WO2001008664A1

WO2001008664A1 - Acetylsalicylic acid controlled-release compositions

Info

Publication number: WO2001008664A1
Application number: PCT/EP2000/007277
Authority: WO
Inventors: Mauro Valenti; Flavio Fabiani
Original assignee: Farmaceutici Formenti S.P.A.
Priority date: 1999-08-03
Filing date: 2000-07-28
Publication date: 2001-02-08
Also published as: ITMI991738A1; IT1313590B1; AU6698300A; ITMI991738A0

Abstract

Acetylsalicylic acid (ASA) controlled-release oral solid formulations, prepared by subjecting to melt granulation the active ingredient with a fatty compound, then mixing the resulting granulate with a hydrophilic polymer and with conventional excipients.

Description

ACETYLSALICYLIC ACID CONTROLLED-RELEASE COMPOSITIONS

Acetylsalicylic acid (ASA) has been commercially available for a long time, as an analgesic and antipyretic drug, in the form of conventional pharmaceutical compositions such as tablets, drops, suppositories and the like. ASA slow- or controlled- release formulations would be desirable, in that the number of administrations could be reduced while maintaining the plasma concentrations of the drug within the therapeutical range.

It has now been found that ASA controlled-release formulations can be effectively and advantageously prepared by using a mixture of a water-swelling hydrophilic polymer with the active ingredient together with a lipophilic fatty compound .

Therefore the present invention relates to controlled- release tablets comprising: a) ASA, or a pharmaceutically acceptable salt thereof, as active ingredient, included in a fatty compound; b) a water-swelling hydrophilic polymer; c) suitable excipients.

The fatty compound consists of high molecular weight hydrophobic compounds, preferably waxes, triglycerids of long-chain fatty acids , vegetable or mineral oils, fatty acids, high molecular weight alcohols or glycols, the esters and ethers thereof . Compounds having melting point ranging from at least 30 to 150°C are preferably used. Glyceryl behenate is most preferred.

Examples of suitable hydrophilic polymers comprise polyethylene glycols, alginates, cellulose and derivatives

(ethers, esters, salts), acrylic acid polymers or co- polymers. Hydroxypropyl methylcellulose is most preferred.

The composition of the invention can further contain conventional excipients commonly used for the preparation of oral dosage solid forms.

Examples of these excipients comprise lubricants, diluents, coloring agents and the like.

Each tablet will typically contain 200 to 1500 mg of active ingredient. The percentage of fatty compound in the mixture with ASA will vary from about 2 to about 40% by weight, preferably from about 2 to 15% by weight.

The percentage of hydrophilic polymer will range from

5 to 50% on the active ingredient weight, preferably 10 to

40%. The invention also relates to multi- layer tablets, preferably double-layer ones, consisting of a controlled- release layer and a prompt-release layer.

The compositions of the invention can be prepared according to a process comprising: a) subjecting acetylsalicylic acid and the fatty compounds to melt granulation; b) mixing the granulate obtained in a) with a hydrophilic compound and with suitable excipients; c) tabletting the mixture obtained in b) . The melt granulation step is carried out by heating the mixture above the melting point of the fatty compound in a fluidized bed, in a static oven or in a conventional granulation device.

According to a preferred embodiment of the present invention, the above mentioned process comprises the further step of subjecting the mixture obtained in b) to either wet- or dry- granulation before the compression step c) . The tablets can be subjected to film-coating in order to provide taste-masking effects or to further increase the release characteristics.

The release characteristics of the composition can be varied by suitably adjusting the ratio of the fatty compound to the hydrophilic polymer.

An in vitro release can typically range from 6-8 up to 24 hours.

The compositions of the invention can therefore be administered twice or even once daily, depending on the desired therapeutical requirements.

The compositions of the invention are further characterized by remarkable stability, most likely due to the protective effect exerted by the fatty compound on the active ingredient .

The invention is described in greater detail in the following examples.

Example 1 :

Each tablet contains:

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Carbomers 50 mg

A melt granulation process is carried out in a high rate granulator, mixing ASA and glyceryl behenate. After that, the resulting granulate is mixed with the other excipients and tabletted. The in vitro release profile is illustrated in the following table. The test was carried out in water, 1000 ml, stirring rate 50 rpm, 37°C, UV detection at 300 nm.

Time (hour) (%) Released

I 5.48 2 14.07

3 23.14

4 32.08

5 41.81

6 52.91 7 69.13

8 82.88

9 92.48

10 99.75

II 104.26 12 106.31 Example 2 :

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Carbomers 100 mg

The preparation procedure and the determination of thetro release were carried out as in Example 1. Time (hours) % Released

I 6.91 2 19.98

3 36.18

4 56.39

5 81.43

6 98.70 7 106.36

8 109.37

9 109.49

10 108.81

II 109.68 12 109.55

Example 3 :

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Carbomers 100 mg

The preparation procedure and the determination of thetro release were carried out as in Example 1.

Time (hours) (%) Released

I 2.07 2 4.81

3 7.41

4 9.60

5 11.63

6 13.53 7 15.18

8 16.78

9 18.53

10 19.98

II 21.45 12 22.81

13 23.94

14 25.30

15 26.59

16 28.01

Example 4 :

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Hydroxypropyl methylcellulose high viscosity 300 mg

Time (hours) % Released

I 3.14 2 8.03

3 12.85

4 17.53

5 22.11

6 26.09 7 29.83

8 33.06

9 36.21

10 39.06

II 41.90 12 44.72

Example 5 :

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg High viscosity hydroxypropyl methylcellulose 200 mg

Time (hours) % Released 1 4.59

2 10.24 ^■

3 16.53

4 22.65

5 27.76 6 32.77

7 37.33

8 41.09

9 44.61

10 48.04 11 51.06

12 53.93

Example 6 :

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Low viscosity hydroxypropyl methylcellulose 200 mg

Time (hours) % Released

I 5.75 2 13.33

3 21.17

4 28.71

5 35.95

6 43.06 7 50.21

8 56.80

9 63.29

10 68.94

II 74.06 12 79.07

Example 7 :

Each tablet contains:

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Low viscosity hydroxypropyl methylcellulose 200 mg Lactose 100 mg

Time (hours) % Released 1 5.28

2 12.89 ■

3 20.45

4 27.75

5 34.81 6 41.56

7 48.03

8 54.21

9 60.69

10 66.53 11 72.11

12 77.25

13 82.41

14 86.67

15 90.81 16 93.72

Example 8 :

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Low viscosity hydroxypropyl methylcellulose 200 mg

Time (hours) % Released

I 6.40 2 13.49

3 20.89 ^■

4 28.16

5 35.32

6 42.41 7 49.40

8 56.48

9 63.62

10 70.25

II 76.32 12 82.41

13 87.71

14 92.74

15 97.10

16 100.98

Example 9 :

Each tablet contains:

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Lactose 100 mg

Low viscosity hydroxypropyl methylcellulose 200 mg Anhydrous colloidal silica 6 mg

Magnesium stearate 9 mg

Time (hours) % Released

1 7.33

2 19.01

3 30.90 4 42.69

5 53.35

6 62.86

7 70.18

8 75.86 9 80.26

10 84.13

11 87.23

12 90.02

13 92.23 14 94.26

15 96.15

16 97.22 Example 10: Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Lactose 100 mg

Low viscosity hydroxypropyl methylcellulose 100 mg The preparation procedure and the determination of thetro release were carried out as in Example 1.

Time (hours) % Released 1 11.21

2 33.76 ^■

3 59.16

4 75.79

5 84.72 6 90.44

7 95.29

8 98.55

9 100.45

10 102.49 11 103.31

12 104.29

13 105.41

14 106.02

15 106.45 16 106.85 Example 11:

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 50 mg Hydroxypropyl cellulose high viscosity 200 mg

Time (hours) % Released

I 3.97 2 8.45

3 11.93

4 15.04

5 17.78

6 20.01 7 22.18

8 24.15

9 26.07

10 27.62

II 29.15 12 30.91

Example 12 :

Each tablet contains:

Acetylsalicylic acid 1,000 mg

Ethylcellulose 33,5 mg Low viscosity hydroxypropyl methylcellulose 200 mg

A microencapsulation process is carried out with acetylsalicylic acid and ethylcellulose starting from an organic solution. The resulting product was mixed with the other excipients and tabletted. The determination of the in vitro release was carried out as in the above Examples .

Time (hours) % Released

1 6.95

2 15.54 3 22.81

4 28.74

5 34.09

6 38.90

7 43.60 8 48.01

9 52.47

10 56.83

11 61.32

12 65.56 13 70.03

14 74.78

15 79.44

16 84.21 Example 13 :

Each tablet contains :

Acetylsalicylic acid 1,000 mg

Ethylcellulose 33,5 mg Low viscosity hydroxypropyl methylcellulose 200 mg Lactose 100 mg

Anhydrous colloidal silica 8 mg

Magnesium stearate 15 mg

The preparation procedure and the determination of thetro release were carried out as in Example 12.

Time (hours) % Released

1 11.70

2 27.02

3 38.52 4 47.06

5 54.07

6 60.21

7 65.99

8 71.94 9 77.71

10 83.18

11 87.89

12 92.27

13 95.44 14 98.63

15 101.31

16 103.68 Example 14 : Each tablet contains :

Acetylsalicylic acid 1,000 mg

Glyceryl Behenate 60 mg Macrogol 200 mg

Microcrystalline cellulose 50 mg

Magnesium stearate 12 mg

1 3.36 ^•

2 6.88

3 9.56

4 12.02 5 14.68

6 17.18

7 19.59

8 21.83

9 24.27 10 26.53

11 28.97

12 31.38

13 34.05

14 36.79 15 39.58

16 42.39

Claims

1. A controlled-release tablet comprising: a) acetylsalicylic acid, or a pharmaceutically acceptable salt thereof, as active ingredient, together with a fatty compound; b) a water-swelling hydrophilic polymer; c) suitable excipients.

2. A controlled-release tablet as claimed in claim 1, wherein the fatty compound is selected from waxes, triglycerids of long-chain fatty acids, vegetable or mineral oils, fatty acids, high molecular weight alcohols or glycols, the esters and ethers thereof.

3. A controlled-release tablets as claimed in claims 1 or 2, wherein the hydrophilic polymer is selected from cellulose ethers and esters, alginates, acrylic acid polymers or copolymers, polyethylene glycols.

4. Controlled-release tablets as claimed in any one of claims 1 - 3 , wherein the fatty compound is glyceryl behenate and the hydrophilic polymer is hydroxypropyl methylcellulose .

5. Controlled-release tablets as claimed in any one of claims 1 - 4, wherein the percentage of fatty compound on the active ingredient weight ranges from 2 to 40%.

6. Controlled-release tablets as claimed in any one of claims 1 - 5, wherein the percentage of hydrophilic polymer on the active ingredient weighx ranges from 5 to 50%.

7. Controlled-release tablets as claimed in any one of claims 1 to 6, containing 1,000 mg of acetylsalicylic acid or a pharmaceutically acceptable salt thereof.

8. A process for the preparation of controlled-release tablets as claimed in claim 1-7, comprising: a) including acetylsalicylic acid and a fatty compound by melt granulation or high pressure compression; b) mixing the fatty granulate obtained in a) with a hydrophilic compound and suitable excipients; c) tabletting the mixture obtained in b) .

9. A process according to claim 8, comprising the further step of subjecting the mixture obtained in b) to either wet- or dry- granulation before the compression step c) .