US20020064561A1

US20020064561A1 - Quick release compositions

Info

Publication number: US20020064561A1
Application number: US09/446,957
Authority: US
Inventors: Patricia-Ann Truter; Emilia Dilova; Thilo Van Der Merwe
Original assignee: Individual
Current assignee: University of the Witwatersrand, Johannesburg
Priority date: 1997-07-01
Filing date: 1998-07-01
Publication date: 2002-05-30
Anticipated expiration: 2018-07-01
Also published as: GB2342044B; GB2342044A; CH694573A5; JP2002507982A; WO1999001108A1; AU8805298A; US6416787B1; GB9929823D0

Abstract

A dosage form comprises a porous extrudate. The extrudate is obtained by extruding, at elevated temperature, a composition comprising a starch, water, a thermostable enzyme, and a pharmaceutically active agent. The porous extrudate is capable of disintegration when exposed to an aqueous environment.

Description

THIS INVENTION relates to a quick-release composition. In particular, it relates to a method of making a water-dispersable composition, to an extrudable composition and to a dosage form suitable for the quick delivery in an aqueous environment such as the mouth, of an adjunct such as a medicine, flavourant, or the like.

According to a first aspect of the invention there is provided a method of making a water-dispersable composition, the method including

admixing together a polysaccharide, an enzyme capable of splitting the polysaccharide into smaller portions thereof, and a liquid, to form an admixture;

extruding the admixture at an elevated temperature to form an extrudate; and

cooling the extrudate, with the liquid evaporating from the extrudate as it cools, thereby forming a porous composition capable of disintegration when exposed to an aqueous environment.

The water-dispersable composition may be a quick-release composition, and may thus be capable of rapid disintegration when exposed to an aqueous environment.

By “quick-release composition” is meant a composition which will disintegrate rapidly, i.e. within 2 minutes when saturated with water; and the constituents, and the proportions thereof, should be selected by routine experimentation, to achieve this object,

According to a second aspect of the invention, there is provided a method of making a water-dispersable quick-release composition, the method including

extruding an at least partially destructurised starch at an elevated temperature in the presence of a blowing agent to form an extrudate; and

cooling the extrudate to form a porous composition capable of rapid disintegration when exposed to an aqueous environment.

The at least partially destructurising of the starch may be by means of the elevated temperature at which the extrusion is effected, by means of an enzyme capable of splitting the starch, by means of an acid or a base, or by a combination of two or more of these methods. The partially destructurised starch may be in admixture with a pharmaceutically active agent or an adjunct. The blowing agent may be water.

The method may include admixing a pharmaceutically active agent into the admixture prior to or during the extrusion of the admixture.

Cooling the extrudate may include allowing the extrudate to cool at room temperature.

The method may include admixing an adjunct, such as a flavourant or the like, into the admixture prior to or during the extrusion of the admixture. More particularly, the adjunct may be selected from the group consisting of a flavourant, a preservative, an anti-oxidant, a surfactant, a colouring agent, a pH modifier, a sweetener, a taste masking agent, a plasticizer, a porosity modifying agent, or two or more thereof. The flavourant, when present, may be a mint flavourant, a lemon flavourant, an orange flavourant, a caramel flavourant, a vanilla flavourant, or the like. The pH modifier, when present, may be citric acid, tartaric acid, or the like. The taste masking agent, when present, may be sodium bicarbonate, an adsorbate, or the like. The plasticizer, when present, may be soya bean oil, polyethylene glycol, polyoxyethylene mono stearate, a light mineral oil, or an at least partially hydrated vegetable oil.

The polysaccharide may be starch and the liquid may be water, which may act as a blowing agent. The enzyme may be of the type which requires an aqueous environment to render it capable of splitting the starch.

The method may include cutting the extrudate, eg with a die face cutter, to provide discs or tablets or rods of the quick-release composition.

The starch and the enzyme may be initially present in the admixture, in a mass ratio of starch:enzyme from 10000:1 to 10:1. Preferably, the mass ratio of the starch to the enzyme in the admixture is from 10000:3 to 100:1, and most preferably, the mass ratio of the starch to the enzyme in the admixture is from 10000:5 to 1000:5.

The starch may be selected from the group consisting of corn starch, rice starch, wheat starch, oat starch, potato starch, or two or more thereof.

The water may be added to the admixture during the extruding by means of a pump. The water and starch may be initially present, in the admixture, in a mass ratio of water:starch of 20:80 to 55:45. Preferably, the initial mass ratio of the water to starch in the admixture is from 20:80 to 50:50, and most preferably, the initial mass ratio of the water to starch in the admixture is from 20:80 to 40:60, e.g. 30:70.

The polysaccharide or starch forms a carrier or excipient for the adjunct, and the carrier may also include sweeteners, e.g. sugars such as sucrose, dextrose, galactose and lactose. The sweetener may also be aspartame. Thus, the method may include adding a sugar to the admixture.

The enzyme is preferably a thermostable enzyme, such as the enzymes available in South Africa under the trade names THERMAMYL 120L and THERMAMYL 60 DT available from Enzymes South Africa (Proprietary) Limited, and manufactured by Novo Industri A/S, Denmark.

The pharmaceutically active agent may be a drug, such as theophylline, prochlorperazine maleate, paracetamol, or loperamyd, a vitamin such as vitamin A, B, C, D or E, and/or a mineral salt, such as calcium lactate, calcium phosphate, magnesium carbonate or magnesium lactate. The pharmaceutically active agent may function as an antacid, an antidepressant, an antihypertensive, an antimigraine, a hormone, or a urinary agent. The adjunct may be micro-encapsulated, so that it is substantially water-insoluble but soluble in the gut of a mammal, to mask the taste of the adjunct.

The elevated temperature at which the extruding of the admixture may be effected is from 80° C. to 135° C., preferably from 90° C. to 120° C. and most preferably from 100° C. to 120° C., e.g. 110° C.

Typically, extrusion of the admixture is with a screw extruder such as a twin-screw extruder, having a screw speed of from 50 to 200 rpm. The die cutter typically has a cutter speed of from 20 to 100 rpm, eg from 50 to 80 rpm and a diameter size of from 2 to 8 mm.

According to a third aspect of the invention, there is provided an extrudable composition comprising, in admixture with each other, a polysaccharide, a blowing agent and an enzyme capable of splitting the polysaccharide into smaller portions thereof.

The polysaccharide may be starch and the blowing agent may be water. The admixture may include a pharmaceutically active agent.

The composition may include an adjunct, which may be as hereinbefore described.

The enzyme may be present in the admixture at a concentration of from 0.01 to 10% mom, based on the total admixture mass. Preferably, the concentration of the enzyme in the admixture is from 0.03 to 1% m/m, based on the total admixture mass, and most preferably, the concentration of the enzyme in the admixture is from 0.05 to 0.5% m/m, based on the total admixture mass, e.g. 0.1% m/m based on the total admixture mass.

The enzyme, starch and adjunct may be as hereinbefore described. The pharmaceutically active agent may be present in a concentration of up to 60% m/m, based on the total admixture mass.

The pharmaceutically active agent may be micro-encapsulated, so that it is substantially water-insoluble but dissolves when ingested by a mammal.

The admixture may include a sugar, such as dextrose, galactose and lactose or an artificial sweetener such as aspartame.

The invention extends to a dosage form obtained by extruding, at elevated temperature, an admixture comprising a pharmaceutically active agent and the extrudable composition as hereinbefore described.

The dosage form may have a diameter of from 5 to 10 mm and may comprise from 2 to 50 mg of the pharmaceutically active agent.

The pharmaceutically active agent may be as hereinbefore described.

The invention will now be described, by way of example, with reference to the following worked example.

EXAMPLE

2 kg of a polysaccharide in the form of AMYRAL corn starch of a moisture content of 10% by mass was mixed with 0.1% by mass (based on the corn starch) of THERMAMYL 120L enzyme, capable of splitting the polysaccharide molecules of the corn starch into smaller portions thereof, and immobilized on carboxy methylcellulose. The mixture also contained, based on the corn starch, 0.5% by mass soya bean oil as plasticizer, 10% by mass lactose for enhancing the porosity of the eventual product, and 10% by mass of a pharmaceutically active agent. [0036]
All the ingredients, with the exception of the enzyme, were premixed in a high-speed mixer for a period of 10 minutes, after which the enzyme was added thereto. The mixture was fed to a hopper of a twin-screw extruder having an extrusion screw speed of 200 rpm, a feed screw speed of 200 rpm and a moisture setting of 20% by mass (setting number 5 on the extruder) with a barrel temperature for the extruder of 110-120° C., and a die of 3 mm diameter. [0037]
An extrudate was obtained which was cut into pellets with a die face cutter, the cut pellets then being air red on a moving transport belt. The pellets were found to have a uniformly porous structure, and when inserted into the mouth were found to have a wetting, time of no more than a few seconds, and a disintegration time of slightly more than 1 minute. [0038]
It is an advantage of the invention, as exemplified, that the solubility. or dispersability of the dosage form in water can be tailor-made-for a particular purpose by the admixing of an enzyme with the starch, so that it can easily and rapidly disintegrate, in saliva in a person's mouth. It is a further advantage of the invention that the composition and dosage form are starch-based, and thus not animal-derived. It is yet a further advantage of the invention, as exemplified, that the porosity of the dosage form can be controlled by the addition of a porosity modifying agent such as lactose. [0039]

Claims

1. A method of making a water-dispersable composition, the method including

admixing together a polysaccharide, an enzyme capable of splitting the polysaccharide into smaller portions thereof, and liquid, to form an admixture;

extruding the admixture at an elevated temperature to form an extrudate; and

2. A method as claimed in claim 1, which includes admixing a pharmaceutically active agent into the admixture prior to the extrusion of the admixture.

3. A method as claimed in claim 1, which includes admixing a pharmaceutically active agent into the admixture during the extrusion of the admixture.

4. A method as claimed in any one of the preceeding claims, which includes admixing an adjunct into the admixture prior to the extrusion of the admixture.

5. A method as claimed in any one of claims 1 to 3 inclusive, which includes admixing an adjunct into the admixture during the extrusion of the admixture.

6. A method as claimed in claim 4 or claim 5, in which the adjunct is selected from the group consisting of a flavourant, a preservative, an anti-oxidant, a surfactant, a colouring agent, a pH modifier, a sweetener, a plasticizer, a taste masking agent, a porosity modifying agent, or two or more thereof.

7. A method as claimed in any one of the preceding claims, in which the polysaccharide is starch and the liquid is water, and wherein the enzyme is of a type which requires an aqueous environment to render it capable of splitting the starch.

8. A method as claimed in claim 7, in which the starch and the enzyme are initially present, in the admixture, in a mass ratio of starch:enzyme from 10000:1 to 10:1.

9. A method as claimed in claim 8, in which the mass ratio of the starch to the enzyme in the admixture is from 10000:3 to 100:1.

10. A method as claimed in claim 9, in which the mass ratio of the starch to the enzyme in the admixture is from 10000:5 to 1000:5.

11. A method as claimed in any one of claims 7 to 9 inclusive, in which the starch is selected from the group consisting of corn starch, rice starch, wheat starch, oat starch, potato starch, or two or more thereof.

12. A method as claimed in any one of claims 7 to 11 inclusive, in which the water and starch are initially present, in the admixture, in a mass ratio of water:starch of 20:80 to 55:45.

13. A method as claimed in claim 12, in which the initial mass ratio of the water to starch in the admixture is from 20:80 to 50:50.

14. A method as claimed in claim 13, in which the initial mass ratio of the water to starch in the admixture rom 20:80 to 40:60.

15. A method as claimed in any of claims 7 to 14 inclusive, which includes adding a sugar to the admixture.

16. A method as claimed in any one of the preceding claims, in which the enzyme is a thermostable enzyme.

17. A method as claimed in any one of the preceding claims, in which the elevated temperature at which the extrusion of the admixture is effected is from 80° C. to 135° C.

18. An extrudable composition comprising, in admixture with each other, a polysaccharide, a blowing agent and an enzyme capable of splitting the polysaccharide into smaller portions thereof.

19. A composition as claimed in claim 18, in which the polysaccharide is starch, the blowing agent is water, the enzyme is of a type which requires an aqueous environment to render it capable of splitting the starch, and wherein the admixture includes a pharmaceutically active agent.

20. A composition as claimed in claim 19, in which the enzyme is present in the admixture at a concentration of from 0.01 to 10% m/m, based on the total admixture mass.

21. A composition as claimed in claim 20, which the concentration of the enzyme in the admixture is from 0.03 to 1% m/m, based on the total admixture mass.

22. A composition as claimed in claim 21, in which the concentration of the enzyme in the admixture is from 0.05 to 0.5% m/m, based on the total admixture mass.

23. A composition as claimed in any one of claims 19 to 22 inclusive, in which the starch is selected from the group consisting of corn starch, rice starch, wheat starch, oat starch, potato starch, or two or more thereof.

24. A composition as claimed in any one of claims 19 to 23 inclusive, in which the admixture includes a sugar.

25. A composition as claimed in any one of claims 19 to 24 inclusive, in which the enzyme is a thermostable enzyme.

26. A composition as claimed in any one claims 19 to 25 inclusive, in which the water and starch are present, in the admixture, in mass ratio of water:starch of 20:80 to 55:45.

27. A composition as claimed in claim 26, in which the mass ratio of the water to starch in the admixture is from 20:80 to 50:50.

28. A composition as claimed in claim 27, in which the mass ratio of the water to starch in the admixture is from 20:80 to 40:60.

29. A composition as claimed in any one of claims 19 to 28 inclusive, which includes an adjunct selected from the group consisting of a flavourant, a preservative, an anti-oxidant, a surfactant, a colouring agent, a pH modifier, a sweetener, a taste masking agent, a plasticizer, a porosity modifying agent, or two or more thereof.

30. A composition as claimed in any one of claims 19 to 29 inclusive, in which the pharmaceutically active agent is present in a concentration of up to 60% m/m, based on the total admixture mass.

31. A composition as claimed in claim 30, in which the pharmaceutically active agent is micro-encapsulate, so that it is substantially water-insoluble but dissolves when ingested by a mammal.

32. A dosage form obtained by extruding, at elevated temperature, the composition of any one of claims 19 to 29 inclusive.

33. A dosage form as claimed in claim 32, which has a diameter of from 5 to 10 mm and comprises from 2 to 50 mg of the pharmaceutically active agent.

34. A dosage form as claimed in claim 32 or claim 33, in which the pharmaceutically active agent is present in a concentration of up to 60% m/m, based on the total mass of the dosage form.

35. A dosage form as claimed in any one of claims 32 to 34 inclusive, in which the pharmaceutically active agent is micro-encapsulated so that it is substantially water-insoluble but dissolves when ingested by mammal.

36. A method of making a water-dispersable quick release composition, the method including

cooling the extrudate to form a porous composition capable of rapid disintegration when exposed to a aqueous environment.

37. A method as claimed in claim 36, which includes at least partially destructurising the starch by means of an enzyme capable of splitting the starch.

38. A method as claimed in claim 36, which includes at least partially destructurising the starch by means of the elevated temperature at which the extrusion is effected.

39. A method as claimed in claim 36, which includes at least partially destructurising the starch by means of an acid or a base.

40. A method as claimed in any one of the preceding claim, in which the at least partially destructurised starch is in admixture with a pharmaceutically active agent.

41. A method as claimed in any one of claims 36 to 40 inclusive, in which the at least partially destructurised starch is in admixture with an adjunct selected from the group consisting of a flavourant, a preservative, an anti-oxidant, a surfactant, a colouring agent, a pH modifier, a sweetener, a plasticizer, a taste masking agent, a porosity modifying agent, or two or more thereof.

42. A method as claimed in claim 37, in which the blowing agent is water and wherein the enzyme is of a type which requires an aqueous environment to render it capable of splitting the starch.

43. A method as claimed in claim 42, in which the elevated temperature at which the at least partially destructurised starch is effected is from 80° C. to 135° C.

44. A method, as claimed in claim 1, substantially as herein described and illustrated.

45. An extrudable composition as claimed in claim 18, substantially as herein described and illustrated.

46. A dosage form as claimed in claim 32, substantially as herein described and illustrated.

47. A method as claimed in claim 36, substantially as herein described and illustrated.

48. A new method, composition or dosage form, substantially as herein described.