WO2001008665A1

WO2001008665A1 - Paracetamol controlled-release compositions

Info

Publication number: WO2001008665A1
Application number: PCT/EP2000/007282
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: ITMI991737A0; AU6831700A; IT1313589B1; ITMI991737A1

Abstract

Paracetamol 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

PARACETAMOL CONTROLLED-RELEASE COMPOSITIONS

Paracetamol, namely, N- (4-hydroxyphenyl) acetamide, is an analgesic — antipyretic drug active through the oral route .

Paracetamol has been commercially available for a long time as an analgesic and antipyretic drug m the form of conventional pharmaceutical compositions such tablets, drops, suppositories and the like. To date, no paracetamol controlled-release formulations have been disclosed.

Paracetamol slow- or controlled- release formulations would be desirable, m that the number of administrations could be reduced while maintaining the plasma concentrations of the drug within the therapeutical range. The controlled-release systems known up to now proved to be unsuitable for paracetamol, whose characteristics involve serious problems concerning the effectiveness of the formulations.

It has now been found that paracetamol 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) paracetamol, or a pharmaceutically acceptable salt thereof, as active ingredient, included m at least one fatty compound; b) a water-swelling hydrophilic polymer; c) suitable excipients. The fatty compound consists of high molecular weight hydrophobic compounds, preferably waxes, triglyceπds 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, celluloses 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 paracetamol 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 paracetamol and the fatty compounds to melt granula ion; 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 therapeutical requirements to meet.

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 :

Paracetamol 1,000 mg

Glycerol palmitoyl stearate 140 mg

High viscosity hydroxypropyl methylcellulose 200 mg

A melt granulation process is carried out in a high rate granulator, mixing paracetamol and glycerol palmitoyl stearate. 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 buffer phosphate pH = 5.8, 1000 ml, stirring rate 50 rpm, 37°C, UV detection at 290 nm.

Time (hour) (%) Released

I 25.80 2 45.89

3 54.40

4 58.30

5 61.39

6 64.02 7 66.39

8 68.16

9 69.78

10 71.24

II 72.63 12 74.00

13 74.96

14 76.01

15 77.00

16 77.94

Example 2 :

Each tablet contains:

Paracetamol 1,000 mg

Glycerol palmitoyl stearate 140 mg Hydroxypropyl methylcellulose low viscosity 200 mg

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

Time (hours) % Released

I 9.59 2 16.25

3 21.53

4 26.33

5 30.81

6 35.06 7 39.08

8 42.73

9 46.16

10 49.40

II 52.74 12 55.72

13 58.73

14 61.60

15 64.40

16 67.10

Example 3

Each tablet contains :

Paracetamol 1,000 mg

Glycerol palmitoyl stearate 140 mg Low viscosity hydroxypropyl methylcellulose 200 mg

Time (hours) (%) Released

I 10.40 2 17.31

3 22.69 ■

4 27.52

5 31.89

6 35.61 7 38.97

8 42.07

9 44.93

10 47.49

II 50.17 12 52.66

13 55.11

14 57.49

15 59.82

16 61.89

Example 4 :

Each tablet contains :

Paracetamol 1,000 mg

Glycerol palmitoyl stearate 150 mg Low viscosity hydroxypropyl methylcellulose 200 mg

Time (hours) % Released

I 9.16 2 14.44

3 18.52

4 22.01

5 25.06

6 27.96 7 30.59

8 33.19

9 35.60

10 37.95

II 40.35 12 42.72

13 45.15

14 47.68

15 50.30

16 52.80

Example 5 :

Each tablet contains :

Paracetamol 1,000 mg

Glyceryl Behenate 30 mg Hydroxypropyl methylcellulose high viscosity 200 mg

A melt granulation process is carried out in a high rate granulator, mixing paracetamol 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 buffer phosphate pH 5.8, 1000 ml, stirring rate 50 rpm, 37°C, UV detection 290 nm.

Time (hours) % Released

I 31.31 2 54.43

3 63.41

4 67.57

5 70.56

6 72.62 7 74.40

8 75.79

9 77.15

10 78.50

II 79.26 12 80.58

13 81.41

14 82.33

15 83.17

16 83.93 Example 6 :

Each tablet contains :

Paracetamol 1,000 mg

Glyceryl Behenate 50 mg Low viscosity hydroxypropyl methylcellulose 200 mg

The preparation procedure and the determination of thetro release were carried out as in Example 5.

Time (hours) % Released

I 13.05 2 20.38

3 26.05

4 30.71

5 34.92

6 38.47 7 41.98

8 45.57

9 49.64

10 54.30

II 59.22 12 64.08

13 68.66

14 72.33

15 75.62

16 78.40

Example 7 :

Each tablet contains:

Paracetamol 1,000 mg

Glyceryl Behenate 30 mg Low viscosity hydroxypropyl methylcellulose 200 mg Lactose SD 100 mg

Time (hours) % Released 1 16.90

2 30.27

3 47.81

4 62.87

5 74.95 6 83.10

7 89.18

8 93.14

9 94.81

10 95.45 11 95.81

12 96.04

13 95.83

14 96.00

15 96.04 16 95.69 Example 8 :

Each tablet contains :

Paracetamol 1,000 mg

Glyceryl Behenate 30 mg Low viscosity hydroxypropyl methylcellulose 200 mg

Time (hours) % Released

I 13.69 2 23.11

3 31.58 ■

4 39.40

5 46.57

6 53.04 7 58.90

8 64.86

9 70.36

10 73.86

II 77.70 12 80.70

13 83.96

14 86.89

15 89.97

16 92.88

Example 9 :

Each tablet contains :

Paracetamol 1,000 mg

Glyceryl Behenate 30 mg Low viscosity hydroxypropyl methylcellulose 200 mg Lactose SD 50 mg

Time (hours) % Released 1 13.45

2 23.91-

3 32.65

4 40.49

5 47.42 6 53.94

7 59.90

8 66.08

9 70.69

10 75.46 11 80.29

12 85.04

13 88.54

14 91.82

15 94.26 16 94.92 Example 10: Each tablet contains:

Paracetamol 1,000 mg

Glyceryl Behenate 30 mg Low viscosity hydroxypropyl methylcellulose 100 mg

Time (hours) % Released

I 15.82 2 26.35

3 35.11 ^■

4 43.02

5 50.59

6 57.82 7 65.14

8 71.10

9 76.11

10 80.43

II 84.08 12 86.54

13 88.83

14 90.84

15 92.89

16 94.37

Example 11 :

Each tablet contains :

Paracetamol 1,000 mg

Glyceryl Behenate 30 mg Low viscosity hydroxypropyl methylcellulose 200 mg

Lactose SD 50 mg

Anhydrous colloidal silica 6.50 mg

Magnesium stearate 13 mg

Cutina HR (Hydrogenated castor oil) 10 mg The preparation procedure and the determination of thetro release were carried out as in Example 5.

Time (hours) % Released

1 17.89

2 27.10 3 34.59

4 41.27

5 47.43

6 53.06

7 58.59 8 63.95

9 68.82

10 72.91

11 76.85

12 80.63 13 84.05

14 87.18

15 89.82

16 91.54 Example 12 : Each tablet contains:

Paracetamol 1,000 mg

Glyceryl Behenate 30 mg Low viscosity hydroxypropyl methylcellulose 193.5 mg

Lactose monohydrate 50 mg

Anhydrous colloidal silica 6.50 mg

Magnesium stearate 13.50 mg

Talc 6.50 mg The preparation procedure comprises a melt -granulation process in a high rate granulator, mixing paracetamol and glyceryl behenate. The resulting product is mixed with

HPMC, lactose and wet-granulated with water. The resulting granulate is tabletted after addition of silica, magnesium stearate and talc.

Time (hours) % Released

1 13.72

2 23.34

3 31.72 4 39.29

5 46.26

6 53.08

7 59.37

8 64.95 9 69.52

10 74.00

11 78.48

12 82.36

13 85.99 14 89.41

15 93.02

16 95.84

The determination of the in vitro release was carried out as in Example 5. Example 13 : Each tablet contains :

Paracetamol 1,000 mg Glyceryl Behenate 30 mg

Hydroxypropyl methylcellulose high viscosity 30 mg Low viscosity hydroxypropyl methylcellulose 120 mg Lactose SD 10 mg

The preparation procedure and the determination of the in vitro release were carried out as in Example 5. Time (hours) % Released

1 18.72

2 34.97

3 49.03 4 59.39

5 65.87

6 69.94

7 73.02

8 75.64 9 77.90

10 79.91

11 81.77

12 83.53

13 85.07 14 86.82

15 88.05

16 88.97 Example 14 :

Each tablet contains: Paracetamol 1,000 mg

Ethylcellulose 57 mg

Low viscosity hydroxypropyl methylcellulose 200 mg

A microencapsulation process is carried out with paracetamol and ethylcellulose, starting from an organic solution. The resulting product is 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 13.49

2 21.04

3 26.93 4 32.26

5 37.26

6 41.99

7 46.48

8 50.67 9 54.36

10 57.87

11 60.72

12 63.71

13 66.61 14 69.10

15 71.39

16 73.40

Example 15 :

Each tablet contains :

Paracetamol 1,000 mg

Ethylcellulose 57 mg Low viscosity hydroxypropyl methylcellulose 200 mg

Lactose 100 mg

The preparation procedure and the determination of thetro release were carried out as in Example 14.

Time (hours) % Released 1 66.22

2 82.16-

3 91.50

4 95.39

5 99.60 6 100.51

7 100.51

8 100.51

9 100.51

10 100.51 11 100.51

12 100.51

13 100.51

14 100.51

15 100.51 16 100.51

Claims

1. A controlled-release tablet comprising: a) paracetamol, 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 weight ranges from 5 to 50%.

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

8. A process for the preparation of controlled-release tablets as claimed in claim 1-7, comprising: a) incorporating paracetamol and a fatty compound by melt granulation or high pressure compression; b) mixing the fatty granulate obtained in a) with a hydrophylic 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) .