IE42952L - Tablet formulation - Google Patents

Abstract

1533243 Tablets containing sulphonamides WELLCOME FOUNDATION Ltd 13 Feb 1976 [13 Feb 1975] 6174/75 Heading A5B A tablet comprises from 80-98% (w/w) of a sulphonamide, a disintegrating agent and a granulating agent, the total amount of both agents being from 2-20% (w/w), wherein the particle size (as defined) of the sulphonamide is less than 40Ám and the disintegrating agent has a swelling capacity (as defined) greater than 5 ml/g. [GB1533243A]

Description

43952 - 2 - This invention relates to sulphonamides and pharmaceutical formulations thereof, particularly those suited for oral administration.

Sulphonamides are well-known inhibitors of bacterial organisms 5 by interfering with the metabolic pathway by which bacteria reproduce. This metabolic pathway includes the synthesis of folinic acid from p-aminobenzoic acid via folic acid and the sulphonamides act by preventing the conversion of p-aminobenzoic acid to folic acid.

In view of their wide therapeutic utility, sulphonamides are formulated in many ways depending on the type of infection being treated and the route of administration which is desired. However, the most preferred and usual formulation is that of a tablet which is suited for oral administration.

Present marketed tablets normally contain from about 100 to 1000 mg of the sulphonamide, e.g. 500 mg, and this usually represents a proportion of the tablet not higher than 85% (w/w), frequently between 75 and 85^ (w/w). The remainder of the tablet is usually taken up with conventionally exciDients such as a disintegrating agent, a granulating or binding agent, a lubricating agent and an inert filler. iS ao 4 29 32 Unfortunately, these marketed tablets often encounter administration problems, particularly with regard to children and old people, when the size of the tablet makes It very difficult to swallow. Moreover, these problems are augmented 5 as the content of sulphonamide in a single tablet 1s Increased to, for example, above 500 mg. Accordingly, there 1s little doubt that it would be highly desirable to reduce the overall size of the tablet without altering the content of sulphonamide present. 10 However, an increase in the proportion of sulphonamide, thereby reducing the overall size of the table, has hitherto resulted 1n poor tablet characteristics, such as a high disintegration time or dissolution time, a high friability value or a low hardness value. These characteristics obviously assume the utmost 15 importance primarily for the reason that they may not comply with certain medical standards required by the Health Authorities 1n many countries. For Instance, poor tablet characteristics may well result in abrasion or fragmentation of the tablets during transportation and the patient would not therefore receive the 20 required amount of active ingredient.

It has now been found that a tablet having excellent characteristics can be achieved with a higher proportion of sulphonamide present than has hitherto been obtained. In fact, the tablet can be manufactured to contain a proportion as high as 95% (w/w) or - 4 - even higher. This is made possible by using a sulphonamide, which has a particle size, as hereinafter defined, of less than 40 urn. Since a reduction 1n the proportion of exclpients is obviously concomitant with the use of a high proportion of 5 sulphonamide, the resulting tablet possesses economic benefits over and above previous tablets.

It has also been found that the inclusion of a disintegrating agent having a swelling capacity, as hereinafter defined, greater than 5 ml/g imparts an even greater improvement in these 10 characteristics. In particular, surprisingly low disintegration times are now also possible for tablets having a high content, for example 95% (w/w), of sulphonamide and, at the same time, a high hardness value, such as 12 kg.

Accordingly, the present invention provides a tablet, which comprises 15 from 80 to 98% (w/w) of a sulphonamide, a disintegrating agent and a granulating agent, the total amount of both agents being from 2 to 20% (w/w), wherein the particle size, as hereinafter defined, of the sulphonamide is less than 40 ym and the disintegrating agent has a swelling capacity, as hereinafter defined, 20 greater than 5 ml/g.

In particular, the tablet comprises at least 85% (w/w), preferably 429 52 at least 87.5% (w/w), more preferably at least 90% (w/w), and most preferably at least 92.52 (w/w), of the sulphonamide, the particle size of which 1s advantageously below 30 urn, desirably below 20 urn, and most desirably about 10 van. 5 Moreover, a tablet comprising from 1 to 5% (w/w) of a granulating agent and from 1 to 5% (w/w) of a disintegrating agent is further preferred.

A tabletcontaining from 100 to 1000 mg of a sulphonamide, for example about 500 mg, constitutes an even further preferred 10 aspect of this invention.

As usad herein, the particle size of the sulphonamide is defined in terms of the "weight median diameter" hereinafter referred to as W.M.D. Thus, each particle is considered as a sphere having a volume Identical with the actual particle and the W.M.D. is 15 that 'diameter', wherein 50% (by weight) of these hypothetical spheres have a larger diameter than that figure and 50% (by weight) a smaller diameter than that figure. The W.M.D. may be determined using a Coulter (registered Trade Mark) counter 1n which the sulphonamide is dispersed 1n an electrolyte comprising 20 an aqueous solution of, for example, sodium chloride saturated 4 ZD Si 2 with the sulphonamide, is passed through a small orifice in a tube on either side of which is immersed an electrode. The changes in resistance as particles pass through the orifice generate voltage pulses whose amplitudes are proportional to 5 the volumes of the particles. The pulses are amplified, and the numbers counted at different threshold levels. From this data the size distribution of the suspended particles and hence the W.M.D. may be determined.

The particular particle size of the sulphonamide which is to be 10 used with the present invention, will depend upon the envisaged content thereof in the resulting tablet. If, for example, 85% (w/w) of sulphonamide is required, then the particle size could be, for Instance, between 20 and 30 wm. On che other hand, 1f a 95% (w/w) content of sulphonamide 1s required. It would be 15 advisable to use an even lower particle size, for example, less than 15 iim, preferably about 10 um.

The particle size of the sulphonamide may readily be reduced by precipitation techniques or by grinding the particles with any apparatus or by any other method known in the art suitable 20 for such purpose. In particular, the hammer mill, which can be used with either the rigid or the swing-hairmer type and is conveniently combined with a fan and a cyclone for collecting the material, is preferred. 429U2 As used herein, the swelling capacity of a disintegrating agent 1s defined as the volume (ml) to which 1 g of a tablet containing 95% (w/w) of the dry, disintegrating agent and 5% (w/w) of polyvinylpyrrolidone (K30) will swell when 1n contact with an 5 excess of water at a temperature of 21°C. It is determined by granulating the disintegrating agent (2 g) with 10% polyvir\yl-pyrrolidone (K30) (1ml) and drying the resultant granules at 60°C. Compression of the granules to a hardness value of 12 kg provides tablets having a diameter of 15 nrn and a weight of 10 approximately 900 mg. Each tablet is then accurately weighed and placed on the bottom of a 25 ml measuring cylinder. A nylon disc of 8 mm thickness and having two grooves provides a close, but sliding, fit in the measuring cylinder, resting on the top of the tablet. The grooves are disposed opposite each 15 other on the circumference of the disc in a direction at right \ angles to the plane thereof and allow for a thin hypodermic needle to be inserted between the disc and the glass wall of the measuring cylinder. A 5 g weight is placed on the nylon disc and water injected through one of the grooves into the space 20 surrounding the tablet; the other groove allowing for air to be displaced. When the water level 1s above the top of the disc, the needle can be removed and water added until 1t 1s 1n excess, e.g., 25 ml. The volume under the disc 1s then noted at periodic Intervals until there 1s no further Increase 1n 25 absorption. In some cases, disintegrating agents absorb water 8 to form viscous gels, and this slows down the rate of absorption I necessitating a longer interval, such as 48 hours, before maximum swelling is achieved.

On completion of swelling, the final volume is read and corrected 5 to the corresponding value for 1 g of the tablet, i.e. the value for the swelling capacity. The whole operation should preferably be performed at an approximately constant room temperature, for o example 21 C.

Disintegrating agents which have a swelling capacity greater than 10 * ml/g and which therefore may be used in the present invention include calcium carboxy methyl celluloses, such as E.C.G. 505, low viscosity sodium carboxy methyl celluloses, such as Copagel and Nymcel, guar based vegetable gums, such as Supercol U and Supercol NG-1, a sodium alginate, such as Alginate YZ, and 15 sodium starch glycolates, such as Primojel. The most preferred disintegrating agent is Primojel, Copagel, Nymcel1, Supercol, Alginate and Primojel are registered Trade Marks.

While it is essential that the disintegrating agent used in the present invention has a swelling capacity greater than 5 ml/g 20 there does not seem to be a maximum value although it would not be expected to find a disintegrating agent having a swelling capacity much greater than about 60 ml/g. 9 - Granulating agents which may be employed in the present invention include starch 1n the form of mucilage, starch derivatives, such as starch 'Snow Flake' cellulose derivatives, such as methylcellulose, gelatin and preferably polyvinylpyrrolidone. 5 Sulphonamides which may be employed in the present invention Include those embraced by formula (I). wherein Q is a substituted cr .^substituted pyrimidin-2-yl, pyrimidin-4-yla quinoxalinyl group, an acyl group or preferably a substituted or unsubstltuted isoxazolyl group. 10 Examples of preferred sulphonamides which fall within formula (I) include sulphamethoxazole {3-(4-aminobenzene-sulphonam1de)-5-methyl1soxazole }, sulpha-dlmethoxlne {6 - (4 - aminobenzene-sulphonamldo ) - 2,4 - d1methyoxypyr1midine}, sulphadlazlne {2-(4-aminobenzene-sulphonamido)pyrimid1ne} , sulphadoxlne {4 -15 (4 - aminobenzenesulphonamido) - 5,6-dimethyoxypyrimidine) , sulphaquinoxaline {2-sulphonamido-quinoxaline }, sulphadimidine 12-(4- aminobenzenesulphonamido) - 4,6 - dimethyl pyrimidine}, sulphafurazole {5 -(4-amino-benzenesu.lphonamido) - 3,4 - dimethyl -isoxazole ), sulphacetamide {N-sulph-anilylacetamide } , sulphag-20 uanidine {N-amidinosulphanilamide}and sulpha-methoxydiazine. The especially preferred sulphonamide is sulphamethoxazole. 4 2 9 rJ 2 10 Sulphonamides may be prepared by any one of a number of suitable methods described 1n the art, for example, sulphamethoxazole can be prepared by the process disclosed in U.K. Patent Specification No. 814,276. 5 It may also be desirable to include a small proportion of a suitable lubricant, such as magnesium sterate, in the tablet so that the tablet is thereby prevented from adhering to the punches and dies of the automatic tableting equipment. Also dyes and preservatives may be added, if required.

In another aspect of the invention, there is provided a method of preparing a tablet which comprises the compression on standard machinery of a formulation containing from 80 to 98% (w/w) of a sulphonamide, a disintegrating agent and a granulating agent, the total amount of both agents not being more than 20% (w/w) of the formulation, wherein the particle size of the sulphonamide is less than 40 urn and the disintegrating agent has a swelling capacity greater than 5 ml/g.

The sulphonamide and disintegrating agent are mixed in a dry state at slow speed, for example around 15 rev/min, in a 20 planetary mixer, followed by wet mixing for up to about 30 minutes with a granulating solution, together with additional 10 15 4 29 22 - 11 - solvent, 1f necessary, for maintaining the consistency of the mass. The material can then be milled and either tray-dried or dried 1n a fluidised bed. The dry material is sifted and a lubricant is added to the granules provided in 5 this manner. Compression of the granules on standard machinery to the specified hardness then gives tablets of the required size and shape.

As used herein, the term (w/w) is used to denote the ratio of the weight of specified excipient or sulphonamide to the total 10 weight of the tablet.

It should be noted that the advantageous characteristics of a tablet made in accordance with the present invention are primarily due to the interactions that exist between the disintegrating agent and each or one of the sulphonamide and the 15 granulating agent.

The disintegrating time may be determined by the method described in the British Pharmacopoeia 1968 which involves the rapid movement of the tablet in water under standardised conditions, until there are no fragments remaining above a supporting wire 20 gauge (vide pages 1366 to 1367).

The British Pharmacopoeia 1968 states that the disintegration time for any tablet must not exceed 15 minutes but desirably this time should be less than 10 minutes, especially below 5 minutes, for safety reasons in view of inevitable variations from tablet 25 to tablet. In addition to this essential requirement it is 429K2 - 12 - generally recommended that the mositure content of the granule from which the> tablet is produced should be below 2%.

The "hardness" of a tablet is the amount of force required to shatter it or is more correctly the crushing strength, and 5 although this may be measured accurately according to various standards, the Monsanto (registered Trade Mark) method is convenient and suitable for testing the tablet produced in accordance with the present invention. Basically the method involves the use of a Monsanto Tablet Hardness Tester, which 10 is a spring-loaded device capable of exerting radial pressure on an edge of the tablet, t!._ shattering force being read from a scale on the sleeve of the device. In this respect the present invention is especially suitable for tablets which are compressed to a hardness value of 6 to 15 kg, preferably, 15 11-13 kg.

The friability of a tablet is a measure of the loss of weight suffered by a tablet from abrasion or shock and may be tested by a "Roche" Friabilator in which a weighed sample of tablets, such as 6 g, is subjected in the apparatus for a length of time, 20 such as 4 minutes, to abrasion caused by a tumbling action, comparable to tablets rubbing one another or being shaken against the walls of their container in general use, and to a 4 2 9 1/2 - 13 - shock resulting from a free-fall of six inches, such as might be encountered during various steps in packaging, handling and transport.

The dissolution time of a tablet may, for instance, be determined 5 according to the U.S.P. XVIII by using an apparatus comprising a cylindrical basket of 1680 um stainless steel mesh, a covered 1000 ml glass vessel, a constant-temperature water bath, and a variable-speed motor. The dissolution medium, which may be for example 0.6% hydrochloric acid, pH 1.2, 1s poured into 10 the vessel which has been previously immersed in the constant-t«nperature bath and the medium i., allowed to come to a temperature of 37°C. A tablet is placed in the basket and the apparatus assembled such that the basket is fully immersed 1n the medium. The basket is rotated at, for example, 120 rev/min 15 and samples are withdrawn at intervals with a syringe and assayed, for instance, by U.V. absorbance.

Further advantages of the present Invention will now become apparent from the following description of embodiments of the invention, which embodiments do not limit this invention in 20 any way.

Example 1 The swelling capacity of a variety of disintegrating agents was 4 2 9 5 2 - 14 - determined according to the method hereinbefore described at a temperature of 21°C. Each disintegrant tested was then included in the following formulation:- Weight/g 5 Sulphamethoxazole 800.0 Disintegrant 19*0 Polyvinylpyrrolidone K.30 20.8 Dloctyl Sodium Sulphosuccinate 0.8 10 Magnesium stearate 10.0 850.6 Sulphamethoxazole having a particle size of 10 urn was mixed with the disintegrant in a Morton mixer for ten minutes. Dioctyl sodium sulphosuccinate was dissolved in 260 ml of 15 8% polyvinylpyrrolidone K30 in a 50/50 (v/v) solution of alcohol in purified water and the resulting solution was used to granulate the mixture of sulphamethoxazole and disintegrant by wet-mixing the materials for 10 minutes. The wet-mass was then passed through a 1200 pm metal screen 20 and subsequently dried overnight in an oven at 50°C. The dried granules were passed through a 1000 um screen and mixed with magnesium stearate which had previously been sifted through a 150 ym screen. The resultant mixture was compressed 4 20 S2 - 15 - on a Manesty ( Trade Mark) D3 rotary machine to provide tablets having a hardness value of 12.0 kg.

The characteristics, in particular the disintegration time, were then examined for each tablet formulation: 5 disintegrating Agent Swel1i ng Capacity (ml/g) Disintegra Time (min sec) Supercol N6-1 43.6 0.50 Nymcel ZSB-10 19.4 0.50 E.r.G. 505 6.0 0.53 10 Primojel 14.8 1.07 Supercol U 23.1 2.05 Alginate YZ 10.2 2.10 Copagel PB25 5.2 2.35 Texamid S058 4.6 11.30 15 Cepo Cellulose Flour 4.8 >15 Veegum Regular 2.3 >15 Crodamix U.35 1.6 >15 Maise Starch 1.3 >15 Protein S 0 >15 20 These results establish that the use of a disintegrating agent having a swelling capacity greater than 5 ml/g in a formulation provides a tablet with superior characteristics particularly f A iff /ii p i nf ^ f nivn i C^ui wv i wo vj i j i ii towtuii untie 42Di>2 - 16 -Example 2 Sulphamethoxazole (880 g) having a particle size of 10 um and Primojel (20.9 g) were mixed 1n the dry state for 10 minutes 1n a Z-blade mixer. A solution containing polyvinylpyrrolidone (18.4 g), 5 dloctylsodlum sulphosuccinate (0.77 g) and purified water (230 g) was prepared. The solution was wet-mixed with the powders for 10 minutes using a slow speed. The wet mass was passed through a 1000 iim metal screen. The granules were dried in a fluidised bed at 60°C for 30 minutes to a moisture content of 0.8%. The 10 dried granules were sifted through a 1000 pm screen and magnesium stearate (11 g), sifted 125 pm, was blended with the granules. The granules were then compressed on a Manesty 03 Rotary machine to provide tdolets having a hardness value of 12.2 kg(Monsanto) a disintegration time of 3 min 30 sec, and a 15 friability value of 0.43% . Each tablet had a thickness of 5.22 mm, a weight of 423.3 mg, a diameter of 10. 2 mm and contained 400 mg of sulphamethoxazole.

Example 3 Phthalysulphathiazole (480 g) having a particle size of 22.5 ym 20 and Primojel (24 g) were mixed in the dry state for 10 minutes in a Z-blade mixer. A solution containing gelatin (16 g), Dioctylsodium Sulphosuccinate (1 g), Alcohol (93 g) and Purified Water (130 g) was prepared. The solution was wet mixed with the powders for 10 minutes, using a slow speed. The wet 25 mass was passed through a lOOOum screen. The granules obtained were dried in a fluidised bed at 60°C for 30 minutes. The dried granules were sifted through a 1000 u"i screen and Magnesium Stearate (4.8 g), sifted 150 um, was blended with the granules. 4 2 9 'J 2 - 17 - The granules were compressed on a Manesty 03 Rotary machine to provide tablets having a hardness value of 12.7 kg (Monsanto), a disintegration time of 1 min 40 sec and a friability value of ^0.1%. Each tablet had a thickness of 5.7 m1n, a weight 5 of 548 mg a diameter of 11.8 mm and contained 500 mg of Phthalyl-sulphathiazole.

Example 4 Sulphad1m1d1ne (480 g) having a particle size of 38.7 un.

Primojel (40 g) and Lactose (30 g) were granulates 1n Example 1. 10 After sifting 1000 pm, Magnesium Stearate (4.8 g), Sifted 150pm, was blended with the granules. The granules were compressed on a Manesty D3 Rotary machine to provide tablets having a hardness value of 13.8 kg, a disintegration time of 2 min 45 sec and a friability value of <0.1%. Each tablet had a thickness of 5.7 15 mm, a weight of 596 mg, a diameter of 11.8 mm and contained 500 mg of Sulphadimidine.

Example 5 20 Sulphaguanidine (480 g) having a particle size of 10.8pm, Pre-gelled Starch (96 g) and Primojel (16 g) were mixed in the dry state for 10 minutes in a Z-blade mixer. Purified 4 2 i) tt 2 - 18 - Water (220 g) was wet mixed with the powders for 10 minutes. The granules were prepared as in Example 1. The granules were compressed on a Manesty D3 Rotary machine to provide tablets having a hardness value of 13.0 kg, a disintegration 5 time of 2 m1n 03 sec and a friability of <0.1X. Each tablet had a thickness of 5.9 mm, a weight of 622 mg, a diameter of 11.0 mm and contained 500 mg of Sulphaguanidine.

Example 6 Sulphamethoxydiazine (480 g) having a particle size of 17 um 10 and Primojel (32 g) were mixed in the dry state for 10 minutes. A solution containing Polyeth>"ane Glycol 6000 (28 g) and Purified Water (122 g) was wet mixed with the powders for 10 minutes. The granules were prepared as in Example 1. Tablets were prepared on a Manesty D3 Rotary machine. Each tablet had a 15 hardness value of 15 kg, a disintegration time of 6 min 40 sec and a friability of<0.2%. Tablets had a thickness of 4.9 mm, a weight of 568 mg, a diameter of 11.0 mm and contained 500 mg of Sulphamethoxydiazine.

Example 7. 20 Sulphafurazole (480 g) having a particle size of 39.6um and Primojel (11.4 g) were mixed in the dry state for 10 minutes in 4 2 9 L* 2 - 19 a Z-blade mixer. A solution containing Polyvinylpyrrolidone, K30 (12.5 g), Alcohol (58 g) and Purified Water (72 g) was prepared. The solution was wet-mixed with the powders for 10 minutes using a slow speed. The granules were prepared as in 5 Example 1. The granules were compressed on a Manesty 03 Rotary machine to provide tablets having a hardness value of 6.1 kg, a disintegration time of 4 min 45 sec and a friability value of 0.8%. Each tablet had a thickness of 5.2 mm, a weight of 532 mg, a diameter of 11.8 mm and contained 500 mg of Sulphafurazole. 4 2952 - 20 -

Claims (16)

CLAIMS:

1. A tablet, which comprises from 80-98% (w/w) of a sulphonamide, a disintegrating agent and a granulating agent, the total amount of both agents being from 2-20% (w/w), wherein S the particle size, as herein defined, of the sulphonamide is less than 40 vim and the disintegrating agent has a swelling capacity, as herein defined, greater than 5 ml/g.

2. A tablet accordinq to Claim 1, which comprises at least 85% (w/w) of a sulphonamide. io

3. A tablet according to Claim 2, which comprises at least b7.5% (w/w) of a sulphonamide.

4. A tablet according to Claim 3, which comprises at least 90% (w/w) of a sulphonamide.

5. A tablet according to Claim 4, which comprises at least >■ 92.5% (w/w) of a sulphonamide.

6. A tablet according to claim 5, which comprises about 95% (w/w) of a sulphonamide.

7. A tablet according to any one of the preceding Claims, which comprises from 1-5" (w/w) of a granulating agent. 4 2 0 rJ 2 21

8. A tablet according to any one of the preceding Claims, which comprises from 1-5X (w/w) of a disintegrating agent.

9. A tablet according to any one of the preceding Claims, wherein the particle size of the sulphonamide is less than

10. A tablet according to Claim 9, wherein the particle size is less than 20 vim.

11. A tablet according to Claim 10, wherein the particle size is about 10 ym. 10

12. A tablet according to any of the preceding Claims, which comprises from 100 to 1000 mg of a sulphonamide.

13. A tablet according to Claim 12, which comprises about 500 mg of a sulphonamide.

14. A tablet according to any one of the preceding Claims, 15 wherein the sulphonamide is a compound of formula (I), 5 30 ym. (I) 4 2D it 2 - 22 - wherein Q is a substituted or unsubstituted pyr1midin-2-yl, pyrimidin-4-yl, a quinoxalinyl group, an acyl group or a substituted or unsubstituted isoxazolyl group.

15. A tablet according to any one of the Claims 1-13, 5 wherein the sulphonamide is selected from sulphamethoxazole, phthalysulphathiazole, sulphadimidine, sulphaguanidine, sulphamethoxydiazine, and sulphafurazole.

16. a tablet according to any one of the preceding Claims substantially as described hereinbefore and with reference 10 to any one of Examples 1 to , . Dated this 12th day of February 1976 CRUICKSHANK & CO., Agents for the Applicants, Youghal House, 13, Trinity Street, Dublin. 2.