WO1998005306A1

WO1998005306A1 - Controlled release tablet formulation of isosorbide-5-mononitrate

Info

Publication number: WO1998005306A1
Application number: PCT/IE1997/000055
Authority: WO
Inventors: Dermot Mccafferty
Original assignee: Cal International Limited
Priority date: 1996-08-02
Filing date: 1997-07-31
Publication date: 1998-02-12
Also published as: AU3861397A

Abstract

A controlled release tablet formulation of isosorbide mononitrate is formed by granulating ISMN with a solution of a polyvinylpyrollidone. The weight ratio of ISMN to water in the solution of granulating aid is from 6:1 to 1:1, preferably approximately 2:1. The dry granules are blended with a cellulose based controlled release agent, the weight ratio of ISMN to controlled release agent being 30:70 to 80:20, preferably approximately 3:2. A tablet is punched out on a 5.5 mm punch to fit a number one capsule which may also contain a second active such as a tablet of coated aspirin.

Description

CONTROLLED RELEASE TABLET FORMULATION OF ISOSORBIDE-5-MONONITRATE

It is well known that a variety of organic nitrates have been available, for some considerable time, to treat angina pectoris. These nitrates have been formulated in many different ways to provide clinical relief of angina. for example, glyceryl trinitrate has been formulated as a sublingual tablet, spray and as a transdermal patch. Modified-release oral preparation (tablets and capsules) have also been made using the longer-acting nitrates, isosorbide dinitrate and isosorbide mononitrate.

Isosorbide-5-mononitrate (ISMN) has been formulated in a number of different ways to allow either immediate release or controlled release of the drug. The use of controlled release has various advantages over immediate release dosage forms. For example, a controlled release system will provide a more uniform plasma concentration of a drug and will tend to avoid the peak and trough effects associated with immediate release dosage forms. The number of daily administrations is reduced with a concomitant increase in patient compliance. Gastrointestinal side-effects also tend to be reduced when taking a controlled release dosage form.

There are a number of different controlled release dosage forms available commercially. However, some of these are expensive to manufacture and can be difficult to swallow, particularly in elderly patients. Therefore, it would be of considerable clinical benefit to design a small diameter tablet that would be much easier for the patient to swallow. A further advantage of a small diameter tablet is that it could be conveniently placed in a No. 1 capsule in combination with another drug substance. This type of technology could also be used to reduce the size of many existing drug formulations. However, since many controlled release dosage forms contain comparatively large amounts of active ingredient it is often necessary to include large amounts of suitable excipients to achieve appropriate controlled release profiles. Clearly, this will tend to increase the size of the dosage form.

The purpose of the present invention is to formulate a controlled release tablet of ISMN, the diameter of which is less than 6 mm. This, in turn, will allow the tablet to be swallowed more easily and also allow the tablet to fit into a No. 1 capsule.. It is another objective of the invention to develop a controlled release formulation containing ISMN. However, due to the comparatively large amount of drug required for this -purpose, typically 60 mg , it is difficult to obtain such a tablet with a suitable controlled release profile due to the die fill required. Clearly, with die diameters less than 6 mm the volume available to receive the final formulation, before compression, is reduced. In practice, this can mean that not more than 140 mg of the final formulation can be filled into the die. However, it has been discovered, with the present invention, that, unusually, suitable controlled release profiles can be achieved using a total formulation weight less than 140 mg .

According to the invention, there is provided a controlled release tablet formulation of an isosorbide mononitrate comprising granules of isosorbide mononitrate and a controlled release agent wherein the weight ratio of isosorbide mononitrate to controlled release agent is from 30:70 to 80:20.

Preferably, the weight ratio of isosorbide mononitrate to controlled release agent is from 1:2 to 7:3. Ideally, the weight ratio of isosorbide mononitrate to controlled release agent is approximately 3:2. In a preferred embodiment of the invention, the controlled release agent is a cellulose-based controlled release agent, most preferably a Methocel™ release agent.

In the examples, we ha.ve used a cellulose based control release agent. From our experiments, we have found that various grades of Methocel give the control release characteristics required.

In one embodiment of the invention, the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a solution of a granulating aid, the weight ratio of isosorbide mononitrate to water in the solution of granulating aid being in the range of from 6:1 to 1:1. Preferably, the weight ratio of isosorbide mononitrate to water in the solution of granulating aid is in the range of from 2.4:1 to 1.5:1, ideally approximately 2:1.

In a preferred embodiment of the invention, the granulating aid is a polyvinylpyrollidone granulating aid, especially Kollidon™ 30.

In one embodiment of the invention, the formulation includes a lubricant in a weight ratio of lubricant to active and controlled release agent of less than 1:20. Preferably, the formulation includes a lubricant in a weight ratio of lubricant to active and controlled release agent of less than 1:100.

According to a particularly preferred embodiment of the invention, the weight of the tablet is less than 140 mg, most preferably approximately 100 mg. Most preferably, the size of the tablet corresponds approximately to a 5.5 mm punch.

The invention also provides a capsule incorporating a tablet of the invention. Most preferred is a No. l capsule.

The capsule may contain a second active ingredient, especially Aspirin which may be in the form of granules, coated granules and especially a tablet, preferably a coated tablet. Most preferably, the weight ratio of isosorbide mononitrate to Aspirin is from 1:5 to 3:2, preferably approximately 4:5.

According to another aspect of the ifivention, there is provided a method for formulating a controlled release tablet formulation of an active ingredient comprising the steps of :-

blending dry granules of isosorbide mononitrate with a controlled release agent in a weight ratio of isosorbide mononitrate to controlled release agent of from 30:70 to 80:20; and

tabletting the resultant mixture to form a controlled release tablet formulation of isosorbide mononitrate.

In a preferred embodiment of the invention, the weight ratio of isosorbide mononitrate to controlled release agent is from 1:2 to 7:3. Ideally, the weight ratio of isosorbide mononitrate to controlled release agent is approximately 3:2.

In a preferred embodiment of the invention the controlled release agent is a cellulose based controlled release agent, preferably a Methocel™ release agent. In one embodiment of the invention, the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a granulating aid and drying the granules thus formed. Preferably, the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a solution of a granulating aid, the weight ratio of isosorbide mononitrate to water in the solution of granulating aid being in the range of from 6:1 to 1:1, most preferably in the range of from 2.4:1 to 1.5:1, ideally approximately 2:1.

The active ingredient is preferably granulated with a solution of a granulating aid, typically a 10% aqueous solution of the granulating aid.

In one embodiment of the invention the active ingredient is granulated with from 15 to 50% w/w, most preferably 30 to 40% w/w of a granulating aid based on the weight of active ingredient.

In a preferred embodiment of the invention, the granulating aid is a polyvinylpyrollidone granulating aid, preferably Kollidon™ 30.

In one embodiment of the invention, the method includes the step of sieving the granules to obtain granules of a desired size. Ideally, the granules are sieved by passing the granules through a lOOOμm mesh screen.

In one embodiment of the invention, the dry granules are dry blended with the controlled release agent, preferably for at least ten minutes and usually for approximately fifteen minutes. In one embodiment of the invention, the method comprises the step, after blending, of adding a lubricant to the mixture prior to tabletting. Preferably, after addition of the lubricant the mixture is further blended prior to tabletting.

Typically, the lubricant is magnesium stearate. The weight ratio of the lubricant to active and controlled release agent is less that 1:10, typically 1:100 active and excipients.

Preferably, the tablets have a tablet weight of less than 140 mg, ideally approximately 100 mg or less.

Typically, the tablets are formed usirfg a 5.5. mm punch.

In a preferred embodiment of the invention, the active ingredient is isosorbide mononitrate.

The invention also provides a controlled release tablet whenever formed by the method of the invention.

The invention further provides a capsule incorporating a tablet of the invention. Preferably, the capsule is a number 1 size capsule.

The capsule may contain a second active ingredient which may be formed into a plug for placing into the capsule. In this case, the plug may be formed by mixing the second active with a plug forming agent, such as a cellulose based agent, preferably Avicel PH 101.

The second active ingredient may comprise or include Aspirin which may be in the form of granules, especially coated granules, or preferably a tablet, most preferably a coated tablet. Preferably, the weight ratio of the ISMN to coated Aspirin is from 1:5 to 3:2, most preferably approximately 4:5.

The invention will be more clearly understooα from the following examples.

Example 1

Isosorbide Mononitrate (ISMN) (600 g) was granulated with a 10% aqueous solution of Kollidon 30 and passed through a 1000 μm mesh. After drying the granules were passed through a 1000 μm mesh. Methocel K100 Premium (400 g) was dry blended with the ISMN granule-s for 15 minutes using a Y-cone blender. Thereafter, magnesium -stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg. Samples of tablets were assessed in vi tro using the rotating paddle standard dissolution apparatus (100 rpm) at a temperature of 37°C using HPLC grade water. A typical dissolution profile is shown in Fig. 1.

Kollidon 30 is a polyvinylpyrollidone granulating aid available from BASF.

Methocel K100 Premium is a cellulose-based coating agent available from COLORCON LIMITED.

Example 2

ISMN (600 g) was granulated with a 10% aqueous solution of Kollidon 30 and passed through a 1000 μm mesh. After drying the granules were then passed through a 1000 μm mesh. Methocel E10 Premium (400 g) was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg . Samples of tablets were assessed in vi tro using the rotating paddle standard dissolution apparatus (.100 rpm) at a temperature of 37"C using HPLC grade water. A typical dissolution profile is shown in Fig. 2. The three samples plotted indicate the reproducibility of these results.

Example 3

ISMN (600 g) was granulated with a 10% aqueous solution of Kollidon 30 and passed through- a 1000 μm mesh. After drying the granules were passed through a 1000 μm mesh. Methocel K15 Premium (400 g) was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg . Samples of tablets were assessed in vi tro using the rotating paddle standard dissolution apparatus ( 100 rpm) at a temperature of 37°C using HPLC grade water. A typical dissolution profile is shown in Fig. 1.

Example 4

ISMN (600 g) was granulated with a 10% aqueous solution of Kollidon 30 and passed through a 1000 μm mesh. After drying the granules were then passed through a 1000 μm mesh. Methocel K100 Premium (400 g) was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg . The formed tablet cores were placed into a No. 1 capsule to which was added 75 mg of aspirin granules which were coated .with ethylcel lulose . The latter was blended with Avicel PHlOl (40 mg) so that a plug could be formed to facilitate placement in the capsule. Sample of capsules were assessed in - vi tro using the rotating paddle standard dissolution apparatus (100 rpm) at a temperature of 37°C using HPLC grade water. Typical dissolution profiles are shown in Fig. 3. Two different capsules - capsules A ana B - formulated in the same way indicate the reproducibility of the results. The results for the ISMN core not contained in a capsule indicate that the capsule containing the ISMN tablet retards the release over the t-ablet not contained in a capsule. The aspirin data relate Co the release of aspirin from the capsule.

Avicel PHlOl is a pharmaceutical excipient available from FMC Corporation.

Example 5

ISMN (600 g) was granulated with a 10% aqueous solution of Kollidon 30 (210 ml). The resultant mixture was dried directly in a fluidised bed dryer. Thereafter, the granules were then passed through a 1000 μm mesh. Methocel K100 M Premium (400 g) was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to an average tablet weight of 103 mg . Samples of tablets were assessed in vi tro using the rotating paddle dissolution test (100 rpm) at a temperature of 37°C using HPLC grade water. A typical dissolution profile of the ISMN tablet is shown in Fig. 1. In vi vo assessment of the formulation was undertaken in six human volunteers. Plasma concentrations were monitored for a 30 hour period and the in vivo controlled release nature of the formulation is shown in Fig. 4. Typical particle size analysis (sieve method) is shown in Fig. 5.

Example 6

ISMN (600 g) was granulated with a 10% aqueous solution of Kollidon 30. After drying the granules were then passed through a 1000 μm mesh and. left overnight before further processing. Methocel K100 Premium (400 g) was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium -s-tearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg. The formed tablet cores were placed into a No . 1 capsule to which was added 75 mg of aspirin granules which were coated with ethylcellulose . The latter was blended with fastflo lactose (40 mg) so that a plug could be formed to facilitate placement in the capsule. Samples of capsules were assessed in vi tro using the rotating paddle standard dissolution apparatus ( 100 rpm) at a temperature of 37°C using HPLC grade water. A typical dissolution profile is shown in Fig. 6.

Example 7

Granular aspirin (750 g) was blended with Sta-Rx 1500 (50g) and stearic acid (15 g) and tabletted using 5.5 mm punches. The resultant tablets (average weight 81.5 mg ) contained 75 mg of aspirin. Tablets conformed to the B.P. specifications for uncoated tablets. Sta-Rx is available from Colorcon. Example 8

Aspirin tablets made according to Example 7 were film coated, 3% w/w of the tablet weight, using a cellulose based agent (Opadry) . The film coated tablets conformed to the B.P. specifications for coated tablets. Opadry is available from Colorcon.

Example 9

Aspirin tablets made according to Example 7 were enteric coated using methacrylic acid based polymers (Eudragit L) at a concentration of 5 mg cm^"* surface area of tablets. The coated tablets conformed to the B.P. specifications for enteric coated tablets. Eudragit ^*is available from Rohm.

The Aspirin tablets -formulated as described in Examples 7 to 9 may be placed in a number 1 size capsule with the isosorbide mononitrate tablets described in Examples 1 to 6 as an alternative to a plug of coated Aspirin.

Example 10

As for Example 5 except Eudragit NE30D was used for granulation instead of Kollidon 30. A typical in vitro dissolution profile (using the same conditions as in other Examples) is shown in Fig. 7.

This result indicates that while a polyvinylpyrollidone granulating aid is preferred, it may also be possible to use other granulating aids. The particular advantage of Eudragit NE30D is that it also functions partially as a control release agent. We have unexpectedly found that it is possible to formulate a relatively small tablet of ISMN with a suitable controlled release profile. The slow release agent is preferably cellulose-based and the weight ratio of ISMN to the agent is from 30:70 to 80:20, preferably 1:2 to 7:3 and, ideally, approximately 3:2. This opens up the possibility of an ISMN tablet with a much smaller relative size than has heretofore been possible. Thus, the tablet is much easier to take, and most importantly, can be fitted into a number 1 size capsule either alone, or, preferably in combination with a second active, especially aspirin, to provide a combined therapy in a single dose. Such a single dose is not only easier for a patient to take but has cons-iderable advantages for patient compliance.

It was observed that ISMN had to be granulated to obtain suitable flow properties; the crystal structure of the compound prevented uniform and consistent flow, for example, into a die of a tablet press. Unusually, for satisfactory granulation to occur, large proportions of granulating liquid were required. Typically these were 15-50% w/w based upon the weight of ISMN used; 30-40% w/w granulating liquid was particularly preferred. These amounts correspond to a weight ratio of ISMN to water in the solution of granulating aid in the range of 6:1 to 1:1, preferably 2.4:1 to 1.5:1. Particle size analyses (sieve method) indicated that the amount of liquid, used for granulation, had a critical effect on particle size distribution. Usually 10-15% liquid is sufficient to provide a satisfactory granulation; the addition of larger proportions of liquid, during a granulation process, will usually cause processing difficulties since the powder being granulated becomes over wet to form a sticky dough. Unusually, ISMN can be granulated, using large proportions of liquid, preferably water, without causing processing difficulties. There are marked differences in granule particle size distribution depending upon whether the ISMN has been granulated using normal quantities (10-20%) of liquid (Fig. 5) or what would normally be classified as excessive amounts of liquid (Fig. 5). As a result of this ISMN granulated with normal quantities of liquid will have a smaller granule size distribution and possess poor flow properties (Fig. 5). In contrast, when granulating with larger proportions of liquid (typically greater than 20% and preferably between 30-40%) the resultant granulation has an overall larger particle size distribution (as shown in Fig. 5₎ which not only flows very well but also compacts to form strong tablets with low friability.

It will also be appreciated that the controlled release tablet of the invention may be used alone. It is not essential that it is placed in a capsule either alone or with another active ingredient. Any suitable active ingredient or ingredients with or without Aspirin may be used in the capsule.

The invention is not limited to the embodiments hereinbefore described which may be varied in detail .

Claims

CLA I MS

1. A controlled release tablet formulation of isosorbide mononitrate comprising granules of isosorbide mononitrate and a controlled release agent wherein the weight ratio of isosorbide mononitrate to controlled release agent is from 30:70 to 80:20.

2. A controlled release tablet formulation as claimed in claim 1, wherein the weight ratio of isosorbide mononitrate to controlled release agent is from 1:2 to 7 : 3.

3. A controlled release tablet formulation as claimed in claim 1 or 2 , wherein the weight ratio of isosorbide mononitrate to controlled release agent is approximately 3:2.

4. A controlled release tablet formulation as claimed in any preceding claim, wherein the controlled release agent is a cellulose-based controlled release agent.

5. A controlled release tablet formulation as claimed in any preceding claim, wherein the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a solution of a granulating aid, the weight ratio of isosorbide mononitrate to water in the solution of granulating aid being in the range of from 6:1 to 1:1.

6. A controlled release tablet formulation as claimed in claim 5, wherein the weight ratio of isosorbide mononitrate to water in the solution of granulating aid is in the range of from 2.4:1 to 1.5:1.

7. A controlled release tablet formulation as claimed in claim 5 or 6, wherein the weight ratio of isosorbide mononitrate to water in the solution is approximately 2:1.

8. A controlled release tablet formulation as claimed in any of claims 5 to 7 , wherein the granulating aid is a polyvinylpyrollidone granulating aid.

9. A controlled release tablet formulation as claimed in any preceding claim, . including a lubricant in a weight ratio of lubricant to active and controlled release agent of less than 1:20.

10. A controlled release tablet formulation as claimed in any preceding claim, including a lubricant in a weight ratio of lubricant to active and controlled release agent of less than 1:100.

11. A controlled release tablet as claimed in any preceding claim, wherein the weight of the tablet is less than 140 mg .

12. A controlled release tablet as claimed in any preceding claim, wherein the weight of the tablet is approximately 100 mg.

13. A controlled release tablet as claimed in any preceding claim, wherein the size of the tablet corresponds approximately to a 5.5 mm punch.

14. A controlled release tablet formulation substantially as hereinbefore described with reference to the examples .

15. A capsule incorporating a tablet as claimed in any preceding claim.

16. A capsule as claimed in claim 15, wherein the capsule is a number 1 size capsule.

17. A capsule as claimed in claim 15 or 16 containing a second active ingredient.

18. A capsule as claimed in claim 17, wherein the second active ingredient is Aspirin.

19. A capsule as claimed in claim 18, wherein the Aspirin is in the form of granules*.

20. A capsule as claimed in claim 18, wherein the Aspirin is in the form of coated granules.

21. A capsule as claimed in claim 18, wherein the Aspirin in the form of a tablet.

22. A capsule as claimed in claim 18, wherein the Aspirin is in the form of a coated tablet.

23. A capsule as claimed in any of claims 18 to 22, wherein the weight ratio of isosorbide mononitrate to Aspirin is from 1:5 to 3:2, preferably approximately 4:5.

24. A capsule substantially as hereinbefore described with reference to the examples.

25. A method for formulating a controlled release tablet formulation of isosorbide mononitrate comprising the steps of:- blending dry granules of isosorbide mononitrate with a controlled release agent in a weight ratio of isosorbide mononitrate to controlled release agent of from 30:70 to 80:20; and

26. A method as claimed in claim 25, wherein the weight ratio of isosorbide mo.nomtrate to controlled release agent is from 1:2 to 7:3.

27. A method as claimed in claim 25 or 26, wherein the weight ratio of isosorbide mononitrate to controlled release agent is approximately 3:2.

28. A method as claimed in any of claims 25 to 27, wherein the controlled release agent is a cellulose- based controlled release agent.

29. A method as claimed in any of claims 25 to 28, wherein the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a granulating aid and drying the granules thus formed.

30. A method as claimed in claim 29 wherein the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a solution of a granulating aid, the weight ratio of isosorbide mononitrate to water in the solution of granulating aid being in the range of from 6:1 to 1:1.

31. A method as claimed in claim 30, wherein the weight ratio of isosorbide mononitrate to water in the solution of granulating aid is in the range of from 2.4:1 to 1.5:1.

32. A method as claimed in claim 30 or 31, wnerein the weight ratio of isosorbide mononitrate to water in the solution is approximately 2:1.

33. A method as claimed in any of claims 29 to 32, wherein the granulating aid is a polyvinylpyrollidone granulating aid.

34. A method as claimed in any of claims 25 to 33 , including the step of sieving the granules to obtain granules of a desired size,

35. A method as claimed in claim 34, wherein the granules are sieved by passing the granules through a lOOOμm mesh screen.

36. A method as claimed in any of claims 25 to 35, wherein the dry granules are dry blended with the controlled release agent for a period of at least 10 minutes .

37. A method as claimed in claim 36, wherein the dry granules are dry blended with the controlled release agent for a period of approximately 15 minutes.

38. A method as claimed in any of claims 25 to 37, including the step, after blending, of adding a lubricant to the mixture prior to tabletting.

39. A method as claimed in claim 38 wherein, after addition of the lubricant, the mixture is further blended prior to tabletting.

40. A method as claimed in claim 38 or 39, wherein the lubricant is magnesium stearate.

41. A method as claimed in any of claims 38 to 40, wherein the weight ratio of the lubricant to isosorbide mononitrate and controlled release agent is less than 1:10.

42. A method as claimed in claim 41, wherein the weight ratio of lubricant to isosorbide mononitrate and controlled release agent is approximately 1:100 or less.

43. A method as claimed in a-ny of claims 25 to 42, wherein the tablets have a tablet wfeight of less than 140 mg.

44. A method as claimed in claim 43, wherein the tablets have a tablet weight of approximately 100 mg .

45. A method as claimed in any of claims 25 to 44, wherein the tablets are formed using a 5.5 mm punch.

46. A method for formulating a controlled release tablet formulation of isosorbide mononitrate substantially as hereinbefore described with reference to the examples .

47. A controlled release tablet formulation of isosorbide mononitrate whenever formulated by a method as claimed in any of claims 25 to 46.

48. A capsule incorporating a tablet as claimed in claim 47.

49. A capsule as claimed in claim 48, wherein the capsule is a number 1 size capsule.

50. A capsule as claimed in claim 49, wherein the capsule contains a second active ingredient.

51. A capsule as claimed in claim 50, wherein the second active ingredient is Aspirin.

52. A capsule as claimed in claim 51, wherein the Aspirin is in the form of granules.

53. A capsule as claimed in claim 51, wherein the Aspirin is in the form of coated granules.

54. A capsule as claimed in claim 51, wherein the Aspirin is in the form of a tablet.

55. A capsule as claimed in claim 51, wherein the Aspirin is in the form of a coated tablet.

56. A capsule as claimed in any of claims 51 to 55, wherein the weight ratio of isosorbide mononitrate to Aspirin is from 1:5 to 3:2, most preferably approximately 4:5.