GB2353933A

GB2353933A - Compositions comprising trehalose for forming tablets

Info

Publication number: GB2353933A
Application number: GB9921335A
Authority: GB
Inventors: Martin John James; Christopher Heath; Hugh Richard Sistern
Original assignee: British Sugar PLC
Current assignee: British Sugar PLC
Priority date: 1999-09-09
Filing date: 1999-09-09
Publication date: 2001-03-14
Also published as: GB9921335D0; AU7023800A; WO2001017503A3; WO2001017503A2

Abstract

A sugar composition for tableting by direct compression comprises a minor fraction, preferably 10-35%, of particulate trehalose in combination with a major fraction of one or more substances, such as sugars other than trehalose, that are not directly compressible to form tablets having high integrity. The tablets may be used as a confectionary item or as a drug. The sugar may be one or more of sucrose, glucose (dextrose), fructose, lactose, maltose and sugar alcohols but is preferably sucrose. Preferably the one or more sugars other than trehalose make up from 50-98 % of the composition and in combination with trehalose make up at least 90% of the composition. The composition is preferably free of binders or granulating agents but may comprise 0.1-10% of a flavouring agent, such as a non-sugar sweetener, and/or comprise 0.1-10% of a medicinal substance. A preferred method of manufacture of the sugar composition comprises spray drying of the constituents or coating trehalose onto the major constituents followed by compression at 40-200 Mpa to give tablets with a crushing strength of at least 2 Kp (Kg force).

Description

2353933 SUGAR COMPOSITIONS The present invention relates to sugar

compositions for tableting by direct compression. The present invention also relates to the use of such compositions 5 in tableting, and to tablets obtainable by direct compression of such compositions.

Some materials do not readily form tablets by direct compression. That is to say, the materials in particulate or powdered form alone do not bind together sufficiently strongly when compressed to form marketable tablets. The degree of direct compressibility of a given substance depends on its chemical composition, and also on its physical form, e.g. crystalline form, water of crystallisation etc.

Many particulate -sugars, including powdered sucrose, are not directly compressible. Therefore, in order to form these materials into tablets they must first undergo granulation with granulating agents such as polyvinyl pyrrolidone, or else must be mixed with a binder or a directly compressible excipient. For example, a commercially available sugar composition that is said to be directly compressible comprises sucrose cocrystallised with 3% of maltodextrins, and is available from Domino Sugar Corporation (USA) under the Registered Trade Mark DI-PAC.

Trehalose (a-D-glucopyranosyl-a-D-glucopyranoside) is a naturally occurring, non-reducing disaccharide. It is found, for example, in the blood of insects, in fungi, in certain yeasts, and in certain droughtresistant plants. It can be manufactured by fermentation of certain strains of yeast. Trehalose is sweettasting, and has been suggested for use as a sweetener having reduced cariogenicity in chewing gum and the like.

The present inventors have found that not only is particulate trehalose directly compressible in itself, but also that particulate compositions containing even a minor fraction of trehalose are directly compressible, even if a major fraction of the compositions is composed of particulate materials that are not directly compressible, such as sucrose.

2 W097/28788 describes tablets comprising a major fraction of trehalose as a diluent or excipient. The resulting tablets can be used as vehicles for oral administration of therapeutic substances. The tablets may be produced by direct 5 compression. However, there is no suggestion that a minor fraction of particulate trehalose could be used to confer direct compressibility on sucrose or other substances that are not directly compressible.

Accordingly, the present. invention provides a sugar composition for 10 tableting by direct compression, comprising a minor fraction of particulate trehalose in combination with a major fraction of one or more substances that are not in themselves sufficiently directly compressible to form tablets having high integrity.

The minor fraction of particulate trehalose is preferably from 2% to 50% by weight of particulate trehalose based on the weight of the composition, more preferably from 5% to 40% by weight of particulate trehalose, still more preferably from 10% to 35% by weight of particulate trehalose, and most preferably from 15% to 30% by weight of particulate trehalose. 20 The particulate trehalose may have any particle size in the ranges conventionally used for tableting. Typically, the particulate trehalose is a powdered trehalose. Preferably, the trehalose is substantially free of water other than water of crystal I isation.

The particulate trehalose may be an amorphous, i.e. substantially noncrystalline as determined by X-ray diffraction. Amorphous trehalose can be formed, for example, by spray drying of an aqueous solution of trehalose, or by spinning trehalose in a candy floss type of machine.

The particulate trehalose may in the alternative be crystalline. The crystalline trehalose may be anhydrous, or may comprise water of crystallisation, 3 for example it may be crystalline trehalose dihydrate. However, the dihydrate is not preferred.

The sugar composition according to the present invention is suitable for 5 tableting by direct compression. Preferably, the sugar composition is substantially free of granulating agents such as polyvinyl pyrrolidone, gum acacia, dextrose, gelatin, starch and starch derivatives, gum tragacanth and the like. The sugar composition may contain other conventional tableting excipients and functional tableting components such as dispersants or disintegrants.

The sugar composition may also comprise conventional binders in order to improve the mouthfeel or other sensory attributes of tablets manufactured therefrom. - Suita.b-le binders include starch derivatives, gum acacia, dextrin, maltodextrin, carboxymethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, polyethylene glycol and the like. However, it should be noted that the presence of binders is not necessary in order to achieve a tablet having good integrity (fracture strength and crush strength) by direct compression when using the compositions of the present invention.

The sugar compositions according to the present invention comprise a major fraction of one or more substances that are not sufficiently directly compressible to form marketable tablets by direct compression alone. That is to say, materials which compact poorly and require high compression forces to produce relatively weak tablets. For example when 500mg of the material is tableted in a 12.5 mm die at 50MPa, the resulting tablet may have a tablet crushing strength less than 5kPa when measured in accordance with Procedure I below. Alternatively or additionally, when a 3mm thickness by 16mm diameter tablet of the material is prepared at 50Mpa pressure and tested in accordance with Procedure 2 below the tablet fracture strength is typically less than 1 000g.

Preferred substances for the major fraction include salts such as sodium chloride, certain pharmaceuticals such as ibuprofen and paracetamol, certain sugars, and mixtures thereof. For example, in certain preferred embodiments the 4 invention provides pharmaceutical tablets that consist mainly of the a pharmaceutical active ingredient with only a small amount of excipients. Preferably, such tablets contain at least 50%, preferably at least 60% by weight of the pharmaceutically active ingredients. A minor fraction of trehalose in such tablet compositions can greatly improve the properties of tablets obtained by direct compression.

Preferably, the major fraction comprises one or more sugars other than trehalose, and more preferably the major fraction comprises at least 50%, more preferably 75% and most preferably at least 90% by weight based on the weight of the minor fraction of one or more sugars other than trehalose. Preferably, the one or more sugars are selected from the groups consisting of sucrose, glucose (dextrose), fructose-, maltose, lactose, sugar alcohols such as inositol or sorbitol, and mixtures thereof. Preferably, the sugars comprise one or more powdered (icing) sugars, and more preferably the sugars consist essentially of powdered sugars.

It is a particular advantage of the present invention that the particulate trehalose can be used to achieve tableting by direct compression of particulate sucrose products that are otherwise not directly compressible to form tablets having high integrity.

Preferably, the major fraction makes up from 50% to 98%, preferably from 60% to 90%, more preferably from 65% to 85% of the sugar composition according to the present invention. Preferably, at least 90% by weight of the composition is made up of trehalose and one or more other sugars that are not directly compressible as hereinbefore defined, preferably sucrose. Most preferably, the composition consists essentially of trehalose and one or more other sugars that are not directly compressible as hereinbefore defined, preferably sucrose.

The sugar compositions according to the present invention are especially suitable for the manufacture of sweets, such as mints, by direct compression.

Accordingly, the sugar compositions according to the present invention preferably further comprise up to 10% by weight, preferably from 0.1 to 5% by weight, of a flavouring agent, preferably selected from the group consisting of honey, essential oils such as citrus, peppermint or eucalyptus, other flavours, acidulants such as 5 citric acid, acidity regulators, colorants, other food additives, and mixtures thereof.

The sugar compositions according to the present invention are also especially suitable for the manufacture of medicated sweets by direct compression. Accordingly, the- sugar compositions according to the present invention preferably further comprise up to 10% by weight, preferably from 0.1 to 5% by weight, of a therapeutic agent, which may preferably be selected from the group consisting of local anaesthetics such as diethyl ether, antiseptics such as trichlorophenol, antacids-such as calcium carbonate or sodium carbonate, anti foaming agents such as simethicone, dietary supplements such as ascorbic acid, and mixtures thereof.

In other preferred embodiments, the invention provides a low calorie sweetener tableting composition comprising an intense sweetener such as aspartame in combination with a bulking agent or a bulk sweetener such as a sugar which is not directly compressible and a minor fraction of trehalose to render the mixture directly compressible.

The present invention also provides a method of manufacture of a sugar composition according to the present invention, wherein the method comprises spray-drying an aqueous solution or dispersion comprising a minor fraction of trehalose and a major fraction of one or more substances that are not suitable for tableting by direct compression.

It has been found that such co-spray-dried compositions are especially suitable for direct compression to form tablets.

The present invention further provides a method of manufacture of a sugar composition according to the present invention, wherein the method comprises 6 coating a minor fraction of trehalose onto particles of a major fraction of one or more substances that are not suitable for tableting by direct compression.

The coating may, for example, be achieved by applying an aqueous solution of trehalose to the solid particles of the major fraction with stirring, followed by drying. Alternatively, the solid particles of the major fraction could be moistened, and then admixed with powdered trehalose. Preferably, the coating process takes place in a spray drier or fluidised bed, in which an aqueous solution of trehalose, or trehalose plus sugar or other non-directly compressible material, is sprayed onto particles of the major fraction and then dries on them to form a coating.

The present i nvention further provides a method of manufacture of a tablet comprising the steps of: providing a sugar composition according to the present invention; followed by directly compressing the sugar composition to form the tablet. The method preferably does not include any granulation step. Preferably, the sugar composition is substantially free of binders or granulating agents. Preferably, the step of direct compressing is carried out at a pressure of from 40 MPa to 200 MPa.

Finally, the present invention provides a directly compressed tablet comprising a minor fraction of trehalose, wherein the tablet is obtainable by a method according to the present invention.

Preferably, the tablet according to the present invention has a hardness, as determined by the method hereinafter described as Procedure 1, of at least 2 kiloponds (Kp), preferably at least 5 Kp, and more preferably at least 10 Kp.

Preferably, the tablet according to the present invention has a fracture strength, as determined for a tablet of diameter 16mm and thickness 3mm by the method hereinafter described as Procedure 2, of at least 1000 g, preferably at least 2000 g and most preferably at least 2500 g.

7 Certain embodiments of the present invention will now be described further with reference to the following examples.

Example 1

A sugar composition according to the present invention is prepared s follows.

Trehalose dihydrate was dissolved in demineralised water to 40% w/w as anhydrous at 40 OC. The solution was then spray dried using an inlet air temperature of 215 OC and an outlet temperature of 115 OC.

The resulting free-flowing powder having a water content of less than 4% was dry blended -in an amount of 19% w/w (based on the weight of the final composition) with 80% w/w of dry powdered sucrose and 1% w/w magnesium 15 stearate to give the tableting composition according to the present invention.

Example 2

The tableting composition of Example 1 was compressed to form tablets as follows.

Tableting was carried out on a Manesty F3 single punch tablet machine at a speed of 30-40 tablets per minute. The tablet diameter was 1 cm and the tableting force was 46 to 62 MPa. The flow of the composition was adjusted to give tablets approximately 3 mm thick.

The resulting tablets had excellent integrity and hardness. The appearance and sensory attributes of the tablets were typical of those desired for confectionery tablets, Example 3

A confectionery mint was prepared by direct compression, as follows.

A tableting composition was made up as described in Example 1, but with the components in the following proportions: 19.7% spray dried trehalose, 78.8% sucrose, 1% magnesium stearate, and 0.5% mint flavour. The composition was then pressed into tablets as described in Example 2.

The resulting tablets had excellent integrity and hardness. The appearance and sensory attributes of the tablets were typical of those desired for confectionery mints.

Example 4

An alternative method of preparing directly compressible tableting compositions was performed as follows.

Trehalose dihydrtae (30% w/w as anhydrous) and sucrose (70% w/w) were dissolved in deionised water to obtain 52% w/w solids at 400C. The solution was spray dried using an inlet temperature of 215'C and an outlet temperature of 11 50C. Sucrose was fed to the top of the tower around the spray nozzles so that it was coated with the trehalose/sucrose blend to give a final tableting composition of 20% w/w trehalose and 80% w/w sucrose. 20 Example 5 The tableting composition of Example 4 was compressed to form tablets as described in Example 2. The resulting tablets were similar to those obtained in Example 2.

Example 6 (comparative) A comparative experiment was carried out to sudy the tableting of sucrose by direct compression.

Comparative compositions were made up consisting of 99% w/w powdered sucrose with 1% w/w magnesium stearate, and 99% w/w particulate crystalline sucrose with 1 % w/w magnesium stearate. Attempts were then made to tablet these compositions by direct compression as described in Example 2.

9 It was found that very few tablets could be produced at all. Those tablets that could be produced were weak, with frequent occurrence of capping and delamination.

Procedure 1 - Measurement of Tablet Crushinq Strength Specimen tablets were prepared using the High Speed Compaction Simulator (EHS Testing Limited, Brierley Hill, West Midlands, UK) modified by the School of pharmacy and Chemistry, Liverpool John Moores University. The quantity of material required for each tablet (500mg) was separately manually loaded into the 12.5mm die. Tableting was carried out at a tableting speed of 300 mm/sec using various compaction forces. During compression, the punch load was monitored to an accu-racy of 0.05kN, For each tablet, 4096 measurements of compaction force for upper and lower punch were carried out.

The crushing strength of the resulting tablets was measured as the force required to fracture a compact in a diametrical compression test on a Schleuniger tablet hardness tester (Copley Instruments Limited, Nottingham, UK). Results were presented in Kiloponds (Kp), where 1 Kp=1 Kg force. It was found that the tablets in accordance with Example 2 of the present invention had crushing strengths in the range 5-20 Kp. The comparative tablets of Example 6 had a crushing strength of less than 2 Kp. Procedure 2 - Measurement of Tablet Fracture Strength 25 The tablet fracture strength is measured for a tablet of diameter 16mm and thickness 3mm, as follows. The method uses a three point rig (Micro Systems TX-TA2). Each tablet under test rests on a two supports spaced 10mm apart and a test probe impacts the top of the tablet midway between the supports to break the tablet. The probe speed during the test is 2 mm/second and the post-test speed is 10 mm/second. The trigger force is 5g and the probe travels 5mm once it has detected the force.

A peak positive force (the total force required to break the tablet) is calculated in grams.

The tablets made from compositions according to the present invention had fracture strengths of 1 OOOg or more up to 30OOg or more. The comparative tablets of Example 6 had fracture strengths much less than 1000g.

The above embodiments have been described by way of example only. Many other embodiments falling within the scope of the accompanying claims will 10 be apparent to the skilled reader.

Claims

1. A sugar composition for tableting by direct compression, comprising a minor fraction of particulate trehalose in combination with a major fraction of one or more 5 substances that are not directly compressible to form tablets having high integrity.

2. A sugar composition according to claim I which comprises from 2% to 50% w/w of particulate trehalose, preferably from 5% to 40% w/w of particulate trehalose, still more preferably from 10% to 35% w/w of particulate trehalose.

3. A sugar composition according to claim 1 or 2, wherein said major fraction comprises one or more sugars other than trehalose.

4. A sugar composition according to claim 3, wherein said one or more sugars are selected from the group consisting of sucrose, glucose (dextrose), fructose, lactose, maltose, sugar alcohols, and mixtures thereof.

5. A sugar composition according to claim 3 or 4, wherein said one or more sugars other than trehalose consist essentially of sucrose.

6. A sugar composition according to claim 3, 4 or 5, wherein said one or more sugars other than trehalose make up from 50% to 98%, preferably from 60% to 95%, more preferably from 65% to 85% of the compositions.

7. A sugar composition according to any one of claims 3 to 6, wherein at least 90% by weight of the composition consists of trehalose and said one or more sugars other than trehalose

8. A sugar composition according to any of claims 3 to 7, wherein the composition consists essentially of trehalose and said one or more sugars other than trehalose.

12

9. A sugar composition according to any of claims 3 to 8, wherein said one or more sugars other than trehalose are powdered sugars.

10. A sugar composition according to any one of claims 1 to 9, further 5 comprising from 0. 1 to 10% w/w of a flavouring agent.

11. A sugar composition according to claim 10, wherein said flavouring agent comprises a non-sugar sweetener.

12. A sugar composition according to any one of claims 1 to 7, further comprising from 0.1 to 10% w/w of a medicinal substance.

13, A method o - fmanufacture of a sugar composition, said method comprising providing an aqueous solution or dispersion of trehalose and one or more substances, followed by spray-drying the aqueous solution or dispersion to provide a sugar composition according to any one of claims 1 to 12.

14. A method of manufacture of a sugar composition, said method comprising coating trehalose onto particles of one or more substances that are not suitable for tableting by direct compression, to provide a sugar composition according to any one of claims 1 to 12.

15, A method of manufacture of a tablet comprising the steps of: providing a sugar composition according to any one of claims 1 to 12; followed by directly compressing the sugar composition to form said tablet.

16. A method of manufacture of tablet according to claim 15, wherein said sugar composition is substantially free of binders or granulating agents.

17. A method of manufacture of a tablet according to claim 15 or 16, wherein said step of directly compressing is carried out at a pressure of 40MPa to 20OMPa.

18. A compressed tablet comprising a minor fraction of trehalose and substantially free from granulating agents, wherein said tablet is obtainable by a process according to any one of claims 15 to 17.

19. A compressed tablet according to claim 18 which has a crushing strength as measured by the method hereinbefore described as Procedure 1, of at least 2 kiloponds (Kp), preferably at least 5 Kp, and more preferably at least 8 Kp.

20. A tablet according to claim 18 or 19, which has a fracture strength, as 10 determined for a tablet of diameter 16mm and thickness 3mm by the method hereinbefore described as Procedure 2, of at least 1000 g, preferably at least 2000 g and most preferably at least 2500 g.