WO1999032124A1

WO1999032124A1 - Pharmaceutical compositios containing (s)-cefuroxime axetil and their use for the treatment of bacterial infections

Info

Publication number: WO1999032124A1
Application number: PCT/EP1998/008208
Authority: WO
Inventors: David Samuel Deutsch
Original assignee: Glaxo Group Limited
Priority date: 1997-12-19
Filing date: 1998-12-17
Publication date: 1999-07-01
Also published as: GB9726781D0; AU1968399A

Abstract

A pharmaceutical composition comprising amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer, together with one or more pharmaceutically acceptable carriers. Pharmaceutical compositions comprising amorphous (S)-cefuroxime axetil, substantially free from the (R)-isomer, are more pleasant tasting than the amorphous 1:1 mixture of cefuroxime axetil isomers and therefore ideally suited to oral therapy of bacterial infections.

Description

PHARMACEUTICAL COMPOSITIOS CONTAINING (S)-CEFUROXIME AXETIL AND THEIR USE FOR THE TREATMENT OF BACTERIAL INFECTIONS

This invention relates to a novel composition in the field of cephalosporin antibiotics. More particularly, the invention is concerned with a novel composition related to an ester derivative of (6R,7R)-3-carbamoyloxymethyl-7- [(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid, which has the approved name 'cefuroxime'. Cefuroxime is the subject of British Patent Specification No. 1453049 and is a valuable antibiotic characterised by broad spectrum activity against gram-positive and gram-negative micro- organisms, this property being enhanced by the very high stability of the compound to beta-lactamases produced by a range of gram-negative microorganisms.

Cefuroxime is poorly absorbed in the gastrointestinal tract and it is known that esterification of the carboxyl group at the 4-position of cefuroxime may improve the effectiveness of the antibiotic upon oral administration. British Patent

Specification No. 1571683 discloses and claims a particular ester of cefuroxime,

1-acetoxyethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2- methoxyiminoacetamido]ceph-3-em-4-carboxylic acid, commonly known as cefuroximel-acetoxyethyl ester or cefuroxime axetil. This compound possesses an asymmetric carbon atom at the 1 -position of the 1 -acetoxyethyl group and can therefore exist in the form of (R)- and (S)- isomers or mixtures thereof. For the avoidance of any doubt, reference hereinafter to (S)-cefuroxime axetil or 'the

(S)-isomer' refers to the (S) configuration at the 1 -position of the 1 -acetoxyethyl group.

Cefuroxime axetil is known in both the crystalline and amorphous forms. A pharmaceutical composition comprising a 1 :1 mixture of the amorphous (R)- and (S)- isomers of cefuroxime axetil has been marketed as Zinnat®. Isolation of the (R)- and (S)-isomers of cefuroxime axetil was described in GB Patent no. 1 ,571 ,683, (corresponding to Examples 9 and 8 respectively), and pharmaceutical compositions of essentially pure (R)-isomer were described and claimed in US Patent No. 5,063,224. US Patent No. 5,063,224 ('224) claims (R)-cefuroxime axetil and its use in treating bacterial infections. '224 reports the unsuitability of the (S)-isomer of cefuroxime axetil for use in the treatment of bacterial infection due to its disadvantageous physiochemical properties. For example, it is reported that the (S)-isomer is hydrolysed in the serum and gut of dogs much more rapidly than the (R)-isomer and it was postulated that the (S)-isomer, therefore, may contribute to a large extent to the low observed clinical bioavailability of marketed cefuroxime axetil of around 50%. Further, '224 reports solubility data indicating that crystalline (S)-isomer is less soluble than the (R)-isomer, which would suggest that the (S)-isomer would be more poorly absorbed in the gastrointestinal tract resulting in a lower bioavailability compared to the (R)- isomer.

A problematic characteristic of the marketed formulation of cefuroxime axetil is its very unpleasant taste. Although taste-masking compositions have been marketed successfully, these are often undesirable for paediatric use where the child is may be unable to swallow a tablet without biting into it.

Pharmaceutical compositions comprising amorphous (S)-cefuroxime axetil, substantially free from the (R)-isomer are new. It has now been surprisingly found that, despite the teaching to the contrary, a pharmaceutical composition comprising amorphous (S)-cefuroxime axetil, substantially free from the (R)- isomer, has a clinically useful bioavailability. In addition, it has been found that pharmaceutical compositions comprising amorphous (S)-cefuroxime axetil, substantially free from the (R)-isomer, are more pleasant tasting than the amorphous 1:1 mixture of cefuroxime axetil isomers.

Thus, according to a first aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer, together with one or more pharmaceutically acceptable carriers.

According to a further aspect, the present invention provides amorphous (S)- cefuroxime axetil substantially free from the (R)-isomer for use in human therapy. According to a yet further aspect, the present invention provides amorphous (S)- cefuroxime axetil substantially free from the (R)-isomer for use in the manufacture of a medicament for combating bacterial infections of the human or animal body.

Pharmaceutical compositions comprising amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer are defined as containing less than 10% by weight of (R)-isomer relative to the (S)-isomer. Preferably, less than 5% of the (R)-isomer relative to the (S)-isomer is present in the composition, most preferably, less than 1%.

Pharmaceutical compositions of (S)-cefuroxime axetil according to the invention may be used for oral administration and may be presented as a suspension, as a dry product for constitution with water or other suitable vehicle before use for administration as a suspension, or for direct administration and then washed down, if required, with water or other suitable liquid. Such preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending and/or binding agents e.g. alkylcelluloses such as methyl cellulose hydroxyalkylcelluloses, hydroxypropylcellulose, and hydroxypropylmethylcellulose, sodium carboxymethylcellulose or mixtures thereof, pregelatinised maize starch or polyvinylpyrrolidone; fillers e.g. sucrose, starch, lactose and microcrystalline cellulose; adsorbents and flow aids such as talc, aluminium oxide and silicon dioxide; emulsifying or thickening agents e.g. lecithin or aluminium stearates; surface active agents e.g. sodium lauryl sulphate or non-ionic polyoxyethylenepolyoxypropylene copolymers; preservatives e.g. methyl or propyl hydroxybenzoates or sorbic acid; colouring agents, e.g. titanium dioxide pigments, lake colours and iron oxide pigments; flavouring agents e.g. "mint" flavours such as peppermint flavouring agents; and bulk sweeteners e.g.sorbitol and sucrose or artificial sweeteners e.g. saccharin sodium and sodium cyclamate.

Where the additives are in solid form, (S)-cefuroxime axetil of the invention may be blended with the additives in the form of a dry mix or the additives may themselves be formulated into an excipient granule for blending with the active particles of the invention, or the particles of the invention may be granulated together with the additives using conventional techniques.

Such granulation techniques include the use of conventional granulators e.g. spray granulators, rotary granulators, centrifugal fluidised bed granulators, high speed mixer granulators and extrusion and comminution techniques. Drying may be carried out by conventional techniques, for example in the granulator or in a drying oven or hot air drier. It is, of course, desirable that the granules should be prepared by a method which is convenient to provide granules of the desired size; this may generally be achieved by conventional adjustment of the conditions of granulation and, if necessary, by screening of the granules thus produced.

The pharmaceutical composition of the invention formulated for oral administration as a suspension may be constituted with a suitable quantity of water, for use in oral administration of (S)-cefuroxime axetil. The particles will typically be presented so as to give a multidose suspension containing the equivalent of 500 mg to 10 g cefuroxime or a single dose suspension containing the equivalent of 100-1000 mg cefuroxime.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising (S)-cefuroxime axetil substantially free of (R)-isomer in a taste-masked or delayed release formulation. Such formulations may be prepared according to US Patent No. 4,865,851 , which describes compositions of a 1:1 mixture of amorphous cefuroxime axetil isomers provided with integral iipid coatings.

Doses employed for human treatment will typically be in the range 100-3000 mg cefuroxime per day, e.g. 250 to 2000 mg cefuroxime per day for adults and 125 to 1000 mg cefuroxime per day for children, although the precise dose will depend on inter alia the frequency of administration.

(S)-cefuroxime axetil in a substantially pure form may be isolated according to the method number GB2127401A, which describes formulation of the 1:1 amorphous mixture of cefuroxime axetil. EXAMPLES

Taste trials

Two taste trials were carried out to compare the taste of amorphous (S)- cefuroxime axetil and amorphous racemic cefuroxime axetil (a mixture of (S)- cefuroxime axetil and (R)-cefuroxime axetil). The first taste trial (N1) compared the taste of amorphous (S)-cefuroxime axetil and amorphous racemic cefuroxime axetil, each suspended in 5 ml water with Hydroxypropylmethyl cellulose 0.5% w/v. The second taste trial (N2) compared the taste of amorphous (S)-cefuroxime axetil and amorphous racemic cefuroxime axetil, each mixed with a sweetening agent (1.7 g sucrose) and suspended in 5 ml water. Each sample contained 300 mg of cefuroxime axetil, which is equivalent to 250 mg of cefuroxime.

In order to verify that there was an appreciable difference between amorphous (S)-cefuroxime axetil and amorphous racemic cefuroxime axetil, both taste trials were conducted according to the method of Triangle taste testing. Triangle testing is a commonly used method in sensory analysis (see English Standard Procedure Code: TAS001). The method of triangle testing requires the taster to distinguish between two different samples. In each taste trial volunteers were asked to taste the samples prepared, that is, the preparations of amorphous (S)- cefuroxime axetil and amorphous racemic cefuroxime axetil. Each sample was rolled over the tongue for a maximum of ten seconds. It was then spat out and the mouth rinsed with a suitable quantity of water. The volunteer was asked to evaluate the taste of both samples by means of a questionnaire provided. The product attributes of sweetness, bitterness, aftertaste, mouthfeel and acceptability were assessed. For each sample tasted the volunteer indicated the level of each attribute evaluated, using the scale provided in Table 1. Total evaluations obtained were averaged and the results of the first and second taste trials are reported in Tables 2 and 3 respectively. Table 1 : Taste test evaluation scale

Scale of taste

Table 2: First taste trial results (N1)

Average of results obtained (expressed as %)

Table 3: Second taste trial results (N2)

Average of results obtained (expressed as %)

The amorphous (S)-cefuroxime axetil scored better in terms of acceptability, sweetness, reduced bitterness and aftertaste compared with the amorphous racemic cefuroxime axetil mixture.

Solubility tests

The measurements of the solubility curve were performed on both amorphous and crystalline (S)-cefuroxime axetil and on both amorphous and crystalline racemic cefuroxime axetil. The solubility curve was obtained by putting each powder in contact with water (thermostated at 25°C), and maintaining the stirring into the suspension during overall the trial. At the established time-points a sample of the suspension was withdrawn, filtered, and injected into an HPLC system, for the determination of drug substance dissolved.

The results obtained are reported in the following table. Over a period of up to an hour there is a reduction of the solubility of (S)-cefuroxime axetil and reformation of the crystalline isomer, with a lower solubility. The general behaviour of the single (S)-isomer is similar to that of the amorphous racemic mixture: in both cases a reduction is observed in solubility due to recrystalization. The data also make clear that the solubility of the amorphous form of (S)-cefuroxime axetil is greater than that of the crystalline form of (S)- cefuroxime axetil.

Table 4: Solubility test results

- = not detected

¹ Solubility assessment made on isolated isomer

² Solubility assessment made on 1:1 mixture of the (R)- and (S)- isomers of cefuroxime axetil and calculated for individual isomers

Claims

CLAIMS:

1. A pharmaceutical composition comprising amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer, together with one or more pharmaceutically acceptable carriers.

2. A pharmaceutical composition according to claim 1 wherein the weight of the (R)-isomer relative to the (S)-isomer is less than 10%.

3. A pharmaceutical composition according to claim 2 wherein the weight of the (R)-isomer relative to the (S)-isomer is less than 5%.

4. A pharmaceutical composition according to claim 3 wherein the weight of the (R)-isomer relative to the (S)-isomer is less than 1 %.

5. A pharmaceutical composition according to claims 1-4 adapted for oral administration.

6. A pharmaceutical composition according to claim 5 in the form of a suspension.

7. A pharmaceutical composition according to claim 5 in the form of a substantially dry product.

8. A pharmaceutical composition according to claim 7 wherein the substantially dry product is reconstituted with a solution to form a suspension before administration.

9. A pharmaceutical composition according to claim 7 in the form of granules.

10. A pharmaceutical composition according to claim 8 in the form of granules being provided with integral lipid coatings.

11. A pharmaceutical composition as claimed in any preceding claim wherein a multidose contains 500 mg to 10 g cefuroxime.

12. A pharmaceutical composition as claimed in claims 1-10 wherein an individual dose contains 100 to 1000 mg cefuroxime.

13. Amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer for use in therapy.

14. Amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer for use in the manufacture of a medicament for combating bacterial infections of the human or animal body.

15. A method for the treatment of an animal, including man, suffering from a bacterial infection which comprises administration of a therapeutically effective amount of amorphous (S)-cefuroxime axetil substantially free from the (R)- isomer.