WO1995007082A1

WO1995007082A1 - A combination tablet comprising acetylsalicylic acid and a process for the preparation thereof

Info

Publication number: WO1995007082A1
Application number: PCT/HU1994/000043
Authority: WO
Inventors: Pál FEKETE; Mária Király; Ágnes VOGT; György UJFALUSSY; Magdolna GÓRA; Erzsébet Bárczay; Sándor DRABANT; Mária SOMOGYI; Blanka Lady; Gábor Sipos
Original assignee: EGIS Gyógyszergyár Rt.
Priority date: 1993-09-10
Filing date: 1994-09-09
Publication date: 1995-03-16
Also published as: AU7791394A; HUT72408A; HU9302561D0

Abstract

The invention refers to a tablet containing acetylsalicylic acid, paracetamol and caffeine as the active ingredients in admixture with the pharmaceutical carriers. The important features of the invention are that the binding agent is poly(vinyl butyral) and the disintegrating agent is hydroxypropyl cellulose of low substitution degree (LHPC). The tablet of the invention has increased stability even after prolonged storage.

Description

A COMBINATION TABLET COMPRISING ACETYLSALICYLIC ACID AND A PROCESS FOR THE PREPARATION THEREOF

The invention refers to a combination tablet comprising acetylsalicylic acid, para¬ cetamol (4-hydroxyacetanilide) and coffein (1 ,3,7-tri ethylpurine-2,6(lH,3H)-dione) and a process for the preparation thereof.

The decomposition of acetylsalicylic acid in pharmaceutical compositions has been generally known and studied in the last decades in detail. Although a part of the studies has dealt with the decomposi¬ tion kinetics of acetylsalicylic acid in aqueous medium, the stability of acetylsalicy¬ lic acid in tablets and the factors influencing the stability have been treated by the greatest number of publications. In case of solid dosage forms such as tablets, the decomposition i.e. hydrolysis of acetylsalicylic acid takes place in the water film adhering to the surface of the acetylsalicylic acid particles. The rate of hydrolysis is influenced by the amount of water present, the pH and the temperature (J. of Pharm. Sci., 1979/2 68, 197-202). The rate of hydrolysis is higher at higher humidity and temperature. Provided that other ingredients influencing the pH are not present in the solid dosage form, the pH of the water film is determined by the pH of the acetylsalicylic acid that dissolves in the water film (about pH 2). It is to be noted that at the latter pH value the decomposition rate of acetylsalicylic acid is the lowest (J.Am.Chem.Soc. , 79, 3401, 1957).

The interactions between acetyl¬ salicylic acid and various pharmaceutical carriers have been also studied in detail. Thus, it was stated that the hydrolysis rate of acetylsalicylic acid is considerably higher in the presence of alcohols and carriers containing hydroxy groups, respectively. Consequently, acetylsalicylic acid is not compatible with poly(ethylene glycol) or surface active agents prepared by the conden¬ sation of poly(ethylene glycol) or cellulose ethers containing hydroxy groups. According to the investigations, the decomposition of acetylsalicylic acid is also considerably accelerated by magnesium stearate that is widely used in tablets as a lubricant. Experience has shown that the decomposition rate of acetylsalicylic acid has been also higher in combination compositions. It is known that the decomposition of acetylsalicylic acid is distinctly promoted by paracetamol that is widely employed in combination compo¬ sitions (Chemical Stability of Pharmaceuticals. John Wiley and Sons, New York, 1979, pages 151 to 160).

The above conclusions are also reflected by the quality requirements re¬ ferring to pharmaceutical compositions com- prising acetylsalicylic acid. Thus, in the United States' Pharmacopoeia, XXII Edition, having the strictest prescriptions, the highest allowable amount of free salicylic acid indicating the decomposition rate is 1 per cent in case of tablets or capsules comprising only acetylsalicylic acid. However, in case of coated or enterosolvent tablets or combination compositions, the presence of 3 per cent of free salicylic acid is allowable, thus, it is admitted that in the latter cases it is more difficult to insure the stability of acetylsalicylic acid.

The above knowledge involves the measures that can contribute to the preparation of acetylsalicylic acid tablets having suit¬ able stability. Thus, the following measures are to be taken: the moisture content of the tablet should be as low as possible; the lowest possible sorts of carrier should be used;

-carriers producing the elevation of the microenvironmental pH should be avoided,*

-carriers absorbing the moisture from the surface of the acetylsalicylic acid particles, thus, reducing the width of the water film on the surface of the particles can be used with advantage.

On basis of literature data, the stability of the acetylsalicylic acid can be improved as follows:

The decomposition rate of acetyl¬ salicylic acid can be reduced by using 1 to 5 per cent of colloidal silica, the optimum amount being about 3 per cent (J. Pharm. Sci. , 1979, 111 197-202).

A stable two- or multilayer tablet comprising acetylsalicylic acid and paracetamol is described in Japanese Kokai Tokkyo Koho 80 47,618. One of the layers contains acetyl¬ salicylic acid and talc, while the other layer contains paracetamol, coffein, ethene amide, starch, talc and magnesium carbonate.

A two-layer tablet of improved stability is described in Japaneses Kokai Tokkyo Koho, 81 77,223. One of the layers contains acetylsalicylic acid, the other layer contains a water absorbing substance such as silica gel.

Tablets comprising acetylsalicylic acid are prepared by compressing a mixture consisting of 80 per cent of acetylsalicylic acid and 20 per cent of potato starch (Sci. Techn. Pharm., 1975 4/6/ 369-70).

Stabilized coated tablets comprising either acetylsalicylic acid or both acetyl¬ salicylic acid and coffein are prepared in US-P No. 4,716,042. The decomposition of acetylsalicylic acid is reduced by the addition of citric acid, alginic acid, glutamic acid or mixtures thereof.

Two-layer tablets having capsule shape are described in CA-P No. 1 220 209. One of the layers contains acetylsalicylic acid, while the other layer contains a mixture of magnesium carbonate and calcium carbonate.

The stability of acetylsalicylic acid granules having a coating that dissolves only in the intestine could be improved by the addition of glutamine hydrochloride according to US-P No. 4,900,599.

Vehicles used widely in tablets such as lactose, calcium hydrogen phosphate or microcrystalline cellulose were investigated as to their effect on the decomposition of acetylsalicylic acid, and it was stated that under normal storage they influenced adversely the decomposition of acetylsalicylic acid, with the exception o f lactose. However, at higher temperature or relative humidity during storage, even lactose produced a higher decomposition rate (Acta Pharm. Sued.,

Thus, the state of art indicates that the stability of tablets comprising acetylsalicylic acid has not been achieved satisfactorily, although the above compound has been used as a drug for more^' than hundred years. This statement is especially true in case of combination tablets wherein the spatial separation of acetylsalicylic acid from the other active ingredients i.e. the accomodation thereof in separate layers has been suggested (Japan Kokai Tokkyo Koho 80 47,618). Of course, such a manufacturing process can be performed, but it is sig¬ nificantly more complicated than the prepara¬ tion of usual tablets consisting of only one layer.

Thus, in case of combination tablets comprising acetylsalicylic acid there is a demand on a tablet containing all the active ingredients in one layer and having an acceptable stability. A further demand is that the above tablet should be produced by the usual manufacturing methods.

The aim of the invention is to fulfil the above demands.

A lot of experiments have been performed using many sorts of pharmaceutical carriers including binding agents and dis¬ integrating agents to produce a combination tablet comprising acetylsalicylic acid, paracetamol and coffein as the active in¬ gredients, and it was found that the above aim was achieved by a tablet in which the binding agent consisted of poly(vinyl butyral) and the disintegrating agent was hydroxypropyl cellulose of low substitution degree (LHPC). Only the tablet of the invention had the required physical properties such as breaking strength, abrasion resistance and disintegra¬ tion time, furthermore chemical stability.

The combination tablet of the invention contains acetylsalicylic acid, paracetamol and coffein as the active in- gredients in a mass ratio of generally (5-10): (5-10): (1-3).

The poly(vinyl butyral) used as the binding agent is prepared by the hydrolysis of poly(vinyl acetate) and reacting the thus-formed poly(vinyl alcohol) with butyr- aldehyde. In general, poly(vinyl butyral) contains 69 to 84 per cent of vinyl butyral group, 12 to 17 per cent of vinyl alcohol group and 1 to 2 per cent of vinyl acetate group; a 5 per cent by w/v solution thereof in ethanol has a viscosity of 6 to 120 cP at 25 C depending on the molecular mass.

In the combination tablet of the invention a preferred poly(vinyl butyral) contains 69 to 71 per cent of vinyl butyral group, 24 to 27 per cent of vinyl alcohol group and 1 to 2 per cent of vinyl acetate group, the 5 per cent by w/v solution of said poly(vinyl butyral) in ethanol having a viscosity of 2 to 12 cP at 25 °C. This sort of poly(vinyl butyral) is known under the trade name Mowital B30T.

The hydroxypropyl cellulose of low substitution degree (LHPC) used as the disintegrating agent is prepared from cellulose with propylene oxide, thus converting a small portion of the hydroxy groups bound to the beta-0-glucopyranosyl ring to ether. The amount of the hydroxypropyl groups is about 8 to 14 per cent, preferably 10 to 12 per cent, the average particle size of LHPC is 40 to 50 micrometer. This type of LHPC is known under the designation LH 11 or LH 21.

From the data of the state of art it could not be expected that the stability of acetylsalicylic acid was hardly influenced by poly(vinyl butyral) and LHPC since both agents contained primary hydroxy groups, too. /In the poly(vinyl butyral) the propor¬ tion of vinyl alcohol groups amounts to 24 to 27 per cent, while in the LHPC that of the hydroxypropyl groups is 10 to 12 per cent./ However, during the stability studies of the combination tablet of the invention comprising the above agents it was found that the free salicylic acid content of the tablets stored at 30 C for 3 months remained under 1.5 per cent. Furthermore the free salicylic acid content of the tablets stored at as high as 40 C for 3 months was only 2.5 to 3.0 per .cent.

A possible subsequent explanation for the above favourable effect of poly(vinyl butyral) and LHPC may be that - although they comprise hydroxy groups - both agents are insoluble in aqueous medium, thus, fail to influence the pH of the aqueous layer on the acetylsalicylic acid particles and, consequently, the hydrolysis rate of acetyl¬ salicylic acid.

The combination tablet of the invention may comprise additional pharmaceutical carriers such as stearic acid and talc to reduce the friction during compressing the mixture to tablet.

The combination tablet of the invention is prepared as follows:

The active ingredients i.e. acetyl¬ salicylic acid, paracetamol and coffein are mixed in a mass ratio of (5-10) : (5- 10): (1:3) and the mixture obtained is granulated with a 96 per cent ethanolic solution of a mixture of poly(vinyl butyral) and stearic acid in a mass ratio of (0.1-0.6) : (0.2-1.0) , wherein the ethanol is used in a mass ratio of 1.5 to 12. The granules obtained are dried and sieved, then homogenized with 0.2 to 1.2 parts by mass of talc and 0.1 to 0.6 part by mass of stearic acid, and the homogeneous mixture is compressed to tablets comprising the active ingredients in the required amount.

The invention is further elucidated by means of the following Examples.

Example 1

250.0 g of acetylsalicylic acid, 250.0 g of paracetamol and 50.0 g of coffein are transferred to the container of a fluidiz¬ ing spray granulator of the type Uniglatt, then the granulator is put into operation and fluidizing air is introduced at 25 to 30 °C to homogenize the above ingredients for 5 minutes under a layer extension of a factor of 1.2 to 1.5. Then a solution of 9.0 g of poly(vinyl butyral) and 13.0 g of stearic acid in 278 g of ethanol is sprayed onto the fluidized mixture. Having finished spraying, the granules formed are dried by running on fluidization until the moisture content is reduced under 0.5 per cent. (The moisture content of the granules is controlled by drying samples at 70 C for 30 minutes.) To the dried granules passed through a sieve having a mesh size of 1 mm, 61.0 g of hydroxypropyl cellulose of low substitution degree (LHPC, LH 11) and 20.0 g of stearic acid are admixed. The mixture obtained is compressed by an eccentric tabletting machine of the type Fette EXI using a 12 mm flat flanged press die to tablets of 665 mg average mass.

The breaking strength of the tablets is 110-150 N, the abrasion loss is lower than 0.5 per cent and the disintegration time is 2 to 4 minutes. At least 90 per cent of the active ingredients are released from the tablets in 15 minutes as determined by the method specified by US Pharmacopoeia, XXII Edition. The free salicylic acid content of the tablets is as follows: after compressing the mixture to tablets: 0.5-0.8 ?_; after storage at 30 C -.for 3 months: -1.2- 1.6 % and after storage at 40 C for 3 months: 2.6-3.1 . Example 2

500.0 g of acetylsalicylic acid, 500.0 g of paracetamol and 100.0 g of coffein are transferred to the container of granulator of the type Lodige, the ingredients are homogenized for 2 minutes by running the mixer, then a solution of 20.0 g of poly(vinyl butyral) and 20.0 g of stearic acid in 120 g of 96 per cent ethanol are added under constant stirring. The wet granules obtained are dried in a fluidizing drying apparatus of the type Retsch by introducing fluidizing air at 30 C. Drying is continued until the moisture content of the granules is reduced under 0.5 per cent. Then the granules are passed through a sieve having a mesh size of 1 mm. To the sieved granules transferred into a cube mixer of the type Erweka, 40.0 g of talc, 20.0 g of stearic acid and 120.0 g of hydroxypropyl cellulose of low substitution degree (LHPC LH 21) are admixed under stirring for 20 minutes. The homogoneous mixture obtained is compressed by a tabletting machine of the type Manesty BB3 using a 12 mm flat flanged press die to tablets of 660 mg average mass.

The breaking strength of the tablets is 100-150 N, the abrasion loss is 0.3 to 0.4 per cent and the disintegration time is 3 to 5 minutes. At least 85 per cent of the active ingredients are released from the tablets in 15 minutes as determined by the method specified by US Pharmacopoeia, 4- h

XXII Edition. The free salicylic acid content of the tablet is as follows: after compressing the mixture to tablets:

0.3-0.6 55, after storage at 30 C for 3 months: 1.4-1.7 % and after storage at 40 C for 3 months: 2.7-3.0 % .

Example 3 2.0 kg of acetylsalicylic acid, 2.0 kg of paracetamol and 0.4 kg of coffein are trans¬ ferred to the container of a fluidizing spray granulator of the type Glatt WSG 5. The granulator is put into operation and fluidizing air is introduced at 25 to 30 C to homogenize the above ingredients for 5 minutes under a layer extension of a factor of 1.2 to 1.5. Then a solution of 96.0 g of poly(vi- nyl butyral) and 104.0 g of stearic acid in 2.2 kg of ethanol is sprayed onto the fluidized mixture. Having finished spraying, the granules formed are dried by running on fluidization until the moisture content is reduced to 1.0 to 1.5 per cent. (The moisture content of the granules is controlled by drying samples at 70 C for 30 minutes). To the dried granules passed through a sieve having a mesh size of 1 mm, 464.0 g of hydroxy¬ propyl cellulose of low substitution degree (LHPC, LH 11), 160.0 g of talc and 56.0 g of stearic acid are admixed. The homogeneous mixture obtained is compressed by a rotary tabletting machine of the type Manesty BB3B using a 12 mm flat flanged press die to tablets of 660 mg average mass.

The breaking strength of the tablets is 110-130 N, the abrasion loss is lower than 0.5 per cent and the disintegration time is 2 to 4 minutes. At least 85 per cent of the active ingredients are released from the tablets in 15 minutes as determined by the method specified by US Pharmacopoeia, XXII Edition. The free salicylic acid content of the tablets is lower than 1 per cent.

Claims

C l a i m s

1. A tablet containing acetylsalicylic acid, paracetamol and coffein as the active ingredients in admixture with pharmaceutical carriers characterized by that the binding agent is poly(vinyl butyral) and the disinteg¬ rating agent is hydroxypropyl cellulose of low substitution degree.

2. A tablet of claim 1 comprising 5 to 10 parts by mass of acetylsalicylic acid, 5 to 10 parts by mass of paracetamol and 1 to 3 parts by mass of coffein in which the binding agent consists of 0.1 to 0.6 parts by mass of poly(vinyl butyral) and the disintegrating agent is 0.5 to 4 parts by mass of hydroxypropyl cellulose of low substitution degree.

3. A tablet of claim 1 or 2 in which the poly(vinyl butyral) contains 69 to 71 per cent of vinyl butyral group, 24 to 27 per cent of vinyl alcohol group and 1 to 2 per cent of vinyl acetate group and a 5 per cent by w/v solution thereof in ethanol has a viscosity of 2 to 12 cP at 25 °C.

4. A tablet of claim 1 or 2 in which the hydroxypropyl cellulose of low substitution degree contains 8 to 14 per cent of hydroxypropyl group and has an average particle size of 40 to 50 micrometer.

5. A tablet of claim 4 in which the hydroxypropyl cellulose of low substitution degree contains 10 to 12 per cent of hydroxy¬ propyl group.

6. A process for the preparation of a tablet containing acetylsalicylic acid, paracetamol and coffein as the active in¬ gredients in admixture with pharmaceutical carriers which comprises using as binding agent poly(vinyl butyral) and as disintegrating agent hydroxypropyl cellulose of low substitu¬ tion degree.

7. A process of claim 6 which comprises using 5 to 10 parts by mass of acetylsalicylic acid, 5 to 10 parts by mass of paracetamol and 1 to 3 parts by mass of coffein, and 0.1 to 0.6 parts by mass of poly(vinyl butyral) and 0.5 to 4 parts by mass of hydroxypropyl cellulose of low substitution degree.

8. A process of claim 6 or 7 wherein the poly(vinyl butyral) contains 69 to 71 per cent of vinyl butyral group, 24 to 27 per cent of vinyl alcohol group and 1 to 2 per cent of vinyl acetate group and a 5 per cent by w/v solution thereof in ethanol has a viscosity of 2 to 12 cP at 25 °C.

9. A process of claim 6 or 7 wherein the hydroxypropyl cellulose of low substitution degree contains 8 to 14 per cent of hydroxy propyl group and has an average particle size of 40 to 50 micrometer.

10. A process of claim 9 wherein the hydroxypropyl cellulose of low substitution degree contains 10 to 12 per cent of hydroxy¬ propyl group.