GB2155330A - Solvent granulation technique for forming solid formulation of nystatin - Google Patents

Abstract

A method is provided for forming granules of nystatin from which nystatin is readily released wherein a mix is formed of nystatin, a binder and optionally other excipients, the mix is granulated in the presence of a solvent in which the binder is at least partially soluble, and the solvent is then removed leaving granules of nystatin. The so-formed granules containing nystatin may then optionally be mixed with one or more additional excipients and compressed to form tablets from which nystatin is readily released.

Description

SPECIFICATION Solvent granulation technique for forming solid formulations of nystatin and products produced thereby Field of the invention The present invention relates to a method for preparing granules of nystatin for use in forming nystatin tablets from which nystatin is readily released employing a solvent or aqueous granulation technique, and to granules and tablets produced thereby.

I Background of the invention Until now, nystatin tablets have been formed by granulating nystatin together with desired excipients until granules of a desired average particle size are obtained, coating the nystatin granules with a solution of binder in an appropriate solvent, drying to remove solvent, and then compressing the granules coated with binder into tablets.

Although nystatin tablets produced by the above technique have enjoyed widespread use, it has been found that, as in the case of any successful product or drug, any improvements thereon would be most welcome by the medical community and the public in general. An area where nystatin tablets might be improved upon is in the release of nystatin from the tablets into the gastro-intestinal tract Summary of the invention In accordance with the present invention, a method is provided for forming granules containing nystatin from which nystatin is readily released, which method includes the steps of forming a mixture of nystatin, binder, and optionally one or more pregranulation excipients, granulating the mixture with a solvent in which the binder is at least partially soluble, to form granules containing nystatin, and then drying the granules to remove solvent therefrom. The invention also provides nystatin granules having binder at least partially coated thereon and having an average particle size of less than about 1000 microns, which readily release nystatin.

By mixing a binder into the pregranulation mix as a dry powder, it is possible to achieve a very good distribution of binder which, when granulating solvent is added, results in particle to particle bonding producing a more porous weak granule than normal. This granule will then readily deaggregate to release primary particles of nystatin. The conventional method of granulation in which a binder is dissolved in granulating solvent and this solution used to densify and agglomerate the granulation mix, requires longer mixing and massing times than employed in the method of the present invention and results in less porous granules which are less likely to deaggregate when required.

Description of preferred embodiments In forming tablets from the so-formed granules, the granules may optionally be mixed with one or more postgranulation excipients and the mixture may then be compressed into tablets.

It has been found that the so-formed tablets easily disintegrate and deaggregate in vitro into very small granules or particles equivalent in size to the particles originally used to form them (primary particles).

Since nystatin is very poorly water soluble, dissolution is likely to take place principally by deaggregation of primary drug particles. Therefore, deaggregation into primary particles is of importance to ensure that a suitable therapeutic response is achieved in vivo.

This action is accomplished, at least in part, through the use of a relatively weak binder and/or undergranulation as will be explained hereinafter.

After tabletting, it is found that the binder is sufficient to hold or bond granules of nystatin to one another yet, upon ingestion, readily deaggregate to release nystatin into the gastro-intestinal tract.

Thus, a balance is struck between using minimum but sufficient amounts of weak binder to achieve tablet structure and integrity without locking the nystatin into the tablet. In accordance with the present invention, a a tablet will have acceptable nystatin release characteristics, if it returns rapidly to the particle size of the nystatin used in its formation.

Acceptable nystatin release from tablets is also obtainable through undergranulation, that is where, during the solvent granulation step, a minimal amount of solvent is employed (that is a ratio of binder to solvent of from about 1:20 to 1:5 and preferably about 1:10, and/or massing or kneading of nystatin powder blend is carried out only for a relatively short period of time (for example, about 15 minutes or less) so that there is minimal contact between solvent and binder coated on the nystatin granules. In this way, it is assured that the binder will not bond particles of nystatin too strongly to one another and thus will not inhibit deaggregation and therefore release of nystatin.

Generally, the granulating solvent will be employed in a weight ratio to the nystatin of within the range of from about 1:1 to about 1:4, and preferably from about 1:2.

As indicated, the binder should be at least partially soluble in the solvent for example, a solubility of at least about 20 mg/ml at 28"C, and preferably a solubility of from about 100 to about 200 mg/ml at 28"C.

The binder will be employed in a weight ratio to the nystatin of within the range of from about 1:25 to about 1:6 and preferably about 1:15. As indicated, where a binder solution is employed in excess amounts or where the binder solution is too concentrated, the granules forming the nystatin tablet may be too strongly adhered to one another and as a result lock in the nystatin so that it will not be readily released upon ingesting. However, a sufficient amount of binder is necessary to ensure the structural integrity of the final tablet, as will be apparent to one skilled in the art.

In the final nystatin tablet produced from compressing nystatin granules prepared by solvent granulation, the nystatin will be present in an amount within the range of from about 20 to about 60% by weight, and the binder will be present in an amount within the range of from about 3 to about 75%, and preferably from about 3 to about 5% by weight, all of the above % being based on the weight of the final granulation excluding any protective and/or polished coating applied thereon.

During the solvent granulation step, nystatin together with binder and any pregranulation excipients will be granulated to achieve an average particle size of less than 1000 microns.

Examples of solvents suitable for use herein include, but are not limited to, water and/or an alcohol, such as methanol, ethanol, isopropyl alcohol, chloroform, methyl chloroform, 1,1-dichloroethane, 1,2- dichloroethane, 1,1,1 -trichloroethane, carbon tetrachloride and the like.

Examples of typical binders which may be employed herein will depend upon the solvent employed and include, but are not limited to, corn starch, lactose, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and/or corn starch being employed when water is used as the solvent, and any of the other binders where an alcohol or other non-aqueous liquid is used as the solvent.

Pregranulation excipients which may be employed herein include various conventional ingredients, such as one or more diluents or fillers present in an amount within the range of from about 10 to about 90% by weight of the total solids, such as lactose, wood cellulose such as microcrystalline cellulose, (for example, marketed underthetrademarkAVICEL PH101), mannitol, sugar, calcium carbonate, magnesium carbonate, barium sulfate, diatomaceous earth, kaolin, calcium sulfate dihydrate and/or corn starch; disintegrants present in an amount of within the range of from about 2 to about 10%, such as starch, modified cellulose gum, (for example, marketed under the trademark AC-DI-SOL), coloring such as any of the various F.D. & C.

colors, and/or other conventional excipients.

Postgranulation excipients which may be added to the nystatin granules before tabletting include further amounts of disintegrant, for example, within the range of from about 2 to about 5% by weight of the nystatin granules, flow-lubrication aids, for example, within the range of from about 0.25 to about 1% of tablet of the nystatin granules, such as talc, magnesium stearate, stearic acid, palmitic acid, calcium stearate, carnauba wax or the like. Silica flow conditioners or glidants may also be included.

Afterthe granules of nystatin are formed as described above, the granules are dried as, for example, by fluid bed drying, tray drying, or microwave. The dry granules are then compressed into tablet form which can take any of the conventional shapes, for example, round, elongated, oval, square, cylindrical, flat face, triangular, spherical, capsule shape, heart shape, and the like. Atablet press fitted with suitably sized punches and dies are used to form a tablet core of any desired weight, shape and composition. A protective coating or film may then be applied over the tablet core employing conventional coating procedures and materials.

The following Examples represent preferred embodiments of the present invention. Unless otherwise indicated, all temperatures are expressed in degrees Centigrade.

EXAMPLE 1 Nystatin tablets having the following composition were prepared as described below.

Quantity/ tablet Total in Ingredient (mug) batch rkgJ Nystatin (sufficient to supply 111* 49.73 500,000 units per tablet and a 20% excess) Lactose (filler) 301 135.5 weak binder Corn starch 43.5 12.78 Talc (flow agent) 2.7 1.22 Magnesium stearate (lubricant) 2.3 1.04 Purified water (solvent) q.s. ** 28 liters * calculated at a potency of 5430 units/mg ** removed by drying A nystatin granulation was prepared by passing lactose (135.5 kg) and above one-third of the corn starch (12.78 kg) through a 20 mesh sieve. The sieved powders together with the nystatin (49.73 kg) were transferred to a Fielder PMA 600 Pharmatrix mixer/granulator and the mix was mixed for 2 minutes.

Solvent granulation was then carried out as follows. About 10 liters of purified water was added to the above mixture and the new mixture was mixed for 3 minutes. This procedure was repeated until a fine granular mass having an average particle size of about 1000 microns was achieved. The quantity of water required was in the order of about 14% w/w of the dry weight.

The resulting damp mass was transferred to a fluid bed drier and the mass was dried at 30 to 50"C for about 30 minutes.

The dried nystatin granules were then passed through a Jackson Crockatt granulator and a Russel Finex vibratory sifter fitted with a 20 mesh screen.

Three additional granulations were prepared as described above.

Corn starch (27.2 kg) and 4.66 kg talc were first passed through a 20 mesh screen and transferred with 4 batches of the nystatin granules to a Lodige FKN 3000D blender and mixed therein for 5 minutes.

Magnesium stearate (4.14 kg) which was initially passed through a 40 mesh screen, was added to the Lodige blender and the mixture was further mixed for 1 minute. The resulting final mix was then transferred to a rotary tablet making machine fitted with 7/16 inch concave tooling and was compressed into tablet cores.

The nystatin tablet cores were then coated by applying a shellac seal coat via conventional sugar coating techniques.

The resulting nystatin tablets when dissolved in water were found to readily disintegrate and deaggregate into granules of average particle size of about 5-10 microns of nystatin equivalent to the original particle size of the nystatin used in its composition, thereby providing the maximum surface area for subsequent solution.

EXAMPLE2 Nystatin granular formulations having the following composition and nystatin tablets containing same were prepared as described below.

Quantity/ tablet Total in Ingredient (mgj batch Rkg) Nystatin (sufficient to supply 250,000 units per tablet and a 10% excess) 50.14* 60.77 Microcrystalline cellulose (AVlCELPHlO1) (filler) 41.36 49.63 Modified cellulose gum (disintegrant) 5.0 6.0 Polyvinylpyrrolidone (Plasdone) (binder) 3.0 3.6 Ethyl alcohol * calculated at a potency of 5430 units/mg ** removed by drying A nystatin granulation was prepared by passing modified cellulose gum (AC-DI-SOL, 6 kg), polyvinylpyrrolidone and microcrystalline cellulose (AVICEL) (49.63 kg) through a 20 mesh sieve. The sieved powders together with the nystatin (60.77 kg) were transferred to a Fielder PMA 600 Pharmatrix mixer/granulator and the mix was mixed for 2 minutes.

Solvent granulation was then carried out as follows. About 15 liters of ethyl alcohol was added to the above mixture and the new mixture was mixed for 3 minutes. This procedure was repeated until a fine granular mass was achieved having an acceptable consistency. The quantity of ethyl alcohol required was in the order of about 50% w/w of the dry weight.

The resulting damp mass was transferred to a fluid bed drier and the mass dried at 30 to 500C for about 10-15 minutes.

The dried nystatin granules were then passed through a Jackson Crockatt granulator and a Russel Finex vibratory sifter fitted with a 20 mesh screen.

A second granulation was prepared as described above.

Modified cellulose gum (26 kg) was first passed through a 20 mesh screen and transferred with the nystatin granules and a total of 720 kg tetracycline granulations to a Lodige FKN 3000D blender and mixed therein for 5 minutes. Magnesium stearate (5 kg) which was initially passed through a 40 mesh screen, was added to the Lodige blender and the mixture was further mixed for 1 minute. The resulting final mix was then transferred to a Manesty RD3 tablet making machine fitted with 7/16 inch concave tooling and was compressed into tablet cores.

The nystatin tablet cores were then coated by applying a shellac seal coat via conventional liquid sub-coating techniques.

The resulting nystatin tablets when dissolved in water were found to readily disintegrate and deaggregate into granules of average particle size of about 5-10 in 30-60 minutes indicating that nystatin is readily released from the tablets.

Claims (21)

1. A method for forming granules of nystatin from which nystatin is readily released, which comprises forming a mix of nystatin, dry binder, and optionally one or more pregranulation excipients, granulating said mix in the presence of a solvent in which the binder is at least partially soluble, to form granules of nystatin and then drying said granules to remove said solvent.

2. The method as defined in claim 1 further including the step of optionally mixing said dry granules of nystatin with one or more postgranulation excipients.

3. The method as defined in claim 1 or 2 wherein sufficient binder is employed to at least partially coat the granules of nystatin.

4. The method as defined in claim 1 or 2 wherein the binder is employed in a weight ratio to nystatin of within the range of from about 1:25 to about 1:6.

5. The method as defined in any preceding claim wherein the solvent is employed in a weight ratio to nystatin of within the range of from about 1:1 to about 1:4.

6. The method as defined in any preceding claim wherein the granules of nystatin have an average particle size of less than about 1000 microns.

7. The method as defined in any preceding claim wherein said solvent is water, an alcohol, chloroform, methyl chloroform, 1,1 -dichloroethane, 1 2-dichloroethane, 1,1,1 -trichloroethane or carbon tetrachloride.

8. The method as defined in claim 7 wherein said solvent is methanol, ethanol or isopropyl alcohol.

9. The method as defined in any preceding claim wherein said binder is corn starch, lactose, polyvinyl-pyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose.

10. The method as defined in any one of claims 1 - 7 wherein the solvent is water and the binder is corn starch, lactose or a mixture thereof.

11. The method as defined in any one of claims 1 - 7 wherein the solvent is ethanol, water or a mixture thereof, and the binder is polyvinylpyrrolidone.

12. The method as defined in any preceding claim wherein the pregranulation excipients include one or more fillers, optionally one or more disintegrants, optionally one or more colors, or mixtures thereof.

13. The method as defined in claim 2 wherein the postgranulation excipients include optionally one or more disintegrants, optionally one or more colors, optionally one or more flow-lubrication aids or mixtures thereof.

14. The method as defined in claim 12 wherein the pregranulation excipients include as fillers, lactose and/or microcrystalline cellulose, and as disintegrants, starch and/or modified cellulose gum.

15. The method as defined in claim 13 wherein the postgranulation excipients include magnesium stearate as a flow-lubrication aid.

16. Nystatin granules having binder at least partially coated thereon and having an average particle size of less than about 1000 microns, which readily release nystatin.

17. Nystatin granules prepared by the process as defined in any one of claims 1 - 15.

18. A method for forming nystatin tablets from which nystatin is readily released in the stomach and/or gut, which comprises mixing nystatin, dry binder and optionally one or more pregranulation excipients to form a nystatin-binder mix, granulating said mix in the presence of a solvent in which said binder is at least partially soluble to form granules of nystatin, drying said granules to remove said solvent, optionally mixing said granules with one or more postgranulation excipients, and compressing said granules into tablets from which nystatin is readily released.

19. A nystatin tablet which readily releases nystatin in the stomach and/or gut prepared by the process as defined in claim 18.

20. A nystatin granular formulation substantially as described in Example 1 or 2.

21. A nystatin tablet substantially as described in Example 1 or 2.