soluble product containing paracetamol and sodium bicarbonate. In the context of the present invention, an increase in the rate of absorption may be demonstrated as an increased in C
max
, where C
max
is the maximum concentration of paracetamol in the serum, or by measuring the area under the concentration vs time curve in the first 20 minutes after dosing (AUC
0-20
) when compared with other paracetamol compositions.
According to the present invention there is provided a swallow tablet or capsule formulation comprising from 300 mg to 600 mg of paracetamol and from 300 mg to 1200 mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is at least 0.74 to 1.
For the avoidance of doubt, a swallow tablet is a tablet which is intended to be swallowed whole and not one which is intended for dissolution or suspension in water prior to administration, for example a tablet containing a substantial amount of an effervescent couple.
The tablet or capsule formulation of the invention preferably contains either 325 mg or 500 mg of paracetamol. The amount of sodium bicarbonate present in the formulation is favourably at least 370 mg, eg at least 400 mg or 500 mg and suitably is no greater than 1000 mg, preferably no greater than 800 mg and more preferably no greater than 700 mg. The weight ratio of sodium bicarbonate to paracetamol is favourably at least 0.8 to 1, preferably at least 1 to 1, and more preferably at least 1.25 to 1.
Formulations of the invention will generally contain at least one pharmaceutically acceptable excipient conventionally used in the art of tablet and/or capsule formulation. Suitable excipients which may be incorporated include lubricants, for example magnesium stearate and stearic acid; disintegrants, for example cellulose derivatives; starches; binders, for example modified starches and cellulose derivatives; glidants, for example colloidol silicas; compression aids, for example cellulose derivatives; as well as preservatives, suspending agents, wetting agents, flavouring agents, bulking agents, adhesives, colouring agents, sweetening agents appropriate to their form.
In addition to paracetamol, sodium bicarbonate and a pharmaceutically acceptable excipient, formulations of the invention may also contain other pharmaceutically active agents, for example other analgesics, anti-inflammatory analgesic agents, decongestants, antihistamines, antitussive agents, etc.. Formulations may also contain a pharmaceutically acceptable analgesic adjuvant, for example caffeine.
The invention also provides a process for the preparation of the tablet or capsule formulation of the invention, which process comprises the admixture of paracetamol and sodium bicarbonate together with any pharmaceutically acceptable excipients, additional pharmaceutically acceptable active agents or adjuvants. Thus the paracetamol and sodium bicarbonate may be mixed together with one or more binders and granulated using water. The resulting granule may then be dried, sieved and mixed with additional excipients such as a lubricant and disintegrant before being compressed into tablets. Alternatively, the sodium bicarbonate may be omitted from the granulation step and subsequently added with the other excipients. In an alternative process, tablets may be prepared using direct compression grades of paracetamol including commercially available forms which obviates the need for a granulation step. Tablets may also be prepared by other processes known in the art such as by shaping of an extruded mixture. For capsule production, the paracetamol and sodium bicarbonate may be mixed and granulated as for tablet production and filled into suitably sized capsule shells to the desired fill weight.
As stated above, the formulations according to the invention have an increased C
max
, where C
max
is the maximum concentration of paracetamol in the serum, when compared with other paracetamol compositions. Comparative experiments have demonstrated an increased C
max
with respect to that obtained not only from swallow tablets containing only paracetamol or paracetamol

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