GB2328154A - A method of tabletting comprising forming a mixture, containing active agent & free-flowing ice particles, into a tablet & removing the ice from the tablet - Google Patents

Abstract

A method of tabletting which comprises admixing a pre-chilled amount of a powdered active agent with free-flowing ice particles, forming the resultant mixture into a tablet and thereafter removing ice from said tablet. Free-flowing ice particles are ice particles that are substantially non-cohesive. Such particles may comprise individual particles having a size less than 2000Á and can be made by allowing air having a high humidity content to flow in juxtaposition with a chilled surface, eg a metal plate. The method is useful for tabletting temperature and process sensitive materials such as biological and microbiological materials, e.g. bio-pharmaceuticals and micro-organisms, as well as other agents such as vitamins and flavouring agents.

Description

NOVEL DOSAGE FORM The present invention relates to a novel dosage form.

In particular, the present invention provides a method for forming powdered active agent into tablets.

Conventionally, active agents such, for example, as drugs are formed into unit dose tablets by charging the die cavity of a tabletting tool with an agglomerated mixture comprising said active agent and one or more excipients, and thereafter operating said tool to form the mixture into a compressed tablet.

This process has been successfully operated for many years in relation to drugs and other temperatureinsensitive materials that are synthesized by conventional chemical techniques. It has now been discovered however that the method is not ideally suited for the correct handling and processing of biopharmaceuticals that are arising from the emerging biotechnology industry, which biopharmaceuticals have relatively poor physical and chemical stability and are temperature sensitive. Problems, for example, are well known to be denatured at elevated temperatures.

It is an object of the present invention to provide an improved method for making tablets.

In particular, it is an object of the present invention to provide a method of tabletting unstable, temperature and/or process sensitive materials.

A specific object of the present invention is to provide a method of tabletting unstable, pharmaceutically-active agents.

According to one aspect of the present invention therefore there is provided a method of tabletting which comprises admixing a pre-chilled amount of a powdered active agent with free-flowing ice crystals, forming the resultant mixture into a tablet and thereafter freezedrying said tablet.

By free-flowing ice crystals is meant ice crystals that are substantially non-cohesive. Said free-flowing ice crystals may comprise individual ice particles having a size in the range 20 to 2000g or smaller. According to a particular aspect to the present invention, said free-flowing ice crystals may be made by causing or allowing air having a high humidity content to flow in juxtaposition with a chilled surface at a temperature in the range -5 to -900C, typically -20 to -300C, so that ice seeded on the surface grows as a crystalline matrix.

Said surface may be a surface of a metal plate. Said plate may be mounted substantially horizontally, so that the ice seeds grow downwardly on the underside of the plate.

Said mixture may be tabletted in a chilled tabletting tool.

The resulting tablet may be porous.

Said active agent may be selected from pharmaceutically active agent, biological and microbiological materials, vitamins and flavouring agents. It is envisaged that the method of the present invention will have broad application in tabletting any process or temperature sensitive material, and also more generally in place of existing tabletting processes for tabletting more stable materials.

In a particular aspect of the present invention, the active agent is a drug for human or veterinary use. Each tablet may comprise a unit dose amount of said drug.

Said drug may be selected from all major types of chemical categories and therapeutic classes of drugs, including peptides, oligopeptides, proteins, hormones, nucleic acids, polysaccharides, peptides with polysaccharide side chains, lipids, lipopolysaccharides, vaccines, vitamins and water soluble and insoluble drugs with a wide range of physico-chemical properties.

Said active agent may comprise micro-organisms.

Said powdered active agent and free flowing ice crystals may be further admixed with one or more excipients which, preferably, are also pre-chilled. Said excipients may be selected from binders, surfactants, fillers, colourings, preservatives, sweeteners, flavourings, lubricants and disintegrants. Any suitable excipients known to those skilled in the art may be used. By way of example said fillers may be selected from calcium sulfate, starch, calcium carbonate, microcrystalline cellulose, modified starches, lactose, sucrose, mannitol and sorbitol.

Said binders may be selected from starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.

Said disintegrants may be selected from starch, alginic acid, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isomorphous silicate and microcrystalline cellulose.

Typically, said tablet may comprise about 1 to 15%, preferably 3 to 5% by weight of the active agent, with the balance being excipients (excluding water).

According to another aspect of the present invention there is provided a tablet that is formed in accordance with the method of the present invention.

In yet another aspect of the present invention there is provided apparatus for making a tablet, which apparatus comprises ice-making means for making free-flowing ice crystals, mixing means for mixing said ice crystals with a pre-chilled active agent and optional excipients, tabletting means for forming said mixture into a tablet at low temperature and freeze-drying means for freezedrying said tablet.

Any suitable mixing means, tabletting means and freezedrying means known to those skilled in the art may be employed.

Said ice-making means may comprise a chilled surface and means for causing or allowing air having a high humidity content to flow in juxtaposition with said surface such that free-flow ice particles grow on said surface.

An advantage of the present invention is the ability to produce and deliver drugs with relative high water solubility in a single, stable freeze-dried dosage form, avoiding in a single step the natural physical phenomenon of freezing point depression of mixtures of substances in water which affects the effectiveness of conventional freeze-drying processes which give an unstable product.

This short-coming of the prior art techniques is overcome by post admixing of the chilled drug to the free-flowing ice particles prior to moulding.

Those skilled in the art will appreciate that the disintegration and dissolution properties of the tablet in accordance with the present invention can be varied according to the drug and excipients to be incorporated in the formulation.

The tablets of the present invention can be presented to the patient in variety of packaging formats, e.g in blister packs, bottles and moulded plastic containers.

Following is a description by way of example only of embodiments of the present invention.

Example 1 A metal plate is mounted horizontally in a freezer compartment and is chilled to a temperature of -20 to -300C. Air having a high humidity content is caused or allowed to flow adjacent the under-surface of the plate, with the result that ice seeded on the chilled plate grows downwardly as a crystalline or particle matrix.

The free flowing ice crystals or particles are then removed and mixed with pre-chilled drug powder, a binding agent and any required excipients in a low temperature environment to prevent melting of the ice, and whilst maintaining the crystalline structure and free-flowing properties of the ice-drug particle mixture.

The resulting mixture is then transferred to a chilled die tool and moulded to give a tablet which is then freeze-dried using conventional freeze-drying equipment.

The resulting unit is a dried tablet of the desired shape and physical characteristics which can be packed in primary packaging such as blister packs, bottles etc. and subsequently secondary packed in pouches, cartons or the like.

Claims (18)

1. A method of tabletting which comprises admixing a pre-chilled amount of a powdered active agent with freeflowing ice particles, forming the resultant mixture into a tablet and thereafter removing ice from said tablet.

2. A method as claimed in claim 1 wherein said freeflowing ice particles comprise individual ice particles having a size less than 200O.

3. A method as claimed in claim 1 or claim 2 wherein said free-flowing ice particles are made by causing or allowing air having a high humidity content to flow in juxtaposition with a chilled surface.

4. A method as claimed in claim 3 wherein the temperature of the chilled surface is in the range -5 to -196"C.

5. A method as claimed in claim 3 or claim 4 wherein said surface is a metal plate that is mounted substantially vertically, substantially horizontally, or at any angle therebetweXn such that the ice seeds grow on a vertical surface or on a downwardly facing surface.

6. A method as claimed in any preceding claim wherein the resulting tablet is porous.

7. A method as claimed in any preceding claim wherein said active agent is selected from pharmaceutically active agents, biological and microbiological materials, vitamins and flavouring materials.

8. A method as claimed in any preceding claim wherein the active agent is a drug for human or veterinary use.

9. A method as claimed in claim 8 wherein the tablet comprises a unit dose amount of said drug.

10. A method as claimed in any preceding claim wherein said powdered active agent and free-flowing ice particles are further admixed with one or more excipients which, preferably, are also pre-chilled.

11. A method as claimed in any preceding claim wherein the tablet comprises about 1 to 15% by weight of the active agent, with the balance being excipients (excluding water).

12. A tablet manufactured in accordance with the method as claimed in any preceding claim.

13. Apparatus for making a tablet, which apparatus comprises ice-making means for making free-flowing ice particles, mixing means for mixing said ice particles with a pre-chilled active agent and optional excipients, tabletting means for forming said mixture into a tablet at low temperature and drying means for removing said ice from said tablet.

14. Apparatus as claimed in claim 13 wherein said icemaking means comprises a chilled surface and means for causing or allowing air having a high humidity content to flow in juxtaposition with said surface, such that free-flowing ice particles grow on said surface.

15. A method as claimed in claim 1 or claim 2, wherein the ice is removed by freeze-drying the tablet.

16. A method as claimed in claim 1 or claim 2, wherein the ice is removed by catching the tablet with absolute ethanol at a temperature below O"C.

17. A method as claimed in claim 6, wherein the porosity of the tablet is controlled by controlling the particle size of the ice particles, and the ice/excipients content of the tablet.

18. A method as claimed in claim 1 or claim 2, wherein said free-flowing ice particles are made by spraying water in contact with liquid nitrogen.