GB2192128A - Production of pharmaceutical unit dosage forms - Google Patents

Abstract

A method for the production of composite dosage units, such as granules or tablets, containing one or more medicaments comprises the steps of (1) preparing as a workable paste, a first mixture of the medicament, a disintegrant and a water-protective agent such as light oil or isopropyl alcohol effective to prevent absorbtion of water by the mixture, (2) preparing also as a workable paste, a mixture of a carrier material such as micro-crystalline cellulose and water, (3) mixing the two pastes to form a heterogenous mixture, (4) forming this mixture into a shaped body such as an extruded rod or a moulded tablet, and (5) evaporating the protective agent from that body. The rod may be broken into identical lengths and treated to round off the ends. The dosage units are more quickly disintegrated and absorbed in gastric fluid, than convential tablets. <IMAGE>

Description

SPECIFICATION Production of composite units The invention relates to the production of substructured units, particularly units containing medicaments.

One known method for the formation of spherical granules containing medicaments comprises steps offorming a flowable paste of a composition consisting of, or including, one or more medicaments by adding a suitable liquid which is later eliminated. The flowable paste is extruded as a rod, and the rod is then broken up into segments.

While the segments are still soft, they are rounded off, e.g. "spheronized", to form spherical granules.

However, with this known method, the steps of extrusion and of rounding offthe segments tends to produce granules which are dense and of low porosity. When such granules have been subsequently dried and hardened, they do not efficiently disintegrate, or readily dissolve, when exposed to a suitable agent.

The object of the present invention is to provide a method forthe production of composite units, containing at least one medicament, and composite units prepared in accordance with that method, whereby granules obtained are given such a structure thatthey are more susceptible to disintegration and more rapid dispersion,andthus also the release by reaction or dissolution of an active ingredient or ingredients.

According to the present invention a method for the production of composite units in granularform comprises steps of: (i) preparing a mixture including at least one medicament, a protective agent, and optionally at least one other ingredient which may include a disintegrant, (ii) preparing a paste of a carrier material, (iii) mixing the protected medicament mixture and the carrier paste to form a second mixture, (iv) and forming the second mixture into shaped units, with elimination oftheprotective liquid, and hardening ofthe carrier paste, if necessary.

Themedicamentmixture may conveniently include a formulated powder mix of at least one medicament, and may include action-delaying constituents, as well as the disintegrant.

The protective agent is preferably a water-immiscible liquid which prevents the ingredients of the medicament mixturefrom absorbing waterfrom a paste ofcarrier material when wetted with water. This protective liquid could be a light oil of suitably low boiling point in orderthat it could be dried off later using heat. Using a water-immiscible liquid is preferred, because it better protects the disi nteg rant from ingress of water from the wet carrier paste. However, a water-miscible liquid, for example isopropyl alcohol, may be sufficiently protective.

The steps of mixing ofthe medicament mixture and carrier paste, and of forming the second mixture into a shaped product, may be combined in a single operation.

The disintegrant may be any substance which will swell when contacted by a reactant expected to be found atthe site of use, e.g. starch which will react with water to swell.

In a preferred method, the step of forming the second mixture into a shaped product involves extrusion of the paste mixture, and preferably into a rod.

For preparation of a medicamentfor internal use, the carrier ingredient may be micro-crystalline cellulose, for example that product known commercially underthe Trade Mark "AVICEL" and which when mixed in the proportion 1:1 with water forms an extrudable paste. When the paste is extruded, eg. as a rod, it can readily be broken down into granules.

The granules produced by breaking down ofthe rod may themselves be further shaped, for example by rounding off or "sphernnizing", to provide an acceptable readily-dispensable product.

The dry product,forexample in granularform, when exposed to a reactant, such as the contents of the gut, our solvent such as water, allows entry ofthe reactantfluid into the granule, so causing the disintegrant material to swell, thus breaking upthe granule and making the active medicament available to the surrounding fluid.

Extrusion of the mix of pastes may be carried out with known extruder apparatus by inserting the mix into the chamber of the extruder and forcing it out of a nozzle to provide a shaped product, e.g. a rod which can be usued to prepare spheronized granules.

An embodimentofthe method ofthe invention, and the product obtained thereby, are hereinafter particularly described with reference to the figures of the accompanying drawing, wherein Figure 1 shows the starting materials; Figure2 is a diagram of the sequence of method steps; Figure 3 is a representative cross-section of a composite unit obtained by the method of the invention.

Referring to Figure 1, there are shown the starting materials consisting, in this example, of (i) the medicament-containing powder, eg. a medical formulation, (ii) the disintegrant, such as starch, and (iii) the carrier material, such as "AVICEL".

The medicament-containing powderandthe disintegrant are already mixed, and are protected by the protective liquid, eg. a volatile oil in a quantity sufficient to form a workable paste.

The carrier material is mixed with water to form a workable paste.

Referring to Figure 2, the items (i)-(ii), and (iii), are directly mixed in a conventional mixer, eg. as currently used fortabletgranulation.

The mixture is then placed in an extruder, and is extruded as a rod having all of the three ingredient substances evenly distributed in accordance with their relative bulk.

The extruded rod is used to prepare granules, which may be spheronized.

There may be a further stage offinal drying,to drive off any remaining protective fluid and/or water remaining in the granules.

Figure 3 shows, on a very much enlarged scale, a cross-section through a finished granule. The main body of the granule consists of carrier material, within which is distribuited medicament containing a material in which are small portions of disintegrant.

When the granule is subjectto the action of a reactant, fluid or solvent, entry ofthefluid is allowed through the carrier material and so the disinegrant is caused to swell and release the medicamentto the surrounding reactantfluid.

The carrier material and/or other ingredient including the medicament itself may be rapidly leached out of the granule without the need for any disintegrantas such. This differs from the conventional granulation in thatthe medicament and/or other ingredients(s) are prevented from dissolving in or reacting with the granulating fluid by the protective liquid ingredient which is added first.

This protective liquid may be later removed by drying.

Using the present method, granulated product may then be filled into capsules or compressed into tablets using conventional methods. However, any granulation processes may be by-passed using the present invention. The paste containing carrier and medicament is volumetrically dispensed into a suitable moulding apparatus by extrusion or injection. Pressure is applied to the mould if needed to form a shaped product. This product, when ejected from the mould can be dried, perhaps with the aid of microwave heating, whilst still maintaining its shape. Thus, dosage units may be accurately and continuously reproduced withoutthe use of a conventional tableting press, buy which may be shaped to resemble conventional tablets for ease of ingestion in the case of use in humans.

Claims (18)

1. A method forthe production ofcomposite dosage units containing medicament, comprising steps of: (i) preparing a first mixture of: (a) medicament, and - (b) a protective agent effective to prevent absorbtion of water by the first mixture, (ii) preparing a paste of a carrier material and water, (iii combining the first mixture and the carrier paste to form a second mixture, (iv) forming the second mixture into a body of predetermined shape, (v) eliminating the protective agentfrom that body.

2. The method as claimed in Claim 1, wherein the forming of the second mixture into a body of predetermined shape comprises extruding the second mixture as a rod, and reducing the rod to granules.

3. The method as claimed in either of Claims 1 and 2, wherein the granules are treated to modify their shape.

4. The method as claimed in Claim 3, wherein the granules are made substantially spherical.

5. The method as claimed in Claim 1, wherein the forming ofthe second mixture into a body of predetermined shape comprises dispensing said mixture volumetrically into a mould.

6. The method as claimed in Claim 5, wherein pressure is applied to the mixture in the mould to produce a tablet.

7. The method as claimed in any one of Claims 1 to 6, wherein said first mixture includes a disintegrant.

8. The method as claimed in Claim 7, wherein the disintegrant is a substance which swel Is when contacted by a reactant encountered atthe site of use ofthe medicament

9. The method as claimed in Claim 8, wherein the disintegrant is starch.

10. The method as claimed in any one of Claims 1 to 9, wherein the protective agent is a water-immiscible liquid.

11. The method as claimed in Claim 10, wherein the protective agent is an oil of boiling point such that it can be eliminated by heating without detriment to the medicament.

12. The method as claimed in any one of Claims 1 to 9, wherein the protective agent is a water-miscible liquid.

13. The method as claimed in Claim 12, wherein the protective agent is isopropyl alcohol.

14. The method as claimed in any one of Claims 1 to 13, wherein the carrier member is micro-crystalline cellulose.

15. The method as claimed in any one of Claims 1 to 14, wherein steps (iii) and (iv) are carried out in a single combined operation.

16. The method as claimed in any one of Claims 1 to 15, including a further step of drying to eliminate, from the granules, any remaining protective agent and/orwater.

17. The method forthe production of composite dosage units containing medicament, substantially as described herein.

18. Composite dosage units, containing medicament, prepared in accordance with any one of Claims 1 to 17.