GB2066662A - Cephalexin powder compositions containing silicon dioxide - Google Patents

Abstract

A powder composition for filling into capsules comprises cephalexin, a lubricant and from 0.1 to 2.5% by weight, based on the total weight of the composition, of colloidal silicon dioxide. The silicon dioxide is for improving the flow properties of the powder during the capsule filling operation.

Description

SPECIFICATION Pharmaceutical compositions This invention relates to improvements in the for mulation of cephalexin.

In recent years the use of hard gelatin capsules as a form of solid oral medicament has steadily inereased due to their relative ease of formulation and manufacture as compared with tablets and dragees. Capsule shells conventionally comprise a body and a cap. During the filling of such capsules, a powder containing the desired active ingredient, if desired mixed with excipients, is placed in the body of the capsule and then the cap is fitted on the body to close the capsule. This operation may be carried out automatically (where the powder is first mechanically pressed into a plug which is then automatically dropped into the body) or semi-automatically (i.e.

with direct manual filling).

Whilst the size of capsule and choice of excipient (where used) are largely dependent on the therapeutic dose of the active ingredient, it is of course desirable that the capsule be of a convenient size to handle and to swallow. Capsule shells are generally available in 8 standard sizes ranging from size 000 (capacity 1.36 ml) to size 5 (capacity 0.13 ml). Capsules of size 4 (capacity 0.20 ml) and size 5 are generally considered to be too small to be handled with ease by the aged and infirm whereas size 00 capsules (capacity 0.95 ml) and size 000 capsules are rather difficult to swallow because of their large size.

From a manufacturing point of view, capsules which contain drugs of low therapeutic dose, e.g.

10-100 mg are generally easier to formulate, since it is possible to include a large proportion of excipient whilst still keeping the capsule to a reasonable size.

A large proportion of excipient in a blend to be filled into capsules is often advantageous since the greaterthe proportion of excipient contained in the blend, the closer will properties such as average particle size, surface area, flowability and apparent density of the blend as a whole approximate to the properties of the excipientperse and excipients having the desired combination of properties may more readily be selected.

Qn the other hand, with drugs such as the known antibiotic cephalexin where the therapeutic dose is large, e.g. 200-600 mg., there is very little room to include excipients in the blend to be placed in the capsule if the capsule is to be kept to a reasonable size. In such cases, the physical properties of the drug itself play a decisive role in the ease of the capsule filling process.

Of the properties of a powder, the apparent density, i.e. the mass per unit volume, gives an indication of how the powder will pack or compress in a confined space whilst the flowability often gives a good indication of how the powder is likely to behave when filled into capsules using an automatic capsule filling machine. Powders which do not flow satisfactorily tend to give rise to considerable variation in the fill weight since the formation of the plug by such machines for placing in the body of the capsule usually depends on powder flow during the metering process. In addition whilst not wishing to be bound by theoretical considerations, it is believed that, because of short range forces of attraction, the particles will tend to adhere not only to each other but also to metal parts of the filling machine thus impeding the flowability of the powder.Adherence of powder particles to the precision made compo nents present in these machines can also cause severe damage to the machine and disrupt the release of performed plugs into the capsule bodies.

It is therefore usually desirable to include so-called lubricants in the formulation. Such lubricants include, for example, stearic acid, calcium stearate, magnesium stearate and talc. These lubricants are in general hydrophobic and thus it will normally be preferred to avoid their use in excessive amounts since this may prolong the time required for disintegration of the capsule in the gastro-intestinal tract of a patient.

Cephalexin is a compound well known in the pharmaceutical industry for its desirable antibacterial activity (see for example Cephalosporins and Penicillins, Ed. E. H. Flynn, Academic Press Inc., 1972, p 521-523). In the case of cephalexin as produced by some methods, the apparent density may be such that, without further treatment, the capsule sizes preferred from the standpoint of ease of handling and swallowing are not in general large enough to accommodate the required fill weight, particularly where larger dosages are concerned. In addition the flowability of the cephalexin may be poor and thus it may not generally be possible to fill cephalexin into capsules on an automatic machine within an acceptable range of fill weight.

These problems may be resolved by a method known as "slugging" or"compaction". According to this method, the cephalexin is mixed with a lubricant such as magnesium stearate and compressed into large tablets (slugs) on a heavy duty press. The slugs are then granulated through a sieve to give a granular powder. According to a modification of thins method, the powder, instead of being made into slugs, is passed between rollers to form "flakes" which are then crushed to give a granular material.

This conversion of cephalexin powder to a granular material, known as densification, not only increases the apparent density but also improves its flowability.

This densification step is, however, a disadvantage in that it constitutes an additional stage in the manufacturing process which is not only time consuming but also costly. In addition, this step can lead to some deterioration in the physical properties of the drug.

A number of alternatives to these methods have been suggested. Thus, a recognised method for the densification of powders is a wet granulation step.

Wet granulation has, however, failed to give satisfactory results with cephalexin. Combinations of cephalexin with a variety of excipients known from the literature e.g. starch, lactose, Avicel and StaRx Elcema have also been tested but have been found still to give unsatisfactory results in that the amount of excipient which may be incorporated into a capsule of reasonable size is insufficient to signif icantly increase the apparent density and the flowability of the blend to be filled into the capsule such that the necessity for the densificarion step may be avoided.

The present invention is based on the discovery that a satisfactory cephalexin-containing blend for filling into capsules, and in particular on an automatic machine, may be obtained if the cephalexin is mixed with from 0.1 to 2.5% by weight, based on the total weight of the blend, of colloidal silicon dioxide.

Not only is the flowability of the blend improved as compared with cephalexin perse thus assisting the capsule filling process but also the apparent density is increased, this being of particular advantage where larger dosages of cephalexin are to be administered since it permits these larger dosages to be more readily formulated.

According to one aspect of the present invention there is provided a blend suitable for filling into capsules, the said blend comprising cephalexin, a lubricant and from 0.1 to 2.5% by weight, based on the total weight of the blend, of colloidal silicon dioxide.

According to a further aspect of the present invention there are provided capsules containing such a blend.

The proportion of colloidal silicon dioxide used is of particular importance; it has been found that proportions of colloidal silicon dioxide greaterthan 2.5% or less than 0.1%, in each case based on the total weight of the blend, do not give the desired result. The preferred proportion of colloidal silicon dioxide is 0.3 to 1.5%, particularly about 0.5% by weight based on the total weight ofthe blend.

Preferably the silicon dioxide will have a particle size in the region of 12 millimicrons and a BET surface area of about 200 m2/g. Suitable colloidal silicon dioxide is available under the trade names Aerosil, Cab-0-Sil, Wacker HDK N 20 and QUSO silica, particularly preferred being the colloidal silicon dioxide marketed underthetrade nameAerosil 200.

Without wishing to be limited by theoretical considerations, it is believed that the increased apparent density and improved flowability of the blend are due to the extremely fine particles of the silicon dioxide acting as a glidant. Thus the silicon dioxide acts as a glidant between the cephalexin particles and/or causes slight separation between the individual cephalexin particles hence substantially reducing or overcoming the effects of short range forces between the cephalexin particles.

The lubricant present in the blend can be any of those conventionally used in the pharmaceutical field such as, for example, those mentioned above.

In general the lubricant will preferably be present in an amount of from to 0.1 to 2% by weight based on the total weight of cephalexin in the blend. Particularly preferred is the use of magnesium stearate as the lubricant preferably in an amount of about 1% by weight based on the weight of cephalexin.

The cephalexin-containing blend of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry.

Thus, for example, the cephalexin and colloidal silicon dioxide may be admixed together with the lubricant to give a final amount of from 0.1 to 2.5% by weightofcolloidal silicon dioxide, based on the total weight of the blend. According to a preferred method, the colloidal silicon dioxide and the lubricant are mixed with an equal volume of cephalexin and passed through a suitable sieve to ensure uniformity of blend. The sieved mixture is then blended with the remaining cephalexin. The blend may be accurately filled into capsules at the required target weight using conventional equipment of either the automatic or semi-automatic type without any need to subject the cephalexin to a densifying step, thus reducing time and cost as well as resulting in an improved final product.

The following non-limiting examples illustrate the present invention.

Example 1 Formulation for Function 250 mg 500 mg Cephalexin Active ingredient 279.21 mg 558.42 mg Magnesium stearate (1% by weight based on Lubricant 2.79 mg 5.58 mg weight of cephalexin) Colloidal silicon dioxide (approx. 0.5% by weight Glidant 1.40 mg 2.80 mg based on total weight of blend) (Aerosil 200) Fill weight - 283.4 mg 566.8 mg Capsule size No.2 No. '0' (0.37 ml (0.67 ml capacity) capacity) Method 1 Magnesium stearate and Aerosil 200 are mixed with an equal volume of cephalexin in a suitable mixer. The blend is then passed through a suitable (30 or 40 mesh) sieve.

2 The above pre-mix (1) is blended with the remaining cephalexin using suitable equipment.

3 The indicated fill weight of the blend (2) is filled in size 2 or 0 capsules on an automatic or semiautomatic filling machine.

Example 2 Formulation for250 mg for 500 mg Cephalexin 279.21 mg 558.42 mg Magnesium Stearate 2.79 mg 5.58 mg Aerosil 200 (approx 1% by weight based on total weight of blend) 2.79 mg 5.58 mg Fill weight 284.79 mg 569.58 mg Capsule size No. 2 No. '0' Method The blends are formulated and filled into capsules as ih Example 1.

Example 3 for 500 mg Cephalexin 558.42 mg Magnesium Stearate 5.58 mg Aerosil 200 (approx 2% by weight based on total weight of blend) 11.16 mg Fill weight 575.16 mg Capsule size No '0' Method 1 Cephalexin, magnesium stearate and Aerosil 200 are screened and blended through a 30 mesh sieve.

2 The indicated fill weight of the above blend (1) is filled into size 0 capsules on an automatic or semiautomatic filling machine.

Example 4 Formulation for500 mg for500 mg Cephalexin 558.42 mg 558.42 mg Magnesium Stearate 5.58 mg 5.58 mg Cab-o-sil M5 (approx 0.5% by weight based on total weight of blend) 2.8 mg Wacker HDK N20 (approx 0.5% by weight based on total weight of blend) - 2.8 mg Fill weight 566.8 mg 566.8 mg Method 1 Cephalexin, magnesium stearate and the colloidal silicon dioxide are mixed manually to increase the bulk density.

2 The indicated fill weight of the blend (1) may be filled into size 0 capsules for 500 mg capsules.

Claims (12)

1. A blend suitable for filling into capsules, the saidtlend comprising cephalexin, a lubricant and from 0.1 to 2.5% by weight, based on the total weight of the blend, of colloidal silicon dioxide.

2. - A blend as claimed in claim 1 containing from 0.3 to 1.5% by weight, based on the total weight of the blend, of colloidal silicon dioxide.

3. A blend as claimed in claim 2 containing about 0.5% by weight, based on the total weight of the blend, of colloidal silicon dioxide.

4. A blend as claimed in any preceding claim wherein the colloidal silicon dioxide has a particle size in the region of 12 millimicrons and a BET surface area of about 200 m2/g.

5. A blend as claimed in any preceding claim wherein the lubricant is present in an amount of from 0.1 to 2% by weight based on the weight of cephalexin in the blend.

6. A blend as claimed in any preceding claim wherein the lubricant is magnesium stearate.

7. A blend as claimed in claim 6 wherein the magnesium stearate is present in an amount of about 1% by weight based on the weight of cephalexin in the blend.

8. A blend substantially as herein described in a.W one of Examples 1 to 4.

9. A capsule containing a blend as claimed in any preceding claim.

10. A capsule substantially as herein described in any one of Examples 1 to 4.

11. A process for the preparation of a blend as claimed in claim 1 which comprises mixing cephalexin, colloidal silicon dioxide and a lubricant to give a final amount of from 0.1 to 2.5% by weight of colloidal silicon dioxide, based on the total weight of the blend.

12. A process as claimed in claim 11 wherein the colloidal silicon dioxide and lubricant are mixed with an equal volume of cephalexin and then sieved, the sieved mixture then being blended with the remaining cephalexin.