WO2001017503A2

WO2001017503A2 - Sugar compositions

Info

Publication number: WO2001017503A2
Application number: PCT/GB2000/003436
Authority: WO
Inventors: Martin John James; Christopher Heath; Hugh Richard Sistern
Original assignee: British Sugar Plc
Priority date: 1999-09-09
Filing date: 2000-09-07
Publication date: 2001-03-15
Also published as: GB9921335D0; GB2353933A; AU7023800A; WO2001017503A3

Abstract

The invention provides sugar compositions for tableting by direct compression, consisting essentially of a minor fraction by weight of a substantially amorphous particulate trehalose in combination with a major fraction of one or more substances that are not directly compressible to form tablets having high integrity. The invention also provides sugar compositions for tableting by direct compression comprising a minor fraction by weight of a substantially amorphous particulate trehalose, wherein said composition is substantially free of granulating agents or binders other than said trehalose. Preferably, the compositions consist primarily of a minor fraction of powdered trehalose and a major fraction of powdered sucrose. Preferably, the amorphous trehalose is a spray dried. Also provided are methods of manufacturing a tablet by direct compression of the compositions, and tablets obtainable thereby.

Description

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 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, for example its crystalline form and water of crystallisation.

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 such as lactose or AVICEL (Registered Trade Mark). The sugar may alternatively be combined with a directly compressible excipient. For example, a commercially available sugar composition that is said to be directly compressible comprises sucrose co-crystallised with 3% of maltodextrins, and is available from Domino Sugar Corporation (USA) under the Registered Trade Mark DI-PAC.

Trehalose (α-D-glucopyranosyl-α-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 drought-resistant plants. It can be manufactured by fermentation of certain strains of yeast. Trehalose is sweet- tasting, and has been suggested for use as a sweetener having reduced cariogenicity in chewing gum and the like. Trehalose is normally manufactured and used as the crystalline dihydrate.

The present inventors have found that not only is amorphous trehalose directly compressible in itself, but also that particulate compositions containing even a minor fraction of amorphous 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. The present inventors have found that compositions containing amorphous trehalose give substantially stronger tablets by direct compression than compositions containing only crystalline trehalose.

WO97/28788 describes tablets comprising various forms 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 compression, and optionally contain binders and granulating agents. 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 otherwise directly compressible, without the addition of binders or granulating agents.

WO98/05305 describes tablet dosage forms comprising clavulanic acid, amoxycillin, a trehalose excipient, and a binder. The trehalose excipient is said to confer greater stability on the active ingredients.

EP-A-0788791 describes the use of certain crystalline sugars and sugar alcohols in an amount of 0.02 to 40% by weight to improve the direct compression properties of effervescent tablet compositions. Data are presented for compositions containing maltitol. There is no suggestion to use an amorphous trehalose to improve direct compression properties.

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

The present invention also provides a sugar composition for tableting by direct compression, comprising a minor fraction by weight of a substantially amorphous particulate trehalose, wherein said composition is substantially free of granulating agents or binders other than said trehalose.

The minor fraction of amorphous particulate trehalose is preferably from 2% to 50% by weight of amorphous particulate trehalose based on the weight of the composition, more preferably from 5% to 40% by weight of amorphous particulate trehalose, still more preferably from 10% to 35% by weight of amorphous particulate trehalose, and most preferably from 15% to 30% by weight of amorphous particulate trehalose. Here and elsewhere in this specification, weight percentages are based on the dry weight of the whole composition.

The amorphous 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 crystallisation. Preferably, the sugar composition according to the present invention is substantially free of water other than water of crystallisation.

The particulate trehalose is amorphous, i.e. substantially non-crystalline 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. Preferably, the amorphous trehalose comprises spray-dried trehalose, and more preferably it consists essentially of the spray dried trehalose.

The sugar composition according to the present invention may further comprise a crystalline particulate trehalose. The crystalline trehalose may be anhydrous, or may comprise water of crystallisation, for example it may be crystalline trehalose dihydrate. Preferably, the crystalline trehalose is present in a smaller amount by weight than the amorphous trehalose. It has been found, surprisingly, that small amounts of crystalline trehalose added to the amorphous trehalose in these compositions improves the force-crushing strength of the resulting tablets. The sugar composition according to the present invention is suitable for 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 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 as described hereinafter, the resulting tablet may have a tablet crushing strength less than 5kPa when measured in accordance with Procedure 1 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 1000g.

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 invention provides pharmaceutical tablets that consist mainly of 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 amorphous 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 amorphous trehalose. Preferably, the one or more sugars are selected from the groups consisting of crystalline trehalose, sucrose, glucose (dextrose), fructose, maltose, lactose, sugar alcohols such as inositol or sorbitol, and mixtures thereof. Sucrose is especially preferred. 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 amorphous 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 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.

Preferably, the compositions according to the present invention comprise no more than 20% by weight, preferably no more than 10% by weight, more preferably no more than 2% by weight, and most preferably substantially no substances that can be tableted by direct compression, other than trehalose.

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 providing an aqueous solution or dispersion comprising trehalose, followed by spray-drying the aqueous solution or dispersion to provide the said sugar composition.

The aqueous solution or suspension may further comprise one or more of the other components of the composition according to the invention, whereby the composition is formed at least in part by co-spray-drying. Alternatively, particles of one or more of the other components of the composition according to the invention may be injected into the spray drying tower, whereby the amorphous spray-dried trehalose is coated onto the particles.

It has been found that such co-spray-dried compositions are especially suitable for direct compression to form tablets. The solution of trehalose for spray drying may be prepared by redissolving a solid trehalose in water. Alternatively, the solution may be made by an enzymatic process for the production of trehalose from starch, without intermediate isolation of a solid trehalose. Such solutions contain small amounts of other saccharides and by products that may further enhance the compression properties of the amorphous trehalose.

The present invention further provides a method of manufacture of a sugar composition suitable for tableting by direct compression, said method comprising coating a substantially amorphous trehalose onto particles of a second material that is not a binder or a granulating agent.

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 invention 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 350 MPa, more preferably from 60 Mpa to 120Mpa.

Finally, the present invention provides a directly compressed tablet comprising a minor fraction of substantially amorphous 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.

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 as follows.

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

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 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 dihydrate (30% w/w as anhydrous) and sucrose (70% w/w) were dissolved in deionised water to obtain 52% w/w solids at 40°C. The solution was spray dried using an inlet temperature of 215°C and an outlet temperature of 115°C. 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.

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 study 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.

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 Crushing 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 accuracy 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

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 1000g or more up to 3000g or more. The comparative tablets of Example 6 had fracture strengths much less than 10OOg.

Procedure 3 - Comparison of Crystalline and amorphous trehalose

Measurements of tablet crushing strength (CS) in Kp at increasing maximum average punch forces (MAPF) in kN were carried out in accordance with Procedure 1 for tablets made from pure crystalline trehalose dihydrate, pure anhydrous crystalline trehalose, and amorphous spray dried trehalose. A sample of the well known directly compressible material Fast Flow Lactose (FF Lactose) was included for comparison. The results were as set forth in Table 1 :

Table 1

It can be seen that the amorphous, spray-dried trehalose gives tablet crushing strengths substantially greater than those achieved with crystalline trehalose at intermediate and high tableting pressures. Indeed, the performance of the anhydrous trehalose is comparable to that of free flowing lactose, which is a well known directly compressible excipient.

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

Claims

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

2. A sugar composition for tableting by direct compression, comprising a minor fraction by weight of a substantially amorphous particulate trehalose, wherein said composition is substantially free of granulating agents or binders other than said trehalose.

3. A sugar composition according to claim 1 or 2 which comprises from 2% to less than 50% by weight of substantially amorphous particulate trehalose.

4. A sugar composition according to any preceding claim, wherein said composition comprises one or more sugars other than said amorphous trehalose.

5. A sugar composition according to claim 4, wherein said one or more sugars are selected from the group consisting of crystalline trehalose, sucrose, glucose

(dextrose), fructose, lactose, maltose, sugar alcohols, and mixtures thereof.

6. A sugar composition according to claim 5, wherein said one or more sugars other than said amorphous trehalose consists essentially of sucrose.

7. A sugar composition according to claim 5, wherein said one or more sugars other than said amorphous trehalose comprises crystalline trehalose.

8. A sugar composition according to any one of claims 4 to 7, wherein said one or more sugars other than said amorphous trehalose make up from 50% to

98% by weight of the compositions.

9. A sugar composition according to any one of claims 4 to 8, wherein at least 90% by weight of the composition consists of said amorphous trehalose and said one or more sugars other than said amorphous trehalose

10. A sugar composition according to any of claims 4 to 9, wherein the composition consists essentially of said amorphous trehalose and said one or more sugars other than said amoφhous trehalose.

11. A sugar composition according to any of claims 4 to 10, wherein said one or more sugars other than said amoφhous trehalose are powdered sugars.

12. A sugar composition according to any one of claims 1 to 11 , further comprising from 0.1 to 10% by weight of a flavouring agent.

13. A sugar composition according to claim 12, wherein said flavouring agent comprises a non-sugar sweetener.

14. A sugar composition according to any one of claims 1 to 13, further comprising from 0.1 to 10% by weight of a medicinal substance.

15. A sugar composition according to claim 1 which comprises no more than 20% by weight of substances that can be tableted by direct compression, other than trehalose.

16. A sugar composition according to any preceding claim, wherein the substantially amorphous trehalose comprises a particulate spray dried trehalose.

17. A method of manufacture of a sugar composition according to any one of claims 1 to 16, said method comprising providing an aqueous solution or dispersion of trehalose, followed by spray-drying the aqueous solution or dispersion to provide the said sugar composition.

18. A method of manufacture of a sugar composition according to claim 17, wherein said step of providing consists of providing a trehalose rich solution from the enzymatic production of trehalose by starch, without intermediate isolation of a solid trehalose.

19. A method of manufacture of a sugar composition suitable for tableting by direct compression, said method comprising coating a substantially amorphous trehalose onto particles of a second material that is not a binder or a granulating agent.

20. A method of manufacture of a tablet comprising the steps of: providing a sugar composition according to any one of claims 1 to 16; followed by directly compressing the sugar composition to form said tablet.

21. A method of manufacture of a tablet according to claim 20, wherein said step of directly compressing is carried out at a pressure of 40MPa to 350Mpa.

22. A compressed tablet comprising a minor fraction of substantially amorphous trehalose and substantially free from granulating or binding agents, wherein said tablet is obtainable by a process according to any one of claims 20 to 21.

23. A compressed tablet according to claim 22 which has a crushing strength, as measured by the method hereinbefore described as Procedure 1 , of at least 2 kiloponds (Kp).

24. A tablet according to claim 22 or 23, which has a fracture strength, as determined for a tablet of diameter 16mm and thickness 3mm by the method hereinbefore described as Procedure 2, of at least 1000 g.