AU762545B2 - Synthetic sweeteners, their production and uses thereof - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: Fujisawa Pharmaceutical Co., Ltd.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Synthetic sweeteners, their production and uses thereof" The following statement is a full description of this invention, including the best method of performing it known to us: IP Australia Documents received on: 0 2 5 OCT 200 Batch No: PAOPERMCJLx-am divI.dAo-25/10M 1A- SYNTHETIC SWEETENERS, THEIR PRODUCTION AND USES THEREOF This application is a divisional of Australian Patent Application No. 17347/97, the entire contents of which is incorporated herein by reference.

TECHNICAL FIELD This invention relates to synthetic sweeteners useful in the preparation of pharmaceutical compositions, in particular self-disintegrating tablets. The synthetic sweeteners are particularly useful in masking the bitter taste of pharmaceutical agents, such .as 3-lactam antibiotics. Self-disintegrating tablets made using the sweetener of the present invention can be orally taken either as such or, for taking by, for example, the aged who have difficulties in swallowing, as a dispersion available upon dropping the same into water in a glass for self-disintegration.

BACKGROUND TECHNOLOGY Particularly in Europe and America, where P-lactam antibiotics such as cefixime and cefdinir are administered generally in single doses of as great as 200 mg to 400 mg potency, unit dosage forms, whether they are capsules or tablets, have to be considerably large in size. When 400 mg potency capsules are prepared, for instance, the capsule size reaches approximately No. 0, so that not only patients having difficulties in swallowing but also ordinary adult patients become reluctant to take them or get a repulsive sensation in 20 taking them. Such capsules are indeed difficult to take. In the case of tablets, too, 400 mg potency tablets generally weight 700 to 1,000 mg per tablet and accordingly are largesized.

The problems encountered in taking such large dosage forms give an unnecessary sensation of oppression to patients on the occasion of taking them. Improvements in their administrability have thus been required.

Therefore, the present inventor attempted to provide a dosage form with improved administrability by reducing the tablet size as much as possible to thereby facilitate the taking of tablets by the recipient and at the same time to provide a dosage form capable of being taken in the form of a dispersion resulting from rapid self-disintegration upon its being simply dropped into water or the like in a glass, for instance, to thereby make said dosage form administrable to persons of advanced age or children having difficulties in P:\OPER'MJCJcm di*.doe-23/1M)3 -2swallowing the dosage form as such. The expression "rapid self-disintegration" as used herein means that when the preparation is dropped into a glass containing a liquid such as water, the tablet form spontaneously collapses generally within 3 minutes, preferably within 1 minute, so that said preparation can be orally taken in dispersion form without awaiting long before taking.

It is indeed easy to produce tablets capable of self-disintegrating very rapidly by incorporating an effervescent agent comprising a combination of sodium hydrogen carbonate and tartaric acid, for instance. However, when such tablets are orally taken, they give off bubbles in the oral cavity, so that patients feel a discomfort or an unnecessary sensation of anxiety. For securing a good shelf-life in a humid environment, it is necessary to use a moisture-proof packaging material, which increases the production cost.

Therefore, in developing the dosage form which the present invention is intended to provide, it has been a tough problem to find out a formulation enabling very rapid selfdisintegration without the aid of any effervescent component.

For producing P-lactam antibiotic-containing tablets which can be easily ingested as they are and be also ingested in the form of a dispersion resulting from selfdisintegration thereof, a technology is described in European Patent EP 0281200 B (corresponding Japanese patent application: Kokai Tokkyo Koho S63-301820), which comprises adding 24 to 70% by weight, based on the weight of the P-lactam antibiotic, of 20 microcrystalline cellulose or microfine cellulose as a first disintegrator and 2 to 20% by weight, on the same basis, of low-substituted hydroxypropylcellulose or the like as a second disintegrator.

However, said first disintegrator, which is used in a large amount, increases the tablet size. In addition, the proportion of a binder component for wet granulation is as low as 0 to 0.1% by weight based on the antibiotic, hence is substantially nil. This is because the use of a binder renders tablets extremely poor in self-disintegrating properties. In the process for producing these tablets, in which no binder is used, a special method of insuring an integrity of the artefact is employed which comprises mixing the antibiotic bulk substance with microcrystalline cellulose and kneading the mixture with the aid of water under application of a great deal of force, without using any alcohol. As a result, large lumps are formed inevitably and they are milled in the wet state and then dried, P:\OPER\MJC\lacim div.doc-23/10/A -3followed by further milling to provide granules for tableting. It is a problem that these steps are very inefficient.

Meanwhile, tablets containing amoxicillin, which is a p-lactam antibiotic, are commercially available under the trade name of Flemoxin Solutab 500 from Brocades Pharma (Netherlands), the patentee to whom said European patent has been granted. Said tablets each contains 500 mg potency (about 570 mg) of amoxicillin and weights about 970 mg, hence is very large and not entirely suited for oral administration.

Most p-lactam antibiotics are bitter. Therefore, aqueous dispersions prepared from tablets containing them, when orally taken, give a bitter taste, although the tablets, when 10 taken as such, taste not so bitter. For masking the bitter taste, it thus becomes necessary to incorporate a sweetener, preferably a synthetic sweetener, which is effective at low addition levels and thus suited for tablet miniaturization. However, when a commercial synthetic sweetener is incorporated, a problem arises, namely the self-disintegrating properties of tablets become poor, since synthetic sweeteners are soluble in water and 15 become viscous and sticky.

DISCLOSURE OF THE INVENTION In an attempt to develop a method of improving the rate of self-disintegration of tablets and at the same time miniaturizing the same, the present inventor made investigations concerning the disintegrator species to be used, the level of addition thereof, 20 the binder addition level, the synthetic sweetener particle size and the method of incorporating the same, among others and, as a result, the inventor invented p-lactam antibiotic-containing tablets which are small-sized, show good self-disintegrating properties and can be produced by a conventional method.

Furthermore, the inventor found that when granulation is performed using ethanol, isopropyl alcohol or an aqueous solution of ethanol or isopropyl alcohol, tablets showing better dispersibility upon self-disintegration can be obtained. Such tablets are the subject of Australian Patent Application No. 17347/97 ("the parent invention").

p-lactam antibiotic-containing tablets of the parent invention contain, per tablet, to 85% by weight of an p-lactam antibiotic, 1 to 10% by weight of low-substituted hydroxypropylcellulose and/or crosslinked polyvinylpyrrolidone as a disintegrator, and to 2% by weight of a binder.

P:\OPER\MJCacnam div.doc-23/10A)O -4- Preferably, the p-lactam antibiotic-containing tablets of the parent invention further contain, per tablet, 0.5 to 15% by weight of a synthetic sweetener and/or a granulated synthetic sweetener.

It is particular synthetic sweeteners and/or granulated synthetic sweeteners which form the subject of the present invention. These sweeteners may be used in formulating self-disintegrating tablets of bitter pharmaceutical actives, including p-lactam antibiotics.

While the present invention will be described with particular reference to the formulation of tablets of p-lactam antibiotics, it is to be understood that the sweetener of the invention may have other uses, especially in the formulation of other bitter pharmaceutical active 10 agents.

In a first aspect the present invention provides a synthetic sweetener selected from the group consisting of saccharin or a salt thereof, and cyclamic acid or a salt thereof, each of which is produced by wet granulation or dry granulation, and has a mean particle size of not less than 150Mm.

15 In a second aspect the invention provides a granulated synthetic sweetener which comprises a synthetic sweetener, and light anhydrous silicic acid and/or hydrated silicon dioxide.

The p-lactam antibiotic-containing tablet production method of the parent invention is characterized in that the above-specified respective proportions of a p-lactam antibiotic, 20 the disintegrator and a binder, optionally together with one or more excipients, are granulated using ethanol, isopropyl alcohol or an aqueous solution of ethanol or isopropyl alcohol, the granulation product is mixed with the above-specified proportion of a synthetic sweetener and/or a granulated synthetic sweetener, optionally together with one or more other additives, and the resulting mixture is compressed.

The P-lactam antibiotic to be used in the practice of the parent invention is one capable of producing a beneficial effect upon oral administration and includes, for example, cefixime and cefdinir respectively represented by the structural formulas shown below as well as cefaclor, cefroxadine, cefadroxil, cefaloglycin, cefalexin, cefradine, amoxicillin, ampicillin and the like.

P:\OPER\MJClacam div.doc-23/10/lX) Cefixime

COOH

HN ON CH=CH 2 N II s NOCH 2 COOH H H Cefdinir

OOH

H

2 N S I "N Y CH=CH 2 N

II

NOH H H Each tablet contains such P-lactam antibiotic in a proportion of 60 to 85% by weight, preferably 65 to 80% by weight.

As a result of investigations concerning the disintegrator species to be used in the practice of the parent invention and the level of addition thereof, it was found that, as compared with such salt type disintegrators as ECG 505 (trademark; carboxymethylcellulose calcium), AC-Di-Sol (trademark; crosslinked carboxymethylcellulose sodium) and Primojel (trademark; starch glycolic acid sodium), nonion type disintegrators, such as low-substituted hydroxypropyl cellulose (L-HPC) and crosslinked polyvinylpyrrolidone, can produce a very good disintegrating effect even when they are added in small proportions. Low-substituted hydroxypropylcellulose is a product derived from cellulose by partial substitution with the 2-hydroxypropoxy group, the degree of substitution being not higher than 25%, preferably 7 to 16%.

Generally, low-substituted hydroxypropylcellulose and crosslinked polyvinylpyrrolidone are incorporated in tablets independently, although both may be used combinedly.

Such disintegrator is used in a proportion of 1 to 10% by weight, preferably 3 to 8% by weight, on a per-tablet basis.

The tablets of the parent invention further contain binder as an essential constituent.

P:\OPERMJC\actam div.doc-23/10o/A -6- The addition of a binder has an adverse effect on the self-disintegrating properties of tablets, hence is not desirable from the self-disintegration viewpoint. However, the production of tablets without adding any binder give such inconveniences as mentioned hereinbefore.

As preferred binders, there may now be mentioned, for example, polyvinylpyrrolidone, hydroxypropylcellulose, preferably low-viscosity type (L-type) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, starch, pregelatinized starch, partly pregelatinized starch, gum arabic, dextrin, pullulan and the like. Among these binders polyvinylpyrrolidone, hydroxypropylcellulose and 10 hydroxypropylmethylcellulose are more preferred, and polyvinylpyrrolidone is most preferred. When these binders are used in an amount of 0.5 to 2% by weight, preferably 0.8 to 1.5% by weight, on a per-tablet basis, tablets which can self-disintegrate rapidly can be produced by a conventional production method.

The level of synthetic sweetener in self-disintegrating tablets, which may vary 15 according to the synthetic sweetener species and the active ingredient, is generally in a proportion of 0.5 to 15% by weight, preferably 1 to 10% by weight.

The commercial synthetic sweetener products are generally small, i.e. less than 150/zm, in mean particle size, with particle not smaller than 1 5 0 gm accounting for at most 4% of the whole. Incorporation of such products markedly reduces the rate of 20 disintegration of tablets. To improve the disintegration rate, the prior art employs a method which comprises incorporating a large amount of an excipient such as microcrystalline cellulose. However, incorporation of a large amount of such excipient according to said method results in an increase in tablet size, thereby making the tablets difficult to take with ease. The present inventor found that when the particle size of a synthetic sweetener is increased or when a granulated mixture of a synthetic sweetener and light anhydrous silicic acid, hydrated silicon dioxide or the like is added, the rate of disintegration can be improved, namely prevented from retardation.

As a result, the present invention allows the production of miniaturized tablets which can be easily taken as such and, when dropped into water in a glass, can rapidly selfdisintegrate, enabling administration thereof in dispersion form.

When such a synthetic sweetener as saccharin, a salt thereof thereof saccharin P: OPERMJC\I2C m divdoc-23/lO1/ -7calcium, saccharin sodium), cyclamic acid or a salt thereof sodium cyclamate, calcium cyclamate, ammonium cyclamate) is used, said sweetener is required to be not less than 150.tm in mean particle size, preferably not less than 150.m in particle size. In the case of a sweetener capable of producing a satisfactory bitter-masking effect in small amounts, for example aspartame, it is not always necessary that the mean particle size be not less than 150.m, since the disintegrability of tablets is little affected.

The synthetic sweetener may be incorporated either in the form of crystalline grains having a mean particle size of not less than 150.m or in the form of a granulation product meeting the particle size requirement as obtained by wet granulation from the powder form 10 small in mean particle size or by wet granulation or dry granulation from such powder together with a color additive and/or microcrystalline cellulose or a like excipient.

The granulation product containing light anhydrous silicic acid or hydrated silicon dioxide in addition to a synthetic sweetener can be produced by mixing the synthetic sweetener with 1 to 30% by weight, relative to the synthetic sweetener weight, of light anhydrous silicic acid or hydrated silicon dioxide and granulating the mixture in the conventional manner, if necessary using a binder and/or one or more other additives in common use. It was found that in the case of granulation products containing a synthetic S"sweetener together with light anhydrous silicic acid or hydrated silicon dioxide, the particle size is not critical, with the result that the self-disintegrating properties are never adversely 20 affected even when the mean particle size is below 150ptm. As regards other ingredients to be used in producing the tablets of this invention, the same ingredients or additives as used conventionally in the production of solid preparations may be mentioned. Thus, in addition to the above-mentioned synthetic sweetener or granulated synthetic sweetener, excipients such as microcrystalline cellulose, lactose, mannitol, starch, etc., flowability improvers such as light anhydrous silicic acid, hydrated silicon dioxide, etc., lubricants such as magnesium stearate, stearic acid, talc, etc., flavoring agents and other agents may be incorporated unless the self-disintegrating properties are adversely affected. When the active agent has a large particle size, it may be ground prior to use. In this case, however, wet or dry granulation is required to improve the powder flowability in the step of compression.

In a preferred process for producing tablets incorporating a synthetic sweetener of P:OPER~MIJC lam div.dow-23110Mo -8the present invention, the above-specified disintegrator and binder, optionally together with other ingredients, are added to the active agent, the mixture is granulated by a conventional method, the above-mentioned synthetic sweetener and/or granulated synthetic sweetener, optionally together with one or more other ingredients flowability improver, lubricant, flavor), are then further added, and the resulting mixture is subjected to tableting.

When, in the above production process, water is used for granulation in the granulation step, tablets with good self-disintegrating properties are generally obtained. In this connection, the inventor of this invention further found that when ethanol, isopropyl alcohol or a mixture of water and ethanol or isopropyl alcohol is used for granulation, tablets with good self-disintegrating properties and with very good dispersibility upon S"allowing dispersion in water can be obtained. The concentration of the aqueous solution of ethanol or isopropyl alcohol, which is suited for use, is 3 to 99% (volume/volume), preferably 10 to 60% (volume/volume).

INDUSTRIAL APPLICABILITY The synthetic sweetener of the present invention allows the formulation of selfdisintegrating tablets of bitter active agents which are small in size. For example, a tablet S"containing 400 mg potency (about 449 mg) of cefixime may weigh not more than 650 mg and a tablet containing 300 mg potency (about 307 mg) of cefdinir not more than 450 mg.

20 They can be orally taken as such with ease. When they are to be taken by the aged, for instance, complaining of some difficulty in swallowing, in an aqueous dispersion form, the tablets can be rapidly disintegrated and dispersed in water.

Moreover, the use of ethanol, isopropyl alcohol or an aqueous solution of ethanol or isopropyl alcohol for granulation in the granulation step makes it possible to obtain tablets with still better dispersibility in water.

The invention will now be described with reference to the following Examples which illustrate some preferred embodiments of the invention as well as providing details of some comparative testing.

Test Example 1 (Disintegrator effect) According to the formulation shown below in Table 1, cefixime bulk substance, microcrystalline cellulose, one of the disintegrators, light anhydrous silicic acid and P:\OPER\MJC\actam div.doc-23/10/a0 -9magnesium stearate, taken in the respective specified proportions, were mixed up and the mixture was compressed on a single-punch tablet machine to give tablets having a diameter of 11 mm.

The tablets produced by the above method were evaluated for disintegration time in 1,000 ml of water (20 1 C) using a Japanese Pharmacopeia disintegration tester, but without using any disk, with 30 cycles per minute of basket ascending and descending.

The disintegration time data thus obtained are shown in Table 1.

Table 1 Cefixime bulk substance Microcrystalline cellulose Disintegrator Light anhydrous silicic acid Magnesium stearate 448.9 (400 mg potency) 38.9 38.9 1.2 5.9 Total 533.8 mg Table 2 Disintegrator Disintegration time (min.) n=6 Carboxymethylcellulose calcium 1.2-1.3 Starch glycolic acid sodium 1.0-1.2 Crosslinked carboxymethylcellulose sodium 0.8-1.1 Low-substituted hydroxypropylcellulose 0.3-0.4 Crosslinked polyvinylpyrrolidone 0.3-0.4 As is evident from Table 2, those tablets which contain low-substituted hydroxypropylcellulose or crosslinked polyvinylpyrrolidone in accordance with the present invention disintegrate very rapidly.

Test Example 2 (Binder study) According to the formulation shown below in Table 3, cefixime bulk substance micronized by a pin-type mill, microcrystalline cellulose and one of the binders, together with 50% (by volume) ethanol, were granulated in a high speed shear mixer, followed by P:\OPER\MICUacm div.doc-23/10AX) drying under flowing air at 40 0 C for 17 hours and sizing through a 500-imr sieve. The granules sieved out were mixed with low-substituted hydroxypropylcellulose, light anhydrous silicic acid and magnesium stearate, in the respective specified proportions, followed by compression on a single-punch tablet machine, to give tablets each having the specified weight and a diameter of 11 mm.

The tablets produced by the above method were evaluated for disintegration time under the same conditions as in Test Example 1. The disintegration time data thus obtained are shown in Table 4.

Table 3 Cefixime Microcrystalline cellulose Binder Low substituted hydroxypropylcellulose Light anhydrous silicic acid Magnesium stearate Total 448.9 (400 mg potency) 38.9 4.9 (14.6) 38.9 1.2 5.9 538.7 mg (548.4 mg) Table 4 Binder addition level (weight Disintegration time in mg) (min.) n=6 Polyvinylpyrrolidone 0.9 0.6-0.8 Polyvinylpyrrolidone 2.7 (14.6) 2.1-2.1 Hydroxypropylcellulose (L type) 0.9 1.4-2.0 Hydroxypropylmethyl-cellulose 0.9 1.0-1.5 As is evident from Table 4, the tablets produced by using polyvinylpyrrolidone, hydroxypropylcellulose (L type) or hydroxypropylmethylcellulose as the binder disintegrate rapidly.

P:\OPERWJClactam div.doc-23110) 11 Test Example 3 (Synthetic sweetener particle size study) According to the formulation shown below in Table 5, cefixime bulk substance micronized by a pin-type mill, microcrystalline cellulose, low-substituted hydroxypropylcellulose and polyvinylpyrrolidone, together with 50% (by volume) ethanol, were granulated in a high speed shear mixer, followed by drying under flowing air at 40 0

C

for 17 hours and sizing using a 500-[im sieve. The granules sieved out were mixed with light anhydrous silicic acid, magnesium stearate, strawberry powder flavor and commercial saccharin calcium, the large particle size saccharin calcium prepared in Example 1 to be mentioned later herein or the granulated mixture of saccharin calcium and light anhydrous 10 silicic acid prepared in Example 2 to be mentioned later herein, in the respective specified proportions, followed by compressing on a single-punch tablet machine to give tablets each having the specified weight and a diameter of 11 mm.

The tablets produced by the above method were evaluated for disintegration time under the same conditions as in Test Example 1. The disintegration time data thus obtained are shown in Table 6.

S. *oo t* fr Table Cefixime Microcrystalline cellulose Low-substituted hydroxypropylcellulose Polyvinylpyrrolidone Light anhydrous silicic acid Magnesium stearate Strawberry powder flavor Saccharin calcium or granulated saccharin calcium Total 448.9 (400 mg potency) 38.9 38.9 4.9 1.2 5.9 20.0 566.2 mg P:\OPER\MJCdacm div.doc-23/IOA)1 -12- Table 6 Synthetic sweetener Mean disintegration time n=6 Saccharin calcium (mean particle size 150 jim) Saccharin calcium 0.6 (particle size 150-840 lim) Saccharin calcium-light anhydrous silicic acid 1.3 mixture granulated (particle size 75-500 Im) As is evident from Table 6, the tablets produced by using the saccharin calcium not a less than 150 pIm in particle size or the granulated mixture of saccharin calcium and light 5 anhydrous silicic acid are positively shorter in disintegration time than the tablets produced by using the commercial saccharin calcium smaller than 150 p.m in mean particle size.

Test Example 4 (Influence of the composition of the solution for granulation on the dispersibility of tablets) A 2,200 ml portion of water or an aqueous solution of ethanol was used to 10 granulate a mixture of 4,566 g of cefixime bulk substance micronized by a pin-type mill, 405 g of microcrystalline cellulose, 405 g of low-substituted hydroxypropylcellulose and 50.6 g of polyvinylpyrrolidone in a high speed shear mixer and, after drying under flowing air at 40 0 C for 17 hours, the granulation product was sized using a 500-[pm sieve. The granules sieved out were mixed with 50.6 g of light anhydrous silicic acid, 101.2 g of magnesium stearate, 75.9 g of strawberry powder flavor and 202.6 g of saccharin calcium (particle size: 150-840 followed by compressing on a rotary tablet machine to give oblong tablets each weighing 579 mg.

The tablets produced by the above method were evaluated, by the method mentioned below, for disintegration time as well as for dispersibility for use in dispersion form.

Disintegration time The disintegration time evaluation was made in 1,000 ml of water (20 1 C) using a Japanese Pharmacopeia disintegration tester, but without using any disk, with 30 cycles per minute of basket ascending and descending.

P:\OPER\MJCIac am div.doc-23/1O Io -13- Dispersibility after standing of dispersions prepared One tablet was dropped into 20 ml of water placed in a 50-ml beaker and the whole was allowed to stand for 5 minutes for self-disintegration. Then, the beaker was shaken gently for stirring and thereafter allowed to stand for 1 minute, followed by observation of the appearance.

Table 7 Disintegration time (sec.) Dispersibility after standing Granulation using 50% ethanol 39 a Granulation using 10% ethanol 84 a Granulation using water 62 b Flemoxin Solutab 500 46 b (commercial product) a: Wholly uniform in color, substantially without any precipitate.

b: A supernatant and a slight amount of a precipitate.

The tablets derived from the granules prepared using ethanol are still better in dispersibility after standing as compared with those derived from the granules prepared using water.

Test Example 5 (Disintegration test) Test preparations A: Tablets produced in Example 1 to be mentioned later. B: Tablets produced in Example 7 to be mentioned later. C: Tablets produced in Example 8 to be mentioned later.

Test method The disintegration time evaluation was performed in distilled water at 20 1°C with 4 cycles per minute of basket ascending and descending, using an apparatus prescribed in the Japanese Pharmacopeia 12 th edition) under Disintegration Test.

Test results A: 1.13 minutes B: 1.30 minutes C: 1.02 minutes P:\OPERlMJCIaum div.doc-23/10/ 14- The disintegration test results indicate that the test preparations A to C of this invention each shows good disintegrability.

EXAMPLES

Example 1 Water was added to saccharin calcium and the mixture was granulated by a conventional method, followed by drying, sieving and sizing to give saccharin calcium granules not less than 150 pm in particle size.

According to the formulation shown below, micronized cefixime bulk substance, 10 microcrystalline cellulose, low-substituted hydroxypropylcellulose (L-HPC) and polyvinylpyrrolidone were weighed and mixed together, water was then added, and the mixture was granulated. The granulation product was dried under flowing air at 40 0 C for 17 hours and then sized using a 500- pm sieve. The granules sieved out were mixed with magnesium stearate, light anhydrous silicic acid, strawberry flavor and the aboveo 15 mentioned granulated saccharin calcium according to the formulation shown below, followed by compressing on a single-punch tablet machine to give tablets each having the specified weight.

S00Table 8 Micronized cefixime bulk substance 448.9 mg (400 mg potency) Microcrystalline cellulose 38.9 mg (Avicel T M PH 101; Asahi Chemical Industry) L-HPC 38.9 mg (LH-21; Shin-Etsu Chemical) Polyvinylpyrrolidone 4.9 mg (Kollidon TM 30; BASF) Light anhydrous silicic acid 1.2 mg (Aerosil

TM

Tomita Seiyaku) Magnesium stearate 5.9 mg Saccharin calcium 20.0 mg (not less than 150 pmr in particle size) Strawberry flavor 7.5 mg Total 566.2 mg P:\OPER\MJClactm div.doc-23/ X) Example 2 Saccharin calcium and light anhydrous silicic acid were mixed together in a ratio of 20:1 and then water was added. The resultant mixture was granulated by a conventional method, followed by drying and sizing to give a granulated mixture of saccharin calcium and light anhydrous silicic acid (75-500 pm in particle size).

Then, tablets were produced following the procedure of Example 1 except that 21 mg of the above granulated mixture was used in lieu of 20 mg of saccharin calcium (Example 1, Table 8).

Example 3 10 Saccharin calcium and hydrated silicon dioxide were mixed together in a ratio of 20:1 and then water was added. The resultant mixture was granulated by a conventional method, followed by drying and sizing to give a granulated mixture of saccharin calcium and hydrated silicon dioxide (75-500 p~m in particle size).

Then, tablets were produced following the procedure of Example 1 except that 21 15 mg of the above granulated mixture was used in lieu of 20 mg of saccharin calcium (Example 1, Table 8).

Example 4 Tablets each containing 400 mg (potency) of cefixime were produced in the same manner as in Example 1 except that L-HPC of Example 1 (Table 8) was replaced by the 20 same amount of crosslinked polyvinylpyrrolidone (Kollidon T M CL; BASF).

Example Tablets each containing 400 mg (potency) of cefixime were produced in the same manner as in Example 1 except that polyvinylpyrrolidone of Example 1 (Table 8) was replaced by the same amount of hydroxypropylcellulose (HPC-L; Nippon Soda).

Example 6 Tablets each containing 400 mg (potency) of cefixime were produced in the same manner as in Example 1 except that polyvinylpyrrolidone of Example 1 (Table 8) was replaced by the same amount of hydroxypropylmethylcellulose (TC-5RM; Shin-Etsu Chemical).

-16- Example 7 According to the same formulation as that shown in Example 1 (Table 8), micronized cefixime bulk substance, microcrystalline cellulose, L-HPC and polyvinylpyrrolidone were weighed and mixed together, 50% aqueous ethanol was added, and the mixture was granulated. The granulation product was dried under flowing air at 0 C for 17 hours and then sized using a 500-p.m sieve. The granules sieved out were mixed with magnesium stearate, light anhydrous silicic acid, strawberry flavor and the granulated saccharin calcium prepared in Example 1 (not less than 150 p.m in particle size) and the resultant mixture was compressed on a single-punch tablet machine to give tablets having the same composition as that in Example 1 (Table 8).

Example 8 According to the formulation shown below, cefdinir-containing tablets were produced in the same manner as in Example 7.

Table 9

S

5* 5* 5550

*SS.

0 Micronized cefdinir bulk substance Microcrystalline cellulose (Avicel PH101)

L-HPC

(LH-21) Polyvinylpyrrolidone (Kollidon Light anhydrous silicic acid (Aerosil) Magnesium stearate Saccharin calcium (not less than 150 pm in particle size) Strawberry flavor Total 306.8 mg (300 mg potency) 29.2 mg 29.2 mg 3.7 mg 0.9 mg 4.4 mg 15.0 mg 5.6 mg 394.8 mg H:\OPER\MJCactam divl.doc-25/100o -17- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

S

S

S

*S

Claims (1)

18- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A synthetic sweetener selected from the group consisting of saccharin or a salt thereof, and cyclamic acid or a salt thereof, wherein said synthetic sweetener is produced by wet granulation or dry granulation, and has a mean particle size of not less than 150 um. 2. A synthetic sweetener as claimed in claim 1, wherein the particle size is not less than 150 -tm. 3. A granulated synthetic sweetener which comprises a synthetic sweetener, and light anhydrous silicic acid and/or hydrated silicon dioxide. 4. A granulated synthetic sweetener which comprises a synthetic sweetener as claimed in claim 1 or claim 2 and light anhydrous silicic acid and/or hydrated silicon dioxide. 5. A synthetic sweetener according to claim 1 or a granulated synthetic sweetener S. 15 according to claim 3 or claim 4 substantially hereinbefore described with reference S. to the examples. DATED this 17 th day of April, 2003 Fujisawa Pharmaceuticals By DAVIES COLLISON CAVE S* Patent Attorneys for the Applicants